Virtual Library

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    FP01 - Early Stage/Localized Disease (ID 111)

    • Event: WCLC 2020
    • Type: Posters (Featured)
    • Track: Early Stage/Localized Disease
    • Presentations: 5
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      FP01.01 - Uniportal Versus Multiportal Video-Assisted Thoracoscopic Surgery for Non-Small Cell Lung Cancer: An Updated Meta-Analysis   (ID 3517)

      00:00 - 00:00  |  Presenting Author(s): Maria P. Fergadi  |  Author(s): Dimitrios E. Magouliotis, Kyriakos Spiliopoulos, Kalliopi Athanassiadi

      • Abstract
      • Slides

      Introduction

      Minimally invasive surgical techniques have become the standard approach for treating patients with non-small cell lung cancer. In this context, the uniportal video-assisted thoracoscopic surgery (UVATS) approach has been proposed as a feasible alternative to the multiport VATS to perform feasibly and safely a wide range of thoracic surgical operations, including lobectomy for non-small cell lung cancer. As the number of studies comparing the feasibility and safety of UVATS and MVATS increases, it is necessary to reevaluate whether the results between the two techniques are at least equivalent. The purpose of the present study was to summarize and analyze the existing data by comparing the surgical outcomes of UVATS and MVATS, in order to provide the best evidence that is currently available.

      Methods

      A thorough literature search was performed in three databases: (i) Pubmed (Medline), (ii) Cochrane Central Register of Controlled Studies (CENTRAL), and (iii) Scopus (ELSEVIER) (last search: April 20th, 2020). Original studies that evaluated perioperative and long-term outcomes of UVATS versus MVATS were identified, from January 1990 to April 2020. The perioperative, along with the oncologic and long-term survival outcomes were calculated according to either a fixed and a random effect model, appropriately. The Q statistics and I2 statistic were used to test for heterogeneity among the studies.

      Results

      Twenty studies were included, incorporating a total of 1,469 patients treated with UVATS and 3,231 treated with MVATS. The incidence of complications was lower in patients treated with UVATS [OR: 0.76 (95% CI: 0.62, 0.93); p=0.008]. The chest tube duration was significantly decreased in the UVATS group (WMD: -0.63 [95% CI:-1.03, -0.23]; p=0.002). L.O.S. was also lower in the UVATS patient group (WMD: -0.54 [-0.94, -0.13]; p=0.009), along with the reported levels of postoperative pain [WMD: -0.57 (95% CI:-0.97, -0.18); p=0.004]. No significant differences were found regarding the M.O.T., mean blood loss, the number of resected lymph nodes, the 30-day mortality, along with the survival at one and three years postoperatively.

      forest plot complications.jpg

      Conclusion

      The present meta-analysis indicates that UVATS is associated with enhanced outcomes in patients undergoing surgery for lung cancer. However, the decision regarding the procedure of choice should be made based on the shared decision-making process. Well-designed, randomized studies, comparing UVATS to MVATS, are necessary to further assess their long-term clinical outcomes.

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      FP01.02 - The Efficacy of Postoperative Radiotherapy in IIIA-N2 Non-Squamous NSCLC with Different EGFR Mutation Status: A Retrospective Analysis (ID 3680)

      00:00 - 00:00  |  Presenting Author(s): Fang Wu  |  Author(s): Chunhong Hu, Yan Huang, Xingxiang Pu, Chaoyuan Liu, Xianling Liu, Fang Ma, Lishu Zhao, long Shu, Yue Pan, Yue Zeng

      • Abstract
      • Presentation
      • Slides

      Introduction

      The effect of postoperative radiotherapy (PORT) on completely resected IIIA-N2 non-squamous non-small cell lung cancer (NSCLC) remains controversial. Growing postoperative therapies for epidermal growth factor receptor (EGFR)-mutant patients make the role of PORT ambiguous. Previous in-vitro studies have indicated that the status of EGFR mutation status can influence the radio-sensitivity of lung cancer, which needs more clinical investigation to verify. In this retrospective study, we aim to assess the efficacy of PORT in IIIA-N2 non-squamous NSCLC with different EGFR mutation status.

      Methods

      We enrolled patients who were diagnosed with completely resected stage IIIA-N2 non-squamous NSCLC, receiving postoperative radiotherapy or not, between April 2011 and May 2017 from the Second Xiangya Hospital and Hunan Cancer Hospital. And we analyzed the influence of PORT on disease-free survival (DFS) and overall survival (OS) in NSCLC patients with different EGFR mutation status.

      Results

      In total, 124 patients were eligible. The median follow-up time was 43.2 months (range 6-103 months). In multivariate analysis, age (>60 years old), cycles of chemotherapy (<4) and multiple-station N2 metastasis were correlated with shorter DFS. Multiple-station N2 metastasis,wild-type EGFR and no PORT were independent risk factors for OS. PORT significantly improved OS (46.40 months vs. 34.17 months, P = 0.021) but not DFS (19.02 months vs. 17.23 months, P = 0.266). In the EGFR wild-type group, PORT prolong OS (43.20 months vs. 28.67 months, P = 0.007), especially in EGFR wild-type group with multiple-station N2 metastasis (39.73 months vs. 24.9 months, P = 0.006) rather than DFS (18.43 months vs. 17.77 months, P = 0.775). There was a trend that PORT improved OS (69.30 months vs. 49.97 months, P = 0.057) and DFS (21.17 months vs. 17.17 months, P = 0.075) in the EGFR-mutant group, although there was no significant difference. In EGFR-mutant patients with multiple-station N2 metastasis, the DFS was significantly prolonged (23.13 months vs. 14.10 months, P = 0.021) in the PORT group. Nevertheless, the OS (72.5 months vs. 60.63 months, P = 0.189) and DFS (13.7 months vs. 24.33 months, P = 0.664) were not improved in EGFR-mutant patients with single-station N2 metastasis(Figure 1).figure 1.jpg

      Comparison of overall survivall (A,C,E) and disease-free survival (B,D,F) between the PORT and the non-PORT group. PORT=postoperative radiotherapy.

      Conclusion

      It is necessary for stage IIIA-N2 non-squamous NSCLC patients to receive PORT,especially for EGFR wild-type patients. Meanwhile, PORT can reduce local recurrence and metastasis in EGFR-mutant group, particularly in EGFR-mutant patients with multiple-station N2 metastasis. More prospective studies are needed to clarify the role of PORT in the EGFR-mutant IIIA-N2 non-squamous NSCLC patients.

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      FP01.03 - Genetic Predisposition for Pre-Invasive Lung Adenocarcinoma Manifesting as Ground-Glass Nodules with Family History of Lung Cancer (ID 1512)

      00:00 - 00:00  |  Presenting Author(s): Rui Fu  |  Author(s): Jia-Tao Zhang, Rongrong Chen, Zai-Xian Tai, Hao-Xiang Lin, Jian Su, Xiang-Peng Chu, Chao Zhang, Wen-Fang Tang, Jun-Tao Lin, Qiang Nie, Xue-Ning Yang, Yi-Long Wu, Wen-Zhao Zhong

      • Abstract
      • Slides

      Introduction

      Lung cancer with family history have been increasing gradually of late years in East Asian, especially those presenting as pulmonary ground-glass nodules (GGNs). The predisposition of GGN with lung cancer family history remains baffling.

      Methods

      This prospective study (NCT04220268) enrolled patients with pulmonary pre-invasive or invasive adenocarcinoma, which presenting as GGN in computer tomography (CT) scans. We used extreme phenotype approach to select 50 GGN patients with a family history of lung cancer (FHLC) in one or more first-degree relatives. Blood samples were collected and sequenced by whole exome sequencing (WES) to investigate rare but potential pathogenic germline mutations with a stepwise filtering strategy including: variant quality and classification, minor allele frequency (MAF) < 0.01 in public and local database, functional prediction and family segregation.

      Results

      In total, 2325 single nucleotide variants (SNVs) and 238 frameshift mutations with MAF <0.01 were finally identified through the filter. The number of these rare, damaging germline mutations in non-smoking patients were significantly higher than those in smoking patients (Spearman’s ρ= -0.33, p=0.02). Fifty-nine SNVs and 10 frameshifts were not only rare and deleterious but also presented in more than two families. Importantly, twenty of them had been reported to be associated with higher risk or carcinogenesis of lung cancer. Two of them were validated in 126 nonoverlapping susceptibility loci for lung carcinogenesis identified by genome-wide association studies (GWAS).

      Conclusion

      Patients with GGNs and FHLC may have inheritable carcinogenesis mutations. These variants may potentially contribute to the risk of pulmonary pre-invasive adenocarcinoma susceptibility in Chinese population. Non-smoking patients with GGN probably had higher genetic predisposition than the smoking patients.

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      FP01.04 - BTCRC LUN19-396:  Adjuvant Chemotherapy Plus Atezolizumab in Stage IB-IIIA Resected NSCLC and Clearance of ctDNA (ID 3164)

      00:00 - 00:00  |  Presenting Author(s): Melissa Yan  |  Author(s): Gregory A Durm, Shadia Jalal, Lawrence Einhorn, Kenneth Kesler, Karen Rieger, Thomas Birdas, DuyKhanh Ceppa, Nasser Hanna

      • Abstract
      • Slides

      Introduction

      The vast majority of patients with stage IB - IIIA NSCLC are managed with upfront surgery, followed by 4 cycles of empiric adjuvant chemotherapy. However, many patients are cured with surgery alone and do not need any adjuvant therapy. While some patients require adjuvant therapy to achieve cure, the amount of adjuvant therapy necessary to achieve this goal is unknown. In order to optimize treatment, a predictive biomarker is needed to evaluate which patients benefit from adjuvant therapy and to personalize duration of treatment. Emerging data has evaluated the use of circulating tumor DNA (ctDNA) as a promising biomarker for early detection of minimal residual disease to predict risk of relapse. BTCRC LUN19-396 is a multicenter, phase II trial that aims to evaluate the role of concomitant chemotherapy and checkpoint inhibitor in the adjuvant setting for stage IB-IIIA resected NSCLC, and the clearance of ctDNA as a surrogate biomarker for long term disease free survival.

      Methods

      All patients with stage IB (tumors > 4cm), IIA, IIB, and select IIIA (T3N1, T4N0-1) resected NSCLC will be screened for study entry and will have ctDNA assessed within 60 days after surgery. All patients (regardless of whether they have detectable ctDNA after surgery) will be enrolled and treated with 4 cycles of cisplatin based chemotherapy plus concomitant atezolizumab, followed by up to 13 additional cycles of atezolizumab alone. Sequential analysis of ctDNA will be performed in all patients every 3 months until the end of treatment, up to 17 cycles at 13 months. The trial will enroll a total of 100 patients. The primary objective is to estimate the percentage of patients with detectable ctDNA after surgery who have clearance of ctDNA at designated time points during adjuvant therapy. The key secondary objective is to estimate the 1-year disease free survival in patients with undetectable ctDNA after 4 cycles of adjuvant chemotherapy plus atezolizumab who had detectable ctDNA after surgery. This trial opened to accrual in May 2020. Clinical trial information: NCT04367311

      studyschema.png

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      FP01.05 - The ASCENT Trial: A Phase II Study of Neoadjuvant/Adjuvant Afatinib, Chemoradiation +/- Surgery for Stage III EGFR-Mutant NSCLC (ID 3752)

      00:00 - 00:00  |  Presenting Author(s): Andrew Piper-Vallillo  |  Author(s): Raymond Mak, Michael Lanuti, Alona Muzikansky, Julia K Rotow, Pasi Antero Jänne, Mari Mino-Kenudson, Scott J Swanson, Cameron Wright, David Kozono, John Paul Marcoux, Zofia Piotrowska, Henning Willers, Lecia V. Sequist

      • Abstract
      • Slides

      Introduction

      The ADAURA trial showed benefit to adjuvant osimertinib in stage III EGFR-mutant (EGFRm) NSCLC, but the role of TKI induction is unknown. In 2011, we began ASCENT, a phase II trial of neoadjuvant and adjuvant afatinib in addition to standard of care (SOC) curative-intent therapy for EGFRm stage III NSCLC (NCT01553942). The study closed early for slow accrual. This is the final analysis.

      Methods

      ASCENT enrolled patients with EGFRm, stage IIIA/B (AJCC 7th ed.) NSCLC amenable to curative-intent chemoradiation therapy (CRT) ± surgery. Resectability was determined by the treating multidisciplinary team at diagnosis. Patients received neoadjuvant afatinib 40mg QD x 2 months, then concurrent CRT (up to 4 cycles of cisplatin/pemetrexed and 3D conformal RT or intensity-modulated RT personalized to tumor size, site, operability) +/- surgery and an optional 2 years of adjuvant afatinib. The primary outcome was objective response rate (ORR) to neoadjuvant afatinib. Major pathologic response (MPR) was defined as < 10% residual tumor at resection, complete pathologic response (CPR) as no residual tumor.

      Results

      19 patients (14F/5M), median age 56 (range 34-75) were enrolled. 12 had EGFR del19, 7 L858R. 10 were classified as potentially resectable stage IIIA at diagnosis, 9 as unresectable IIIA/B. All completed two months of neoadjuvant afatinib; 5 (26%) required afatinib dose reduction. The ORR after neoadjuvant afatinib was 11/19 (58%; 95% CI, 33-80%). 1 patient initially deemed inoperable became a surgical candidate based on response to neoadjuvant afatinib; 2 patients progressed on neoadjuvant afatinib or exhibited findings that clarified their presenting stage as IV; both discontinued the protocol. The remaining 17 patients proceeded to CRT with pre-op median radiotherapy dose of 54 Gy (range 45-66; n=10), definitive median dose of 67 Gy (range 63-72; n=7). Among 10 patients who underwent resection (all via lobectomy), the MPR rate was 70% (6 MPR, 1 CPR). 13 (68%) patients started adjuvant afatinib after surgery (7) or definitive CRT (6); 4 completed 2 years, 3 discontinued early (median 1.5 months), 2 recurred during adjuvant afatinib and 4 remain on adjuvant therapy. Key grade 3/4 toxicities included rash (n=6), diarrhea (5), esophagitis (3), nausea (3), pneumonitis (2) and febrile neutropenia (1); there were no treatment-related deaths. With median follow-up of 30.6 months (range 3.1-96.3), 9 (47%) patients have recurred, with 5/9 having CNS-only recurrence. Recurrences occurred in 3/10 surgical patients and 5/7 definitive CRT patients. Median PFS was 34.6 months (95% CI 16.9-66.1) and median OS was 69.1 months (95% CI 29.4-NR). 2-year OS is 88% (95% CI 59-97%).

      Conclusion

      In stage III EGFRm NSCLC, 2 months of neoadjuvant afatinib is associated with an ORR comparable to that seen in advanced disease and does not impair receipt of SOC chemoradiotherapy ± surgery. PFS and OS are favorable in this single-arm study. The high rate of CNS-only recurrence highlights a potential for improved outcomes with more CNS-penetrant EGFR TKIs. Along with the interim results of ADAURA, these results support genotype-directed therapies in stage III EGFRm NSCLC, though the optimal sequence of TKI therapy will need to be defined.

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    FP02 - Health Services Research/Health Economics (ID 120)

    • Event: WCLC 2020
    • Type: Posters (Featured)
    • Track: Health Services Research/Health Economics
    • Presentations: 10
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      FP02.01 - Patient Responses to Passive Enrollment into a Large, Pragmatic Clinical Trial: A Qualitative Content Analysis (ID 1064)

      00:00 - 00:00  |  Presenting Author(s): Emily Jane Rozema  |  Author(s): Beth Creekmur, Visanee Vicky Musigdilok, Michael K Gould

      • Abstract
      • Presentation
      • Slides

      Introduction

      The Watch the Spot Trial is a cluster-randomized, pragmatic clinical trial comparing two guideline-based strategies for surveillance of small lung nodules. The study utilizes a passive enrollment approach in which eligible patients are notified of the study and given the opportunity to opt-out. While such pragmatic trials enable large studies to be efficiently implemented in real-world settings, they pose unique ethical considerations. In this exploratory study, we provide a summary of patient questions and concerns that may be useful for future studies.

      Methods

      Throughout the enrollment period, we documented incoming patient contacts in a database by copying emails verbatim and taking notes for phone calls. To analyze these contacts, we performed a conventional content analysis. After creating an initial codebook, we first identified simple requests to opt-out. For the remaining contacts that contained questions or comments, one primary and two secondary coders independently applied the codes to a random 10% sample of patient contacts. We discussed results to achieve consensus on discordant cases, revised the codebook, and repeated this process with another sample to ensure inter-coder reliability. The primary coder applied final codes to all contacts. We calculated the proportion of contacts for which each code was present.

      Results

      Of the 17,291 patients that were notified of the study, 857 (5%) reached out to the study team. Of these, there were 248 simple requests to opt-out. There were 609 with questions or comments eligible for the content analysis, 111 of whom also opted out. The most common reasons for patient contacts included opt-outs, clarification about study procedures, and being unaware of the lung nodule prior to research notification (Table 1). Some patients expressed anger or stress around learning about their lung nodule this way. Relatively few patients expressed concerns about the access to and sharing of protected health information (PHI).

      Table 1 – Conventional Content Analysis Results
      Code number Code description

      Contacts containing code
      (n, %)*

      Example of patient contact notes
      1 Simple opt-out 248, 28.9 Patient left message stating they opt out.
      1.1 Opt-out with other questions or concerns 111, 13.0 Patient wishes to opt-out (in addition to other questions or concerns in codes listed below).
      2 Study procedures clarification 292, 34.1 Asked if participating would mean additional traveling and CT scans.
      2.1 Explicit consent provided 40, 4.7 Replied to notification “I agree to participate.”
      3 Nodule care

      84, 9.8

      Said their doctor described their nodule as scar tissue and are unsure if we’re referring to the same thing.
      3.1 Unaware of nodule 115, 13.4 Had not heard about the nodule until receiving notification letter.
      4.1 PHI sharing with research team 20, 2.3 Asked how the study team got this information about them.
      4.2 PHI sharing outside of health system 22, 2.6 Said they did not want their personal information transferred.
      5 Ineligible 7, 0.8 Doctor told patient there was no lung nodule. After looking into the case the team realized they were erroneously enrolled due to programming error .
      6 Survey technical support 38, 4.4 Patient could not figure out how to electronically sign their survey consent form.
      7 Deceased 13, 1.5 Family member let us know the patient had recently passed away.
      8 Non-member 7, 0.8 Let us know they recently left the health care system.
      9 Misc 16, 1.9 Sent a long email complaining about a health care issue unrelated to the study.
      10 Unknown or undocumented 15, 1.8 Left a voicemail saying they had questions, but we were unable to ever reach them.
      E.1** Angry or upset 32, 3.7 Said they are angered by the fact that they are finding out this way.
      E.2** Stress, worry, or anxiety 24, 2.8 Said that they are very worried about their nodule and need to speak someone.
      *% of out 857 total contacts. Codes are not mutually exclusive.

      **E codes were used as supplemental codes only, most often to augment code groups 3 and 4.

      Conclusion

      We identified several insights based on patient contact issues. Confusion about study procedures reinforces the importance of having dedicated study staff to respond to inquiries. Patients being previously unaware of and sometimes distressed about their nodule highlights the need to include the whole care team when implementing trials in real-world settings. The few concerns about PHI access and sharing warrant close involvement of an institutional review board. Even when the public health benefits of well-designed, pragmatic, passive enrollment trials are thought to outweigh the ethical risks, patient perspectives are an invaluable resource for minimizing inconveniences and miscommunications when designing future studies.

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      FP02.02 - Real-World Outcomes Among Advanced Non-Small Cell Lung Cancer Patients Re-Treated with Immunotherapy in the US (ID 3706)

      00:00 - 00:00  |  Presenting Author(s): Alex I. Spira  |  Author(s): Alisha Monnette, Chuck Wentworth, Justin Doan, Chunlan Chang, John Hartman

      • Abstract
      • Presentation
      • Slides

      Introduction

      Immunotherapy (IO)-based regimens (alone or in combination with chemotherapy) are the current standard of care for the first-line (1L) treatment of advanced non-small cell lung cancer (aNSCLC). However, many patients undergoing 1L IO progress and need subsequent treatment. Currently, there is limited information regarding outcomes for patients who receive subsequent treatment following 1L IO for aNSCLC. This real-world study aimed to assess treatment patterns and clinical outcomes among patients retreated with IO-based regimens as second-line (2L) therapy following 1L IO in a US community oncology setting.

      Methods

      A retrospective observational study was conducted to identify patients from the US Oncology iKnowMed database who received 1L IO-based therapy followed by 2L treatment for aNSCLC between October 1, 2016 and September 30, 2019. Data were collected up to March 31, 2020 to allow at least 6 months of potential follow-up for each patient. Clinical trial participants, those under the age of 18, or those treated for other primary cancer were excluded. Patients were determined to have transitioned from 1L to 2L therapy if there was a change in regimen (e.g., Pembrolizumab to Nivolumab), the addition of a new antineoplastic agent, or a gap of at least 90 days between treatments. Baseline patient characteristics were described, and treatment outcomes were estimated from 2L initiation (i.e., index date) using Kaplan-Meier methods.

      Results

      The study population included 490 patients: 30% (n=149) received IO-based 2L treatment while 70% (n=341) received non-IO 2L therapies. The three most common non-IO 2L therapies included chemotherapy (n=253), chemotherapy+targeted therapy (n=53), and targeted therapy (n=35). Prior 1L treatment patterns showed 56% (n=276) received 1L IO monotherapy, 40% (n=194) received 1L combination IO+chemotherapy, and 4% (n=20) received some other form of IO therapy (e.g., IO+IO). Key findings are reported in the table below.

      TABLE 1: Patient Characteristics and Outcomes for Patients Initiating 2L Treatment

      IO-Based

      Non-IO based

      (n=149)

      (n=341)

      Patient Characteristics

      Median Age at 2L Treatment Initiation (years)

      70

      69

      Male (%)

      53.7

      52.5

      No History of Smoking (%)

      12.8

      16.1

      Squamous Histology (%)

      22.2

      15.5

      ECOG Status (%)

      0

      12.8

      15.5

      1

      57.1

      53.7

      2+

      16.4

      17.3

      Not Available

      14.8

      13.5

      PD-L1 (%)

      <1%

      11.4

      16.7

      1-49%

      7.4

      12.9

      50%+

      39.6

      32.6

      Not Available

      41.6

      37.9

      Median 1L Treatment Duration (Months)

      3.3

      3.7

      2L Treatment Outcomes

      Median 2L Treatment Duration (Months)

      4.5

      2.5

      Median Overall Survival (Months)

      18.4

      10.6

      Conclusion

      Patients who received IO or non-IO based therapies in 2L appeared similar, although a higher proportion of patients who received 2L IO retreatment had PD-L1 ≥50%. Retreatment with IO did not suggest to negatively affect outcomes, and unadjusted treatment duration and survival were longer in patients receiving 2L IO (p-value=0.02). Stratifications by 1L therapy (IO monotherapy and IO+chemotherapy) were consistent with the combined results reported below. Further study on the effects of 1L treatment duration and optimal duration of overall IO therapy are warranted.

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      FP02.03 - Changing Survival and Treatment Patterns in Patients Aged 80 or Older with Stage IV Non-Small Cell Lung Cancer (NSCLC) (ID 3739)

      00:00 - 00:00  |  Presenting Author(s): Matthew Anaka  |  Author(s): Amanda Jane Williams Gibson, Michelle Dean, Anifat Elegbede, Lars Petersen, Roxana Tudor, Randeep Sangha, D Gwyn Bebb

      • Abstract
      • Slides

      Introduction

      NSCLC is a disease of the elderly, with a median age at diagnosis of 70 years old. Yet elderly patients with NSCLC are under-represented in clinical trials, and studies of real-world treatment patterns have consistently identified lower rates of systemic therapy administration in this patient population. However there are clinical trial data to suggest that even the very elderly (age 80+) with advanced NSCLC can benefit from system therapy. We therefore looked at real-world patterns of treatment and survival in a cohort of patients aged 80 or older with metastatic NSCLC.

      Methods

      We performed a retrospective analysis of a cohort of 721 patients aged 80 or older diagnosed with de novo stage IV NSCLC in Alberta, Canada between 2011-2016 using the Glans-Look database. Data was derived from the provincial cancer registry and supplemented with additional chart review for a subset of cases. Univariate survival analysis used the Log-Rank method, and multivariate analysis Cox Regression. All other tests were Chi-Squared. Median overall survival (OS) in months is shown with 95% confidence intervals. The number of patients included for specific tests is indicated where the full cohort population is not included.

      Results

      Over the study period, an increasing proportion of patients were treated with systemic therapy (9.5% in 2011-2012, 21.6% in 2015-2016; P < 0.001), and the proportion of patients treated with 1st line targeted therapy also increased (N = 54; 43.8% in 2011-2012, 79.2% in 2015-2016; P < 0.029). Receiving systemic therapy was associated with improved OS (17.53 (14.01 – 21.06) vs 3.67 (3.30 – 4.04) months; P < 0.001). While there was a trend towards improved OS for the entire population over time (median 3.63 (2.99 – 4.27) months in 2011-2012 vs 5.33 (4.36 – 6.30) months in 2015-216; P = 0.19), survival improved significantly for those who received systemic therapy over the study period (median 7.10 (5.087 – 9.11) months in 2011-2012 vs 20.80 (17.09 – 24.51) months in 2015-2016; P = 0.02). There was no significant difference in OS for those who received chemotherapy vs targeted therapy (N=54; 15.97 (7.84 – 24.09) months vs 18.50 (13.05 – 23.95) months; P = 0.74), suggesting that improved access to systemic therapy rather than the intrinsic nature of the therapies themselves underlie improving survival amongst treated patients.

      Conclusion

      We identified increasing rates of systemic therapy use in patients aged 80 or older with de novo metastatic NSCLC, and improving OS amongst treated patients over the study period. While we cannot account for all potentially relevant changes to the management of NSCLC over that time, the improvement in increasing rates of systemic therapy use and survival in treated patients are potentially driven by availability and increasing use of targeted therapies. This suggests that elderly patients with NSCLC have benefited significantly from the use of these medications.

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      FP02.04 - NSCLC with TPS&gt;90% could have Higher Possibility of Causing Severe irAE; Retrospective Investigation in one Institution (ID 869)

      00:00 - 00:00  |  Presenting Author(s): Yuki Akazawa  |  Author(s): Aki Yoshikawa, Tomoki Kuge, Fukuko Okabe, Yuji Yamamoto, Mikako Ishijima, Takeshi Uenami, Masaki Kanazu, Yukihiro Yano, Toshihiko Yamaguchi, Masahide Mori

      • Abstract
      • Slides

      Introduction

      Recently, immune checkpoint inhibitors (ICI) have been introduced into clinical treatment strategy for advanced or recurrent NSCLC. However, little is known about the relation between the risk of irAE and patients’ clinical backgrounds. In this research, we attempted to reveal which types of clinical backgrounds are likely associated with the development of severe irAE when they were treated with ICI.

      Methods

      We have treated over 300 advanced or recurrent NSCLC with ICI in our institute since January 2016, and the results of TPS were obtained in 240 patients. We retrospectively analyzed the relationship between patients’ clinical backgrounds and severe irAE which caused discontinuation of treatment.

      We excluded patients who were treated with durvalmab because it has different treatment strategy from other ICIs.

      Results

      Patients' background is shown below. We defined TPS>90% as ultra-high TPS, because those patients are shown to have preferable response to ICI. All the patients with EGFR mutation received EGFR-TKI before ICI.

        first-line group second or later-line group
        95 145
      charasteristic
      Age, years    
      median 71.9 70.2
      range (95% C.I.) 70.2-73.6 68.9-71.6
      Sex    
      female 18 ( 18.9%) 56 ( 38.6%)
      male 77 ( 81.1%) 89 ( 61.4%)
      Histologic diagnosis    
      adenocarcinoma 48 ( 50.5%) 89 ( 61.4%)
      squamouscarcinoma 38 ( 40.0%) 37 ( 25.5%)
      others 9 ( 9.5%) 19 ( 13.1%)
      ECOG performance status    
      good (0 or 1) 80 ( 84.2%) 96 ( 76.8%)
      poor (2 -4) 15 ( 15.9%) 29 ( 23.2%)
      TPS    
      high expression (>50%) 67 (70.5%) 40 (27.6%)
      low expression (1-49%) 22 (23.2%) 56 (38.6%)
      negative (<1%) 6 ( 6.3%) 49 (33.8%)
      ultra-high expression (>90%) 32 ( 33.7%) 19 ( 13.1%)
      Driver mutation    
      no 92 ( 96.8%) 105 ( 72.4%)
      yes 3 ( 3.2%) 40 ( 27.6%)
      EGFR / KRAS / HER2 / others 0 / 2 / 1 / 0 36 / 1 / 2 / 1
      ICI    
      pembrolizumab 84 ( 88.4%) 57 ( 39.3%)
      nivolumab 0 ( 0%) 62 ( 42.8%)
      atezolizumab 11 ( 11.6%) 26 ( 17.9%)

      Forty-six had severe irAE of any grade of ILD or >Grade3 AE, and most of them were treated with steroids. Nineteen of them received ICI subsequently.

      Univariate analysis indicated that TPS>50%, first-line treatment and administration of pembrolizumab showed significantly higher possibility of severe irAE (p<0.05, p<0.001, p<0.05, respectively). Furthermore, patients with ultra-high TPS was likely to experience severe irAE compared to other groups (p<0.01). When we examine the patients in first-line treatment, only ultra-high TPS showed statistically higher tendency of irAE (p<0.05). However, in second or later-line patients, no clinical backgrounds indicated the higher risk of irAE.

      No difference was observed in response rate between ultra-high and other group in first-line treatment (71.9%, 61.9% respectively, p=1.0). In later-line, ultra-high group showed better response rate than others (52.6%, 19.8% respectively, p=0.032). However, no differences were observed in time to treatment failure and OS between ultra-high and others.

      In 1st-line patients, TTF of ultra-high and others was 207days and 175days (p=0.306), OS was 727days and 742days, respectively (p=0.74). In later-line, TTF was 107days and 70days(p=0.109),and OS was 511days and 308days (p=0.448).

      Conclusion

      Patients with ultra-high TPS had higher possibility of irAE especially when they received ICI for first-line. However, no difference was observed in OS between two groups. In our investigation, survival was not translated from better response in ultra-high group.

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      FP02.05 - Value-Based Healthcare Study (VBHC) for Treating Lung Cancer in Victoria, Australia (ID 3782)

      00:00 - 00:00  |  Presenting Author(s): Susan Harden  |  Author(s): Rob G Stirling, Margaret Brand, John Zalcberg

      • Abstract
      • Slides

      Introduction

      Value in healthcare can be defined as the degree of quality of care received as a function of the cost of delivering care. Value of care has never been formally measured for lung cancer. To our knowledge, there are no publications defining value in lung cancer from either the point of view of consumer, health service, government or funder. Any definition of value must however incorporate quality, service and cost.

      figure 1 vbhc.png

      Lung cancer is the leading cancer burden in Australia, and the leading cause of cancer-related death. Population health efforts target prevention, screening and detection of early, potentially curable lung cancer, delivery of curative and palliative treatments to optimally manage lung cancer. Recently, targeted biologic and immunotherapeutics have demonstrated substantial benefit but also attach substantial economic implications. With each initiative to improve lung cancer outcomes, there is an urgent need to understand the cost, quality and value returned to patients and funding bodies to inform patients, providers and governments. This study was designed to address this universal problem.

      Methods

      A cohort of 200 people diagnosed with non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) over 4 months from 1 November 2020 will be identified at Lung Multidisciplinary meetings (MDMs) at 5 participating Victorian health services and data collected from the Victorian Lung Cancer Registry:

      1.Quality indicators and clinical outcome measures stratified by stage, including proportions i) referred for smoking cessation; ii) receiving MDM discussion prior to definitive treatment; iii) stage I-III receiving treatment with curative intent (surgery/radical radiotherapy, multimodality treatment); iv) NSCLC receiving molecular testing, v) early palliative care referral, vi) emergency admissions, vii) screened for supportive care needs, viii) 1 year overall survival, ix) hospital readmissions for treatment related complications.

      2.Patient Reported Measures collected at multiple timepoints including EORTC QLQ-C30, QLQ-LC29, QLU-C10D, a patient experience survey at diagnosis and at 12 months incorporating value-based priorities.

      3.Consumer Focus Groupscto explore patient perceptions of quality and value with regard to care; utility and acceptability of study methods and consumer value rankings for treatments and outcomes by stage of disease.

      4.Health service costs for diagnostic procedures and treatments to establish cost and cost variation for stage specific treatment, based on optimal treatment guidelines.

      Conclusion

      A Value scorecard will be derived establishing a baseline VBHC model for lung cancer treatment in Victoria, aiming to identify stage-specific interventions to increase relative value for lung cancer care.

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      FP02.06 - Implementation of a Lung Cancer Value-Based Care Framework in a Low and Middle-Income Country Institution (ID 3338)

      00:00 - 00:00  |  Presenting Author(s): Clarissa Baldotto  |  Author(s): Nelson Teich, Mariana R Monteiro, Pedro N Aguiar Jr., Maria Clara Andrade, Cecília L Longo, Mayara Batista, Raphaela Lima, Débora Azevedo, Natália Carvalho, Perla Andrade, Mauro Zukin, Luiz Henrique Araújo

      • Abstract
      • Slides

      Introduction

      Assessment of the value of lung cancer treatment, and the performance of institutions delivering care is critical, especially in low and middle-income countries, with limited resources. To fully implement measures that support a value-based approach, cancer care institutions must comply with real-world registries with standardized outcomes. Herein, we present the first report of a prospective study to assess non-small cell lung cancer (NSCLC) patient-centered outcomes based on the International Consortium for Health Outcome Measurements (ICHOM) standard set.

      Methods

      This is a prospective, observational study of NSCLC patients treated at a nationwide private cancer care institution in Brazil between July 2014 and December 2019. The EORTC QLQ-C30 and QLQ-LC13 questionnaires were applied at established time points to analyze the disease burden on patients’ health status, serial changes throughout treatment, and prognostic impact.

      Results

      This first report comprises 337 patients, from a single institution; most patients were males (57.0%), white (64.7%), and smokers (81.3%). Adenocarcinoma was the most prevalent histological subtype (70.9%), and most patients presented with advanced disease (stages III/IV in 80.7%). Chemotherapy was recommended in 276 patient cases (81.9%), targeted therapy in 49 patients (14.6%), and immunotherapy in only 113 (33.5%). Median OS was 22.2 months (95% CI, 15.8-28.8), and 2-year OS for stages III and IV were 53.4% and 28.0%, respectively. EORTC QLQ-LC13 and QLQ-C30 questionnaires were responded by 333 (98%) and 290 (86%) patients at baseline, and by 225 (67%) and 192 (57%) at third evaluation. Advanced stage was associated with higher symptom burden - fatigue (p=0.03), pain (p<0.001), arm pain (p=0.022) - and worse global, social, and physical functioning (all p<0.001). Males (p<0.001), with older age (p<0.001) and more comorbidities (p<0.001) had higher emotional scores. Upon serial comparisons of quality of life (QoL) parameters during the first 2 years, most factors evolved to either improvement or stability. Cough (p=0.02), pain (p=0.002), global (p<0.001), and emotional (p<0.001) functioning showed significant improvement over time. Staging (p<0.001) and fatigue (p=0.001) were independently associated with OS.

      Conclusion

      Our results demonstrate the feasibility of a prospective lung cancer registry based on an international standardized dataset focused on patient-reported outcomes. QoL parameters impacted on NSCLC outcomes and can be a tool to align care delivery, increasing access and quality of cancer care across different institutions in low and middle-income countries.

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      FP02.07 - Predicting the Future: Using AI to Predict Treatment Outcomes in Lung Cancer (ID 3831)

      00:00 - 00:00  |  Presenting Author(s): Lawek Berzenji  |  Author(s): Sophie Debaenst, Suresh Krishan Yogeswaran, Patrick Lauwers, Jeroen Hendriks, Paul Van Schil

      • Abstract
      • Presentation
      • Slides

      Introduction

      In recent years, artificial intelligence (AI) has gained popularity as a tool for processing large datasets. In medicine, computational approaches such as machine learning are increasingly being used in fields such as serum analysis and the assessment of radiological data, dermoscopic images of melanoma, and histopathological specimens. In lung cancer research, a number of studies have already shown that machine learning can be a valuable tool for identifying early-stage disease choosing personalized treatments. However, there is a lack of data on the use of machine learning to predict treatment outcomes and prognosis. In this study, we use machine learning to create prediction models based on our patient data from the International Association for the Study of Lung Cancer (IASLC) staging project database.

      Methods

      Data of 464 lung cancer patients (309 male and 155 female) with a mean age of 64.9±9.4 years (range 32 – 83) were included in this study. Mortality was used as outcome variable for the prediction models. Furthermore, a total of 39 different training variables (patient history, comorbidities, staging data, treatment outcomes, and lab values) were used to train the machine learning models in this study. Random Forest, “Extreme Gradient Boosting”, and regularized regression models were applied to create prediction models for this dataset. Area under the receiver operating characteristic (ROC) curve was used to assess model performance. In addition, the variables of importance per model were analyzed as well.

      Results

      A total of 5 different prediction models were obtained using our training algorithms. The area under the ROC curve values ranged between 0.71 and 0.75, depending on the method of model tuning. Most common variables of importance were: resection margin, N-status, resection extent, and tumor histology.

      Conclusion

      Machine learning models can be used to create prediction models based on patient databases. In the future, these models may provide valuable information in the clinical decision-making process. More prospective studies based on larger datasets are needed to validate these prediction models.

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      FP02.08 - Importance of Stakeholder Engagement in a Patient-Centered Outcomes Research Trial (ID 2393)

      00:00 - 00:00  |  Presenting Author(s): Visanee Vicky Musigdilok  |  Author(s): Beth Creekmur, Emily Jane Rozema, Michael K Gould

      • Abstract
      • Presentation
      • Slides

      Introduction

      The Watch the Spot Trial is a Patient-Centered Outcomes Research Institute (PCORI)- funded, multi-center, pragmatic, comparative effectiveness trial comparing a more- versus less-intensive surveillance strategies for small lung nodules. As a PCORI-funded study, engagement with patients and other stakeholders is an essential aspect of the Watch the Spot Trial. A key component, the Stakeholder Advisory Group (SAG), provides oversight and guidance regarding research methodology, publications, communications, survey development and recruitment, and dissemination of study results.

      Methods

      Twenty stakeholders, including six patient stakeholders who previously underwent evaluation for a pulmonary nodule, have participated in the SAG over the course of the study. Stakeholders were actively involved in the conception, design, planning and execution of the trial. Currently, the SAG is comprised of thirteen stakeholders, including five patient stakeholders and eight stakeholders representing professional societies and advocacy groups. Members of the SAG meet on a recurring basis, monthly during Years 1 to 4 and quarterly from Year 5 onwards. In addition to the SAG meeting, stakeholders were also offered the opportunity to share their perspective in a variety of other workgroups: Intervention Design Workgroup, Patient Survey Workgroup, Provider Survey Workgroup, and a number of manuscript writing workgroups. All engagement from patient stakeholders were recorded in meeting minutes and highlighted in all progress reports to the funder.

      Results

      Key contributions of patient stakeholders include: developing the study protocol; designing the interventions being compared, developing scripts to communicate with study participants, participating in survey development, and writing manuscripts. Patient stakeholder feedback was important in the selection and adaptation of the guideline-based protocols that were compared in the trial. Patient stakeholders were also very involved in the creation and review of all study materials for patient communication and education. This includes the patient brochure, patient notification letter, and radiology reporting templates. SAG members helped identify brochure sections and tailor content to fit the general health literacy level of patients and their families. Similarly, they also vetted and refined a letter used to notify patients about the trial, and helped to define the timeline for notification. Recommendations for patient survey design from patient stakeholders helped prevent any undue anxiety and improved survey user friendliness. Moreover, their participation in survey development ensured that items for patient-reported outcomes and other domains of interest for patients were included. Additionally, their suggestions for survey recruitment strategies improved provider survey response rates as well. For dissemination efforts, patient stakeholders have served as contributors on all manuscripts to date.

      Conclusion

      Input from the SAG, especially from patient stakeholders, has been instrumental to the trial’s start-up and progress. Active participation from patient stakeholders has made important contributions to study design and execution. Most importantly, the patient perspective helped the trial anticipate and address patient concerns. Representation from the SAG committee across study workgroups allowed for patient engagement to be present throughout all aspects of the Watch the Spot Trial. This level of engagement is necessary to produce impactful patient-centered outcomes research.

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      FP02.09 - Effects of Chinese Reimbursement Policy on Molecular Diagnosis and Therapy of NSCLC from the Northern Part of Henan Province (ID 2441)

      00:00 - 00:00  |  Presenting Author(s): Min Zhang  |  Author(s): Jing Zhang, Xing Hao Ji, Ding Liu, Ping Lu

      • Abstract
      • Presentation
      • Slides

      Introduction

      Gefitinib (Irisa) have significantly prolonged the overall survival of advanced non-small cell lung cancer (NSCLC) patients with the EGFR sensitivity mutations positive (EGFR+). Our hospital, the first affiliated hospital of Xinxiang Medical University, is the largest provincial Grade 3A hospital in northern part of Henan Province,most of the patients come from rural areas, and the incomes of the patients and their family members are too low to afford the expensive antitumor costs. Therefore, the expensive costs prevent the timely and sufficient treatment with gefitinib in patients with positive EGFR+ in our hospital. Fortunately, on September 2016, gefitinib was included in health care policy of Henan Province, thus the expenses were reduced significantly. The purpose of this study was to investigate the influence of China's reimbursement policy on molecular diagnosis and treatment of advanced lung adenocarcinoma(LUAD) in our hospital.

      Methods

      Here, the data of the LUAD from February 2015 to August 2016, as well as from September 2016 to March 2018 of our hospital were collected.

      The chi-square test is used to analysis: (1)the detection rate of EGFR gene mutations (EGFR-M) before and after reimbursement. (2)the detection rate of EGFR-M in the department of oncology before and after reimbursement respectively. (3) the detection rate of EGFR-M in the department of non-oncology before and after reimbursement respectively. (4)the application of EGFR-TKIs(including gefitinib and icotinib) in patients with EGFR+ before & after reimbursement.

      Results

      figure1.jpgIn this study, 315 cases and 405 cases were collected befor and after Semptember 2016 respectively:

      (1)The detection rate of EGFR-M was increased from 13.65% to 44.55% after reimbursement (P≤0.01) (Fig1A).

      (2)In the department of oncology, the detection rate of EGFR-M was elevated from 20.53% to 58.94% after reimbursement (P≤0.01).

      (3) In the department of non-oncology, the detection rate was also increased from 3.20% to 35% after reimbursement (P≤0.01).

      (4) The detection rate of EGFR-M was higher in the department of oncology than that of non-oncology department both before and after reimbursement (P≤0.01) (Fig1B & C).

      (5) After reimbursement, the application of EGFR-TKIs on patients with EGFR+ was increased prominently. There are only 21.74%(5/23) patients received treatment of EGFR-TKIs before September 2016, while most of patients with positive EGFR-sensitive mutations (72.55%, 74/102) were treated by EGFR-TKIs after September 2016(Fig1D) (P0.01).

      Conclusion

      Chinese reimbursement policy can affect the molecular analysis and therapy of NSCLC from the northern part of Henan province significantly.

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      FP02.10 - Predictors of Moderate-to-Severe Symptoms in Stage IV NSCLC: A Population-Based Study of Patient Reported Outcomes (ID 3525)

      00:00 - 00:00  |  Presenting Author(s): Michael C Tjong  |  Author(s): Mark Doherty, Laura E. Davis, Wing Chan, Haoyu Zhao, Victoria Delibasic, Julie Hallet, Alyson Mahar, Biniam Kidane, Frances Wright, Gail Darling, Natalie G. Coburn, Alexander Louie

      • Abstract
      • Presentation
      • Slides

      Introduction

      Patients with metastatic NSCLC have significant disease and treatment-related morbidity. In Ontario, Canada, cancer patients complete Edmonton Symptom Assessment System (ESAS) questionnaires, a tool that elicits patients’ self-reported severity of common cancer-associated symptoms at clinical encounters. ESAS domains are: anxiety, depression, drowsiness, appetite, nausea, pain, shortness of breath, tiredness and well-being. The purpose of this study is to examine moderate-to-severe symptom burden in the 12 months following a diagnosis of stage IV NSCLC.

      Methods

      Using administrative databases and unique encoded identifiers, stage IV NSCLC diagnosed between January 2007 and September 2018 were evaluated for symptom screening with ESAS in the 12 months following diagnosis. Proportion of patients reporting moderate-to-severe score (i.e. ESAS ≥4) in each domain within 12 months were calculated. Patients reporting moderate-to-severe within the different ESAS domains of were plotted over time. Multivariable (MV) Poisson regression models with potential covariates such as age, sex, Elixhauser comorbidity index, socioeconomic factors, and cumulative cancer treatments received were constructed to identify factors associated with moderate-to-severe symptoms.

      Results

      Of the 22,799 stage IV NSCLC patients identified, 13,593 (59.6%) had at least 1 completed ESAS recorded (87,791 unique assessments) in the year following diagnosis. Majority (94.6%) reported at least 1 moderate-to-severe score. Tiredness (peak: 67.4%, overall: 84.3%), lack of wellbeing (peak: 62.1%, overall: 80.9%), low appetite (peak: 50.4%, overall: 72.1%), and shortness of breath (peak: 51.0%, overall: 68.1%) were the most prevalent moderate-to-severe symptoms reported by patients within 12 months after diagnosis (these peaked at diagnosis), while nausea (34.92%) was the least common.
      Patients receiving chemotherapy alone (17.5%, n= 2,380), radiotherapy alone (36.3%, n=4,936), or both (24.8%, n=3,369) reported more moderate-to-severe symptoms compared to patients receiving no treatment (risk ratio [RR]: 1.04, 1.04, and 1.06 respectively [all p-values<0.0001). Receiving chemotherapy alone or chemotherapy and radiotherapy combinations was associated with score≥4 in all individual ESAS domains (p-values <0.05), while receiving radiotherapy alone was associated with score≥4 in all domains but shortness of breath (RR: 0.98, p=0.26). Immigrants and patients with worst socioeconomic deprivation index were less likely to report moderate-to-severe symptoms.

      Conclusion

      Moderate-to-severe symptoms were prevalent throughout the first year following stage IV NSCLC diagnosis at the population-level. Patients receiving chemotherapy and/or radiotherapy were at increased risk of moderate-to-severe symptoms and may require more supportive care. Further analyses on predictors of severe-to-moderate score on each ESAS domain will be discussed in the presentation.

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    FP03 - Immuno-biology and Novel Immunotherapeutics (Phase I and Translational) (ID 151)

    • Event: WCLC 2020
    • Type: Posters (Featured)
    • Track: Immuno-biology and Novel Immunotherapeutics (Phase I and Translational)
    • Presentations: 5
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      FP03.01 - Immune Microenvironment Features and Efficacy of PD-1/PD-L1 Blockade in Non-Small-Cell Lung Cancer Patients with EGFR or HER2 Exon 20 Insertions (ID 932)

      00:00 - 00:00  |  Presenting Author(s): Yun Fan  |  Author(s): Kaiyan Chen, Yanjun Xu, Zhiyu Huang, Xiaoqing Yu

      • Abstract
      • Slides

      Introduction

      Insertions in exon 20 (Ex20ins) of EGFR and HER2 are relatively insensitive to first- and second-generation EGFR-tyrosine kinase inhibitors (TKIs) in non-small-cell lung cancer (NSCLC). This study aimed to investigate the immune microenvironment features and efficacy of PD-1/PD-L1 blockade of NSCLC with EGFR and HER2 Ex20ins.

      Methods

      Clinical characteristics, coexisting mutations, and outcomes to EGFR-TKIs and immune checkpoint blockade were reviewed for NSCLC patients with exon 20 mutations of EGFR or HER2. Data obtained included the molecular spectrum (extended genotyping for mutations in 324 cancer-related genes), as well as tumor mutational burden (TMB), PD-L1 protein expression, and the abundance of CD4+ and CD8+ tumor-infiltrating lymphocytes (TILs).

      Results

      1.png1270 NSCLC patients were identified. Of these, 504 (39.7%) cases had EGFR mutations and 6.9% (35/504) of them had EGFR Ex20ins. Meanwhile, 21 (1.7%) cases with HER2 Ex20ins were detected. Comprehensive genomic profiling identified A767_V769dup variant (25.0%) was the most common type in tumors with EGFR Ex20ins. Co-occurring mutations were not uncommon including TP53 (45%), PIK3CA (20%), CDKN2A (10%), and EGFR amplification (20%). The average TMB was 3.3 mutations/megabase. PD-L1 expression in patients with EGFR Ex20ins was significantly higher than for those with HER2 mutations (48.6% vs. 19.0%, P=0.027). High TMB and PD-L1 expression was independently associated with significantly poor prognosis (P=0.025, P=0.045; respectively) while there was no association between CD4+/CD8+ TILs and prognosis in EGFR or HER2 mutant NSCLC. Finally, patients harboring EGFR Ex20ins seemed to be sensitive to PD-1/PD-L1 blockage whereas it showed limited efficacy in patients with HER2 Ex20ins.4.png

      Conclusion

      NSCLC patients with EGFR/HER2 Ex20ins had similar genomic characteristics and distinct immune features when compared to common EGFR mutations. Patients with EGFR Ex20ins had significantly higher PD-L1 expression than those with HER2 mutations, which may be the potential reason for the different responses to PD-1/PD-L1 blockage.

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      FP03.02 - Interim Analysis of Neoadjuvant Chemoradiotherapy and Durvalumab for Potentially Resectable Stage III Non-Small Cell Lung Cancer (NSCLC) (ID 804)

      00:00 - 00:00  |  Presenting Author(s): Min Hee Hong  |  Author(s): Beung-Chul Ahn, Hye Ryun Kim, Sun Min Lim, Seoyoung Lee, Seong Yong Park, Chang Young Lee, Jin Gu Lee, Dae Joon Kim, Sang Hoon Lee, Hong In Yoon, Chang Geol Lee, Jaeho Cho, Hyo Sup Shim, Tae-Min Kim, Byoung Chul Cho

      • Abstract
      • Presentation
      • Slides

      Introduction

      Although definitive concurrent chemoradiotherapy (CRT) is considered standard of care for most stage III NSCLC patients, neoadjuvant-CRT (N-CRT) followed by surgery is an accepted practice with a potential survival benefit. Regarding synergistic effects of combining PD-1/PD-L1 blockade to CRT, we designed a two-stage phase Ib trial (ACTS-30) which assesses the safety and feasibility of the combination of N-CRT with durvalumab (PD-L1 inhibitor) in potentially resectable stage III NSCLC (ClinicalTrials.gov identifier: NCT03694236).

      Methods

      Patients with histologically confirmed, potentially resectable stage III NSCLC were eligible. N-CRT comprised intravenous weekly paclitaxel 45 mg/m2 and carboplatin AUC 2 with radiotherapy of 45 Gy in 25 fractions and durvalumab (Day 1 and 29, 1500mg) during 5 weeks and patients who completed N-CRT subsequently underwent surgery. After surgery, one year of adjuvant durvalumab was planned (every 4 weeks, 1500 mg). The primary objective was to determine the safety and tolerability of N-CRT + durvalumab regimen. The trial was composed of two-stages and the first stage included 9 patients and the trial was planned to proceed to the second stage (n = 21) if treatment-related adverse events (TRAEs) grade≥3 occurred in less than 50% of patients. The secondary endpoints are objective response rate (ORR), R0 resection rate, event-free survival (EFS), overall survival (OS), clinical or pathological downstaging rate, pathologic complete response (pCR) rate, and major pathologic response (MPR) rate. The exploratory analyses including immune marker assessment by FACS, whole-exome sequencing, single-cell RNA sequencing, and multispectral immunohistochemical staining using the specimen of pre-treatment, after surgery, and after recurrence will be performed.

      Results

      At the data cut-off (25th-Feb-2020), a total of 14 patients were enrolled. The median age was 66; 50% were male, and 50% were adenocarcinoma histology including two EGFR mutations. Since there was only one grade 3 TRAE (i.e., neutropenia) during the first stage, the trial entered the second stage. Overall, the grade 3 or more rate of TRAE was 7% (1/14). Currently, 11 patients underwent surgery (R0 resection) while one patient experienced cardiac pacemaker infection grade 3 (not considered as TRAE) and was not able to undergo surgical resection and two others are awaiting surgery. There was no postoperative in-hospital mortality. Among eleven resected patients, the pCR rate and MPR rate were 36.4% (3/11) and 72.7% (8/11), respectively. When excluding two EGFR mutant, the MPR rate was 88.9% (8/9).

      Conclusion

      These early data suggested that the N-CRT regimen with immunotherapy in stage III NSCLC was safe and feasible and had the potential to provide clinical benefit. The trial is ongoing and the final results and the biomarker analyses will be provided in the future congress and scientific journal.

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      FP03.03 - Clinical Activity of BMS-986012, an Anti–Fucosyl-GM1 Monoclonal Antibody, Plus Nivolumab in Small Cell Lung Cancer (ID 3396)

      00:00 - 00:00  |  Presenting Author(s): Neal E. Ready  |  Author(s): Quincy Chu, Natasha Leighl, Veerle Surmont, Carla Van Herpen, Anne Sibille, Ben Markman, Stephen Clarke, Rosalyn Juergens, Mirelis Acosta Rivera, Vladimir Andelkovic, Charles M. Rudin, Stephanie Snow, Dong-Wan Kim, Michael Sanatani, Sarah Tannenbaum-Dvir, Paul Basciano, Deanne Lathers, Katarzyna Urbanska, Georgia Kollia, Chunsheng He, Andrew Dipiero

      • Abstract
      • Presentation
      • Slides

      Introduction

      In patients with extensive-stage small cell lung cancer (ES-SCLC), the addition of an anti–PD-L1 regimen to chemotherapy demonstrated limited benefit, with an increase in survival by 2 months (Horn et al. N Engl J Med. 2018;379:2220–2229). Therefore, future prospects for better outcomes in SCLC lie in novel medicines and new treatment combinations. Fucosyl-GM1 is a monosialoganglioside expressed in 50%–70% of SCLC with limited expression in normal tissues (Brezicka et al. APMIS. 1991;99:797–802; Brezicka et al. Tumour Biol. 1992;13:308–315). BMS-986012 is a nonfucosylated, fully human monoclonal antibody with high binding specificity for fucosyl-GM1 engineered to enhance antibody-dependent, cell-mediated cytotoxicity (Ponath et al. Clin Cancer Res. 2018;24:5178–5189). We previously reported that the combination of BMS-986012 and nivolumab in patients with relapsed/refractory SCLC was well tolerated and demonstrated preliminary antitumor activity (Chu et al. Ann Oncol. 2017;28(suppl 5). Abstract 1528PD). Here, we report updated safety and antitumor activity results from the phase 1/2 trial of the combination of BMS-986012 and nivolumab in patients with relapsed/refractory SCLC (NCT02247349).

      Methods

      Patients with relapsed/refractory SCLC who had not received prior checkpoint inhibitor (CPI) therapy received BMS-986012 400 or 1000 mg with nivolumab 360 mg intravenously every 3 weeks. The primary endpoint was safety. Secondary endpoints included investigator-assessed objective response rate (ORR), median duration of response (mDOR), median progression-free survival (mPFS), and pharmacokinetics. Median overall survival (mOS) was an exploratory endpoint.

      Results

      As of July 22, 2020, 29 patients received BMS-986012 (400 mg, n=21; 1000 mg, n=8) with nivolumab, with a follow-up of 18.6 months (range, 0.6–41.1 months). Median age of patients was 65 years (range, 46–79 years) and 52% were male; ECOG performance status was 0 (38%) or 1 (62%). The combination was well tolerated, with manageable adverse effects. The most common all-grade/grade ≥3 treatment-related adverse events were pruritus (93%/21%), fatigue (28%/0%), dry skin (28%/0%), and hypothyroidism (17%/0%). In most patients, pruritus diminished over time and was managed with antihistamines and low-dose corticosteroids. Confirmed ORR with BMS-986012 plus nivolumab was 38% (CR, n=1 [3%]; PR, n=10 [35%]), with 3 additional patients (10%) having SD, for an overall disease control rate of 48%. At data cutoff, mDOR was 26.4 months (95% CI, 4.4 months–NR); 4 patients were still on therapy. mPFS was 2.1 months (95% CI, 1.4–9.9 months) and mOS was 18.7 months (95% CI, 8.2 months–NR). No differences in response were noted between platinum-sensitive and refractory populations.

      Conclusion

      The results presented here suggest that BMS-986012 plus nivolumab is a promising therapeutic combination for the treatment of patients with relapsed/refractory SCLC not previously treated with CPI therapy, irrespective of whether their cancers were platinum sensitive or refractory. The safety profile was manageable, and although based on a small number of patients, responses were clinically meaningful and durable. These updated data warrant further investigation of this combination in patients with SCLC.

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      FP03.04 - Selinexor can Inhibit Nuclear Export of HMGB1, a Negative Predictive Marker for Immunotherapy Response (ID 3616)

      00:00 - 00:00  |  Presenting Author(s): Jillian W.P. Bracht  |  Author(s): Yang Yang, Maria González-Cao, Miguel Angel Molina-Vila, Peng Cao, Rafael Rosell

      • Abstract
      • Presentation
      • Slides

      Introduction

      The high mobility group box 1 (HMGB1) normally acts as a DNA chaperone in the nucleus, but was previously shown to be involved in various inflammatory diseases and cancer. Endogenous stimuli and oxidative stress can induce the transport of HMGB1 from the nucleus to the cytoplasm through exportin 1 (XPO1/CRM1). In addition, XPO1 was shown to be responsible for nuclear transport of HIV-1. Consequent release of HMGB1 from the cell as a damage-associated molecular pattern (DAMP) was found to have a paradoxical role in cell survival and death, by either activating an immune response through TLRs and RAGE receptors, or by inhibition of the immune response through CD24 and TIM-3 receptors. Selinexor (KPT-330) is an FDA-approved XPO1 inhibitor that prevents the release of HMGB1 from the nucleus to the cytoplasm. Selinexor was previously shown to be effective in KRAS mutant lung adenocarcinoma cell lines. We hypothesized that HMGB1 and XPO1 may be important biomarkers in cancer patients that will receive immune checkpoint inhibitors (ICIs).

      Methods

      Pre-ICI-treatment FFPE tumor tissue samples from 15 HIV-infected and 30 non-HIV-infected cancer patients, mainly lung cancer, were analyzed using the nCounter NanoString platform with the Human PanCancer IO360 panel. The IO360 panel can be used to analyze the expression of 770 genes related to tumor biology, immune response and microenvironment. HMGB1 mRNA expression results were correlated with HIV status and clinical benefit (CB; objective response or stable disease of more than 24 weeks by RECIST1.1 criteria). Next, XPO1 was inhibited in lung cancer cell lines using selinexor and integrase inhibitors (INSTIs) and effects on cell viability and nuclear export of HMGB1 were evaluated. Moreover, combination therapies using selinexor and EGFR or MET inhibitors were tested and effects on cell viability were determined.

      Results

      HMGB1 mRNA expression was lower in patients that had CB from ICI treatment (p = 0.04). No significant differences were found in HMGB1 mRNA expression between patients with- and without HIV-1 infections. Kaplan Meier analysis revealed that patients with lower HMGB1 mRNA expression have better overall survival, both in our patient cohort (p = 0.004), and a TCGA lung adenocarcinoma patient cohort (p = 0.003). Inhibition of the HMGB1 transporter, using either selinexor or INSTIs, can prevent nuclear export of HMGB1 in the PC9 lung cancer cell line and inhibit cell proliferation in EGFR and KRAS mutant cell lines. Combination treatments with selinexor decreased cell viability in lung cancer cell lines when compared to single treatment.

      Conclusion

      In this study we found HMGB1 mRNA to be lower expressed in tumor tissue of pre-ICI-treated cancer patients with clinical benefit from treatment, indicating that HMGB1 expression may be used as a negative predictive marker for immunotherapy response. Further exploration should focus on validating this finding in a larger patient cohort and future in vivo studies should reveal if the combination of ICIs and XPO1 inhibitors could yield better responses to immunotherapy. Therefore, HMGB1 may be used to predict clinical benefit from ICI treatment and provides a new target for cancer treatment.

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      FP03.05 - TLR9 Agonist CMP-001 Plus Atezolizumab +/- Radiation Therapy in Patients With PD-1 Blockade Resistant Advanced NSCLC (ID 3571)

      00:00 - 00:00  |  Presenting Author(s): Marcelo V. Negrao  |  Author(s): Vassiliki A. Papadimitrakopoulou, Andrew C. Price, Alda L. Tam, Muhammad Furqan, Sandeep T. Laroia, Erminia Massarelli, Jose M Pacheco, John V. Heymach, Anne S. Tsao, Gary Walker, Lalit Vora, David Mauro, Heather Kelley, James E. Woolridge, Arthur M. Krieg, Jiaxin Niu

      • Abstract
      • Presentation
      • Slides

      Introduction

      Patients with non–small cell lung cancer (NSCLC) and progressive disease (PD) following programmed death 1 (PD-1) blockade therapy have a poor prognosis. CMP-001 is a CpG-A Toll-like receptor 9 (TLR9) agonist packaged within a virus-like particle. The multicenter, open-label, 2-part, Phase 1b CMP-001-003 study (NCT03438318) evaluated the safety and preliminary antitumor activity of CMP-001 plus atezolizumab with or without radiation in patients with advanced NSCLC.

      Methods

      Eligible patients with PD following anti–PD-1/programmed death ligand 1 (PD-L1) therapy and ≥1 extra-central nervous system, non-bone metastasis amenable for intratumoral injection received CMP-001 and atezolizumab (Part A) or CMP-001, atezolizumab, and radiation (Part B). CMP-001 was administered at 5 mg subcutaneously once weekly during weeks 1 and 2, followed by 5 mg or 10 mg intratumorally once weekly during weeks 3-5 and every 3 weeks thereafter. Atezolizumab 1200 mg was administered intravenously once every 3 weeks starting on week 2. Radiation therapy in Part B consisted of 20 Gy delivered in 5 fractions starting ≥2 days prior to CMP-001 treatment. Following a safety run-in period (n=5), each Part enrolled additional patients in Stage 1; ≥2 of 12 patients were required to have a RECIST v1.1 response to proceed with Stage 2 enrollment. The primary objective was to evaluate the safety of CMP-001 and atezolizumab with or without radiation. A key secondary endpoint was best objective response per RECIST v1.1 as assessed by the investigator.

      Results

      Twenty-nine patients were enrolled in Stage 1 (Part A, n=13; Part B, n=16). The median number of prior lines of therapy received was 3 (range, 1-6); 31.0% of patients had ≥4 prior lines of therapy. Only 5 patients (17.2%) had response to any prior systemic therapy. The median number of CMP-001 intratumoral injections was 3 (Part A range, 1-12; Part B range, 1-6); 12 patients had a total of 65 injections into visceral lesions, including kidney, liver, lung, and pleura, which were safely performed. The most common treatment-related adverse events (TRAEs; ≥30%) overall were flu-like symptoms (ie, chills and pyrexia) and hypotension. Six patients (46.2%) in Part A and 8 patients (50.0%) in Part B had grade ≥3 TRAEs. Only 1 patient discontinued treatment due to TRAEs (Part A, grade 3 pneumonitis). As of April 15, 2020 (Part A median follow-up, 1.9 months [range, 1-19]; Part B median follow-up, 1.7 months [range, 1-4]), no objective responses were observed. Two patients (15.4%) and 4 patients (25.0%) had tumor shrinkage (<30% decrease in tumor size) in Parts A and B, respectively. Three patients (23.1%) and 8 patients (50.0%) had stable disease as best response in Parts A and B, respectively. Study enrollment was stopped after completion of Stage 1 due to lack of objective response. The cytokine response to CMP-001 treatment and tissue biopsy analyses will be presented.

      Conclusion

      CMP-001 plus atezolizumab with and without radiation therapy had a manageable safety profile. Intratumoral injection of CMP-001 into visceral lesions was safely achieved, and stable disease was observed in heavily pretreated patients with PD-1/PD-L1 refractory NSCLC.

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    FP04 - Locoregional and Oligometastatic Disease (ID 126)

    • Event: WCLC 2020
    • Type: Posters (Featured)
    • Track: Locoregional and Oligometastatic Disease
    • Presentations: 5
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      FP04.01 - Heart Dose is a Dosimetric Predictor of Overall Survival in Patients with NSCLC Undergoing Post-Operative Radiation Therapy (ID 1369)

      00:00 - 00:00  |  Presenting Author(s): Annemarie Fernandes Shepherd  |  Author(s): Anthony Yu, Mohammed A Al-Sadawi, Ariel Peleg, Michelle Iocolano, Jonathan Leeman, Brandon S Imber, Aaron Wild, Michael D Offin, Jamie Chaft, James Huang, Andreas Rimner, Abraham J Wu, Daphna Y Gelblum, Narek Shaverdian, Daniel Gomez, Charles B Simone, Ii, Ellen Yorke, Andrew` Jackson

      • Abstract
      • Presentation
      • Slides

      Introduction

      Patients undergoing PORT for locally-advanced NSCLC may be at risk for increased cardiac toxicity. There is an association between radiation dose to the heart and OS in NSCLC patients undergoing definitive radiation therapy (RT). The purpose of this analysis was to evaluate heart dose as a predictor of OS in patients with NSCLC undergoing PORT.

      Methods

      We reviewed 284 patients with NSCLC treated with PORT at our institution from 5/2004 to 1/2017. Complete dosimetric data and clinical records were reviewed, and OS was assessed. Patients were a median of 67 years old (range 28-87), and most had pathologic stage III NSCLC (91%) and received trimodality therapy (90%). Forty-six (16.2%) patients had pre-existing cardiac disease. Patients underwent lobectomy (81%), sublobar resection (12%) or pneumonectomy (7%). The rates of R0, R1 and R2 resections were 81%, 19%, and 0%, respectively. The median RT dose was 54 Gy (range: 45-70 Gy). Patients were treated with IMRT (71%) or 3DCRT (29%). Major adverse cardiac events (MACE, defined as myocardial infarction, coronary revascularization, cerebrovascular accident or heart failure) and all cardiac toxicities (including arrythmia, valvular or pericardial events) were identified. A systematic univariate Cox proportional hazards model analysis of OS and heart dose variables was performed, using the minimum dose to the hottest x% (Dx) and the volume receiving at least xGy (Vx) with x in increments of 5% and 2Gy respectively, together with mean, min, and max doses. Clinical variables that were univariately significant (p < 0.05), together with the most significant dosimetric variable, were entered in a step-up multivariate analysis.

      Results

      The median, 2-year and 5-year OS were 41.5 months, 68% and 37%, respectively. Dosimetric variables across a large range of doses to the heart were highly significant for OS, including mean (MHD), minimum and maximum heart doses. The median MHD for the population was 11.2Gy. The median OS for patients with MHD above vs. below 11.2Gy was 31.7 vs. 57.5 months (p<0.001), respectively. The volume of the heart receiving 8Gy (HV8) was the most significant dosimetric variable (p <0.0001), and the median HV8 was 35.5%. The median OS was 33.2 vs. 53.6 months (p<0.005), for patients with HV8 above or below 35.5%. On multivariable analysis, HV8 (HR:1.015/%, p<0.001), increasing age (HR:1.036/yr, p<0.001), use of anticoagulant therapy (HR:2.24, p=0.007), more extensive surgery (HR:1.49, p=0.012), and pre-operative chemotherapy (HR:1.53, p=0.019) were significant for OS. The rates of MACE and all cardiac toxicities were 7.4% and 14.8%, respectively. No heart dosimetric variables predicted for MACE or all cardiac toxicity.

      Conclusion

      Heart dose, as well as age, use of anticoagulants, presurgical chemotherapy, and the extent of surgery are predictive of worse OS in patients with NSCLC undergoing PORT. Heart V8 is the most significant dosimetric factor associated with OS. Despite the strong correlation between heart dose and OS, heart dose did not predict for cardiac events. This may indicate that the association between OS and heart dose cannot be explained fully by radiation-induced cardiac toxicities in NSCLC patients undergoing PORT.

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      FP04.02 - Feasibility of Radiotherapy Planning in the First 50 Patients Recruited to the ADSCaN Clinical Trial (ID 1884)

      00:00 - 00:00  |  Presenting Author(s): Romaana Mir  |  Author(s): Corinne Faivre-Finn, Claire Lawless, Elaine McCartney, Clive Peedell, Tony Pope, Ann Shaw, Rita Simoes, Matthew Hatton

      • Abstract
      • Slides

      Introduction

      The ADSCaN clinical trial (ISRCTN47674500) randomizes patients with unresectable stage III NSCLC suitable for sequential chemo-radiotherapy to one of four accelerated dose-escalated experimental radiotherapy regimens (CHART-ED, IDEAL, I-START, and Isotoxic IMRT) or a standard radiotherapy regimen of 55Gy in 20 fractions. We present feasibility of radiotherapy planning in the first 50 patients.

      Methods

      ADSCaN was data locked and presented to the data monitoring committee (DMC) in November 2019. Dosimetric data: GTV volume (cc), PTV volume (cc), radiotherapy planning objectives, and dose to organs at risk (OAR) were recorded against the respective OAR constraints for each arm. Linear regression analysis examined the relationship between PTV volume and radiotherapy dose to the respective OAR. Adverse events (AEs) are reported for the first 50 patients.

      Results

      46 radiotherapy plans were available for review; 16 standard arm, 11 CHART-ED, 5 IDEAL, 7 I-START, and 7 Isotoxic IMRT. One of the first fifty recruited patients did not receive radiotherapy. Median GTV volume was 61.96 (cc) (IQR 36.22–91.41); median PTV volume was 285.86cc (IQR 216.65–385.45). The largest PTV volume was 1590.60cc. Radiotherapy delivery was 1-2 full arcs for 7 patients, 2-3 half arcs for 26 patients, and 4-7 static IMRT fields for 13 patients. PTV coverage achieved the mandatory planning objectives of V95% >90% and V90% >98% in all but one case in the I-START arm where the PTV spanned the hemi-thorax and mediastinum. The OAR constraints were achieved in all cases.

      Dose to respective OAR were plotted against PTV volume (figure); there was a positive correlation between lung and heart constraints and PTV volume. There was a negative correlation between PTV volume and D0.1cc oesophagus.

      dose to oar.jpg

      The strength of the correlation between PTV volume and OAR dose were weak to moderate: lung–GTV V20Gy R2=0.15944, D33% heart R2=0.14634, D67% heart R2=0.33828, D100% heart R2=0.58477, D0.1cc oesophagus R2=0.01195, indicating it is feasible to radically plan accelerated dose-escalated radiotherapy over a range of PTV and planning techniques. The overall CTCAE v4.0 grade 2 and 3 toxicity rate was 54% and 28%; specific grade 3 AE were dysphagia 2%, dyspnea 12%, fatigue 4%, oesophagitis 6%, pneumonitis 2%, and upper respiratory infection 2%. One patient developed bronchopneumonia as the sole grade 5 AE.

      Conclusion

      The recruiting ADSCaN clinical trial demonstrates feasibility of accelerated dose-escalated radiotherapy planning across treatment arms, dose objectives, and planning techniques, with no appreciable increase in AEs when compared to the contemporary NSCLC radical radiotherapy evidence base.

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      FP04.03 - Dynamic Liquid Biopsy for Selecting Advanced NSCLC Patients for Primary Tumor Resection After Targeted Therapy (ID 1152)

      00:00 - 00:00  |  Presenting Author(s): Weitao Zhuang  |  Author(s): Lijun Peng, Yu Ding, Haiping Xiao, Yong Tang, Enwu Xu, Zhe He, Zhu-An Ou, Qihang Zhu, Hansheng Wu, Zhen Gao, Shujie Huang, Guibin Qiao

      • Abstract
      • Presentation
      • Slides

      Introduction

      Surgery can provide survival benefit for certain patients after targeted therapies of advanced non-small cell lung caner (NSCLC) with active mutations. However, there is currently no well-established criteria for selecting the potential beneficiaries. Dynamic liquid biopsy, which allows serial systemic assessments of both primary tumor and metastases, might be an option for this purpose.

      Methods

      We performed a retrospective analysis of 37 patients with stage IIIb to IVb NSCLC, who had at least one detectable gene mutation in blood and received targeted therapies for 1 to 20 months before intended resection of primary tumor during 2013 to 2017. All patients were tested for a baseline abundance of mutated genes using next-generation sequencing. Twenty of them were also dynamically monitored within 1 week before and after operation. An optimal cutoff value to categorize patients into low-risk and high-risk groups was determined by X-tile based on proportional change in genetic abundance. Progression-free (PFS) and overall survival (OS) were estimated and compared by Kaplan Meier and log-rank test in SPSS 19.

      Results

      The number of patients in low-risk, high-risk and untested groups was 14 (37.8%), 6 (16.2%) and 17 (46%), respectively, with individual clinicopathological features depicted by heat mapping (Figure 1A). All patients had a PS score of 0-1 and oligo-metastasis less than 5 tumors. With a median follow-up of 34 months, the estimated median OS (mOS) and postoperative PFS (post-mPFS) for the overall cohort were 30 months (95% CI, 23.6-36.4) and 14 months (95% CI, 5.5-22.5), respectively. Patients with unchanged or increased abundance of mutated genes after targeted therapy had a poorer prognosis (Figure 1B). Patients in low-risk group had significantly longer post-mPFS (18 vs. 2 months, p=0.004) and mOS (35 vs. 14 months, p=0.001) than patients in high-risk group (Figure 1C, 1D). Multivariate analysis using Cox proportional hazard model suggested that efficacy of targeted therapy and proportional change in genetic abundance were independent prognostic factors for overall survival.

      figure 1.jpg

      Conclusion

      Dynamic blood test of mutated gene abundance had a good prognostic predictability, which may serve as a “classifier” to select ideal patients with advanced NSCLC for surgical resection of primary tumors. Prospective controlled study is needed to further verify the results. Development of novel biomarkers and methods which have higher detecting sensitivity and more accurate quantification might further increase the efficacy of patient selection.

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      FP04.04 - EGFR Mutations Predict Superior Survival of NSCLC Patients with Oligometastatic Disease Treated with Local Consolidative Therapy (ID 2994)

      00:00 - 00:00  |  Presenting Author(s): Ahsan Farooqi  |  Author(s): Kyle Mitchell, Ethan Ludmir, David Boyce-Fappiano, Ara Vaporciyan, Stephen Swisher, Jianjun Zhang, Xiuning Le, Mara B Antonoff, Daniel Gomez, YASIR Y Elamin, John Heymach, Saumil Gandhi

      • Abstract
      • Slides

      Introduction

      Local consolidative therapy (LCT) following systemic therapy for selected patients with oligometastatic non-small cell lung cancer (NSCLC) is an evolving treatment strategy. We sought to identify predictive genomic markers for overall survival (OS) and progression free survival (PFS) in patients presenting with synchronous oligometastatic NSCLC at diagnosis.

      Methods

      Patients presenting to a single institution (2000-2017) with stage IV NSCLC and ≤3 synchronous metastatic lesions were identified. Of 194 patients who met our inclusion criteria, 121 received comprehensive local consolidative therapy (LCT) to all sites of disease with either surgery or radiation. Intrathoracic nodal disease was counted as one site. Univariable and multivariable Cox regressions were performed to identify factors associated with OS. A ninety-day landmark analysis was performed to limit survivorship bias. Mutational status was obtained via an institutional database, when available.

      Results

      Of 194 patients who met our inclusion criteria and had genomic data available, TP53 mutations were identified in 40 of 55 (72%), KRAS in 30 of 65 (46%), EGFR in 22 of 90 (24%), ALK in 4 of 81 (5%), ROS1 in 2 of 63 (3%), and BRAF in 1 of 32 (3%) patients. The median age was 62 years. After a median follow-up of 52.3 months, median OS and PFS for this cohort was 26.5 (CI 23.0-30.0) months and 11.1 (95%, 9.1-13.0) months, respectively. Among all patients, comprehensive LCT to all sites of disease (N=121) was associated with improved OS (HR 0.67, CI 0.47-0.96, p=0.03) consistent with our previous study. Among all patients, on univariable analysis, patients with EGFR mutations had improved median OS (95.5 vs 37.2 months, p=0.03) compared to EGFR WT patients. Conversely, TP53, and KRAS mutations did not predict for OS. Among patients who received comprehensive LCT with known EGFR mutational status (N=57), EGFR mutations continued to predict for improved median OS (97.5 vs 29.8 months, p=0.02) (Figure 1).

      picture1.jpg

      Conclusion

      Aggressive consolidative therapy to the primary lesion and all metastatic sites was associated with improved OS in a large cohort of oligometastatic patients, supporting results of recent prospective trials. EGFR mutations, but not KRAS or TP53 mutations, predicted for improved OS among oligometastatic patients who are treated with comprehensive LCT in addition to systemic therapy. These data support ongoing prospective trials evaluating the benefit of local therapy in oligometastatic EGFR mutant NSCLC.

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      FP04.05 - Anti-Vascular Drug Anlotinib Combined With SRS Versus SRS Alone for Brain Metastases From NSCLC: A Case Control Study (ID 1227)

      00:00 - 00:00  |  Presenting Author(s): Hongqing Zhuang  |  Author(s): Yuxia Wang

      • Abstract
      • Slides

      Introduction

      Anti-vascular therapy and SRS have both been widely used in tumor treatment. As for the brain metastases, the current research of anti-vascular drugs mainly focuses on the treatment of brain edema and central radiation necrosis (CRN). However, there is no investigation assessing the effect of anti-vascular therapy simultaneously with SRS on the metastatic brain tumor. The difference between clinical efficiency and side effects of anti-vascular drugs combined with SRS versus SRS alone also remains elusive. Anlotinib, as an anti-vascular drug for lung cancer, has been widely used in NSCLC. This case-control study compared patients treated with anlotinib plus SRS to those with SRS alone, hoping to provide reference for the treatment of brain metastatic NSCLC.

      Methods

      A total of 46 SRS patients with NSCLC brain metastases were collected from October 2017 to June 2019, among which 21 patients (33 lesions) were in the group of anlotinib combined with SRS and 25 patients (35 lesions) were in the SRS-alone group. The first observation indexes included the toxicity and local control of the intracranial hypertension, central radiation necrosis induced by treatment. The second observation index was defined to be the intracranial progression-free survival (iPFS). The differences of intracranial efficacy and toxicity between the two groups were compared.

      Results

      The results showed that anlotinib significantly relieved the high intracranial pressure symptoms during SRS ( P < 0.05). There was no difference in response rate (RR) between the two groups ( P = 0.289),and new intracranial lesions are the main reason for the progress. The incidence of CRN was significantly reduced in the SRS plus anlotinib group compared with SRS-alone group (P < 0.05). The iPFS of the combined treatment group was significantly longer than that of the SRS-alone group ( P <0.05).

      Conclusion

      Compared with SRS alone, the anti-vascular drug anlotinib combined with SRS can reduce the toxicity of radiotherapy during and after treatment, and improve the effect of intracranial therapy.

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    FP05 - Mesothelioma, Thymoma and Other Thoracic Malignancies (ID 135)

    • Event: WCLC 2020
    • Type: Posters (Featured)
    • Track: Mesothelioma, Thymoma and Other Thoracic Malignancies
    • Presentations: 4
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      FP05.01 - Real-World Survival Outcomes of Patients with Malignant Pleural Mesothelioma by Choice of Second-line Therapy   (ID 2718)

      00:00 - 00:00  |  Presenting Author(s): Kathleen Claire Kerrigan  |  Author(s): Jonathan Chipman, Yeon Jung Jo, Benjamin Haaland, Eric Johnson, Sonam Puri, Thomas K Varghese, Wallace Akerley, Shiven Patel

      • Abstract
      • Slides

      Introduction

      Malignant pleural mesothelioma (MPM) is an aggressive malignancy with a poor overall survival (OS). Disease biology, patient co-morbidities and performance status (PS), and a lack of biomarkers to guide therapeutic decision making all contribute to poor survival. There is limited data to guide choice of second-line therapy (2L) after progression of disease (POD) on first-line (1L) platinum-based combination chemotherapy. This study evaluates real-world survival outcomes of patients with MPM by physician’s choice of 2L single-agent chemotherapy versus immunotherapy.

      Methods

      The study included patients with MPM in the Flatiron Health nationwide electronic health record-derived de-identified database who initiated 2L therapy after POD on 1L platinum-based chemotherapy between May 2011 – July 2019, with follow-up through July 2019. Propensity weighting was performed to balance potential confounders, weight the Kaplan-Meier estimate of OS from initiation of 2L, and weight a Cox proportional hazard model on OS comparing immunotherapy versus single-agent chemotherapy. Propensity scores were constructed via logistic regression based on age, asbestos exposure, smoking history, region, race/ethnicity, PD-L1 status, histology, time to starting 2L therapy, serum creatinine, hemoglobin, absolute neutrophil, platelet, and white blood cell count, serum albumin, height, weight, 1L therapy, previous heart, kidney, neuropathy, and/or audiologic condition, and ECOG PS. An unweighted Cox proportional hazards model was fit adjusting for these baseline covariates and date of diagnosis.

      Results

      This study included 193 patients with MPM treated with single-agent chemotherapy (n=101) versus single-agent or combination immunotherapy (n=92) after POD on 1L platinum chemotherapy. Documented PD-L1 testing was limitedly available (n=38; 20%). Median age was similar between treatment groups. More patients with sarcomatoid histology and with ECOG PS 0 and 3 were treated with 2L immunotherapy than chemotherapy. Patients receiving single-agent chemotherapy were mostly diagnosed prior to 2016 (74%); only 15% of patients receiving immunotherapy were diagnosed by this time. The propensity score weighted analysis demonstrated an OS hazard ratio (HR) of 2L immunotherapy versus chemotherapy of 0.64 (p = 0.05; 95% CI: 0.41, 1.01). The unweighted analysis was consistent in estimating the HR to be 0.61 (p = 0.08, 95% CI = 0.35, 1.07).

      wclc figure 2 final 2l therapy.jpg

      Conclusion

      This is the largest real-world evidence assessment of 2L therapy following platinum chemotherapy in patients with MPM. While non-significant, single or combination immunotherapy had a suggestive benefit on OS compared to single-agent chemotherapy. The benefit had as much as a 59% HR reduction of death and had no worse than a 1% increased HR on OS.

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      FP05.02 - An Early Detection and Prognostic Blood Biomarkers Signature for Malignant Pleural Mesothelioma Based on Targeted Proteomics (ID 3473)

      00:00 - 00:00  |  Presenting Author(s): Ferdinando Cerciello  |  Author(s): Meena Choi, Sara L. Sinicropi-Yao, Katie Lomeo, Joseph M. Amann, Emanuela Felley-Bosco, Rolf A Stahel, Bruce Robinson, Jenette Creaney, Harvey I. Pass, Olga Vitek, David Paul Carbone

      • Abstract
      • Presentation
      • Slides

      Introduction

      We have investigated an academically developed targeted proteomics signature for the early detection and for prognostication of malignant pleural mesothelioma (MPM) from the blood.

      Methods

      We have studied a multicenter cohort of more than 400 MPM patients and asbestos exposed donors. Serum samples were processed on 96-well plates for enrichment of N-linked glycoproteins before analysis by liquid-chromatography mass spectrometry (LC-MS) based targeted proteomics for a multiplexed peptide biomarkers signature.

      Results

      We have verified the use of a multiplexed MPM proteomics signature identified in our previous work in cell lines and blood (the original signature was composed of seven peptides, the current signature is a reduced version of six peptides). The multiplexing approach offered by LC-MS proteomics in serum allowed to increase the discriminatory capacity of the signature over the single biomarkers. The proteomics signature presented an AUC of 0.738 and for early stage MPM (stage I/II) AUC was 0.765. This performance was comparable to what we observed using well established and commercially optimized MPM blood biomarkers, underlying the potential of our academic developed strategy once optimized for routine clinical use. The signature presented a negative-likelihood ratio of 0.11 for early stage MPM, highlighting the sensitivity of the approach and its potential utility for MPM early detection strategies, once integrated with complementary MPM biomarkers with high specificity. In addition, the proteomics signature was able to significantly separate high and low risk groups of MPM patients based on their survival (HR of 1.659), supporting in this way treatment decisions based on patients prognosis.

      Conclusion

      The targeted proteomics signature in blood represents an additional diagnostic approach for MPM early detection and treatment decisions.

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      FP05.03 - Association between Baseline Tumor Thickness and Response to Neoadjuvant Chemotherapy in Malignant Pleural Mesothelioma (ID 3052)

      00:00 - 00:00  |  Presenting Author(s): Nicolas Zhou  |  Author(s): David Rice, Reza Mehran, Hope A Feldman, Katarzyna J Tomczak, Wayne L Hofstetter, Ara Vaporciyan, Arlene M Correa, Jianjun Zhang, Cara Haymaker, Anne S Tsao, Boris Sepesi

      • Abstract
      • Presentation
      • Slides

      Introduction

      Tumor thickness in malignant pleural mesothelioma has been reported to be prognostic for survival and disease recurrence, but the relationship of tumor thickness and response to chemotherapy has not been explored. We sought to investigate the utility of baseline tumor thickness as a predictor of response to neoadjuvant chemotherapy (NAC).

      Methods

      Patients who underwent NAC followed by cytoreductive surgery were reviewed from 2000-2019. Chest CT performed before and after completion of NAC were measured for tumor thickness using the modified RECIST 1.1 criteria. Total tumor thickness consisted of three mediastinal and three chest wall mesurements. Radiologic response to NAC were categorized into partial response (PR≥30% decrease), progressive disease (PD, ≥20% increase) or stable disease (SD, -29% to +19% change) based on the change in total tumor thickness. Mean and median tumor thickness for each tumor response category was evaluated for total and percent change in tumor thickness after NAC. Overall survival (OS) was defined from time of diagnosis and compared between PD and PR. Multivariable logistic regression was performed for PD after neoadjuvant chemotherapy.

      Results

      143 patients were reviewed. Median age was 65 years, most patients were male (112, 78%), and white (123, 86%). Histology was comprised of 111(78%) epithelioid, 28(20%) biphasic, and 4(3%) sarcomatoid. All patients were pathologic stage I-III, NAC consisted of 108(76%) platinum/pemetrexed, 19(13%) dasatinib, and 16(11%) other. There were 36(25%) patients with PD, 54(38%) SD, and 53(37%) PR. Analysis for OS showed PR with improved survival compared to PD (27 vs. 13 months, p=0.007). There was a positive correlation between baseline tumors thickness and radiological response to NAC (r=0.537, p<0.001); this pattern was consistent for platinum/pemetrexed, dasatinib, and other therapies. The median baseline thickness for PD was 36 mm, which was thinner than SD (63mm, p<0.001) and PR (63mm, p<0.001). In tumors <36mm,10% of patients achieved PR, and 61% of patients achieved PD, compared to 45% PR (p<0.001) and 15% PD (p<0.001) in tumors above 36mm. Tumors <36mm was associated with PD (OR: 5.48; 95% CI: 1.82-17.26; p=0.003) in a multivariable model.

      Table. Multivariable Logistic Regression for Progressive Disease
      Variable Odds Ratio (95% Confidence interval) p-value
      Female sex 0.94 (0.25 - 3.06) 0.927
      Zubrod Performance Status 1.66 (0.71 - 3.90) 0.234
      Clinical N+ 0.74 (0.18 - 2.55) 0.652
      Epithelioid Histology 1.25 (0.39 - 4.46) 0.709
      Platinum/Pemetrexed 0.40 (0.13 - 1.29) 0.119
      Tumor<36mm 5.48 (1.82 - 17.26) 0.003
      Baseline SUVmax (Gray) 1.08 (0.98 - 1.17) 0.128

      Conclusion

      Responders to NAC portends longer survival. There seems to be a correlation between baseline tumor thickness and response to neoadjuvant chemotherapy. While these results will need further validation, it generates a hypothesis of differential tumor environment and response to neoadjuvant therapy in thinner and thicker tumors. Further studies should focus on defining the mesothelioma microenvironment based on radiographic tumor thickness.

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      • Abstract
      • Slides

      Introduction

      TET are rare malignancies, with an annual incidence of 350 cases in France. The main prognostic factors are Masaoka-koga stage and quality of the resection. However, no large cohorts have been published concerning resection outcomes. RYTHMIC (Réseau tumeurs THYMiques et Cancer) is a French network mandated to systematically discuss every case of TET. We aimed to describe the resected tumor outcomes in a large French population.

      Methods

      RYTHMIC database, hosted by IFCT (Intergroupe Francophone de Cancérologie Thoracique), prospectively includes all consecutive pts with a diagnosis of TET discussed in French national or regional tumor boards. We analyzed epidemiologic, clinical and pathological characteristics of 1045 pts operated of a TET.

      Results

      From January 2012 to December 2019, 2909 pts were included in the database. Overall, the median age at diagnosis of TET was 60 (range 9-90) and 52% (n=1513) were male. Of them, 1082 (37,2%) pts were operated. 304/1045 (29%) pts reported autoimmune disorders and Myasthenia Gravis was the most common (250 pts, 82,2%). Masaoka-Koga stages (MK) were well balanced with 23% (n=240) stage I, 17.2% (n=180) stage IIa, 18.2% (n=190) stage IIb, 19.6% (n=205) stage III with lung as a main invaded organ (37%), 8% (n=85) stage IVa and 4.9% (n=51) stage IVb. Among resected tumors, B2 and AB were the most common subtypes (n=247, 23.6% and n=237, 22.7% respectively).

      Sternotomy was the most used approach for resection (n=735, 70.3%). In addition to TET, surgery was extended to lung (35%), pericardium (24%), pleura (13%), recurrent nerve or great vessels (10%) and lymph nodes (46%). Complete resection was assessed in 71% of procedures with a median tumor size of 55mm (1-260) and a range of 0-28 resected pleural metastasis. Intrapleural chemotherapy was used as an associated technique during the first-line surgery (6/17 pts) or after recurrence (9/17 pts, 53%) shrinking the hazard for progression (PD) (OR= 0.5 95%CI [0.29 to 0.84], p<0.00). Induction chemotherapy and adjuvant radiotherapy was administered in 119/182 (65,3%) and 357/1045 (34.2%) pts, respectively. Principal location for progression was the pleura (119/223 pts, 53%) with surgery as the main treatment (31%).

      Median-OS was 263 months (95%CI[NotR-NotR]) and median-PFS was 111 months (95%CI[97,4-124,5]). The Cox proportional Hazard’s model showed a statistically significant greater risk for PD of MK III comparing with other localized tumors (HR=10,618 95%CI[1,172-96,224], p=0,036). Patients presenting thymoma B3 and epidermoid thymic carcinoma assessed risk for PD (HR=1,357 95%[0,531-3,462]; p=0,524 and HR= 1,982 95%CI[0,774-5,073]; p=0,154, respectively). Patients who needed lung or phrenic nerve resection showed higher risk for PD (HR=1,643 95%CI[1,181-2,286]; p=0,003 and HR=1,829 95%CI[1,217-2,748]; p=0,003, respectively). Bigger tumors and those with no complete resection (R1) were more likely to progress (HR=1,009 95%CI[1,004-1,013]; p<0,00 and HR=1,821 95%CI[1,058-3,133]; p=0,03, respectively).

      Conclusion

      Up to 37% of RYTHMIC cohort were resected. MK I and III were the most common resected tumors with 71% of complete resection with impact on survival. Thymic carcinoma and thymoma B3 were more likely to progress. Pleura was the main site for recurrence and surgery the most used treatment, in addition with intrapleural chemotherapy in some cases.

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    FP06 - Palliative and Supportive Care (ID 160)

    • Event: WCLC 2020
    • Type: Posters (Featured)
    • Track: Palliative and Supportive Care
    • Presentations: 4
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      FP06.01 - Discrete Choice Experiment to Estimate Physicians’ Preferences in Terms of G-CSF use for Febrile Neutropenia Primary and Secondary Prophylaxis (ID 3119)

      00:00 - 00:00  |  Presenting Author(s): Christos Chouaïd  |  Author(s): Florian Scotté, Eric-Charles Antoine, Hélène Simon, Nathalie Texier, Philippe Laplaige

      • Abstract
      • Slides

      Introduction

      G-CSF are recommended to prevent febrile neutropenia (FN) in high risk (FN>20%) chemotherapy treatments. When the FN risk is 10-20%, assessment of patient and disease characteristics is necessary. Exploring physicians’ preferences on their use of G-CSF would help to understand what determines their choices.

      Methods

      We use a Discrete Choice Experiment (DCE) method, in a national sample of oncologists to elicit their preferences in term of G-CSF use. The most relevant attributes and their levels were determined with a multidisciplinary expert committee and comprised injection site pain, bone pain, Influenza-like illness (ILI), fever, residual risk of FN with G-CSF, biosimilar use, injections number and cost per cycle. Eight scenarios were completed per participant for primary and secondary prophylaxis. A mixed-effect logit model estimated the preferences.

      Results

      Two hundred and five participants: male, 61%, with ≤10- (40.5%), 11-20 (36.1%), ≥21 (23.4%) years of experience in oncology and private (18%), public (73.2%) or mixed (8.8%) exercise.

      In primary prophylaxis, significant criteria mainly focused on the injection number per cycle (coef. 0.212, p<10-4) and the total cost per cycle (coef. 0.1139, p<10-4), before the safety profile (pain at the injection site as most avoided tolerance criterion, (coef. 0.0768, p<10-4)) and the efficacy (coef. 0.039, p=0.0152). The biosimilar profile is well-received (coef. 0.1446 p<10-4). In secondary prophylaxis, efficacy became a more significant criterion of preference in addition to other criteria (coef. 0.0939, p<10-4).

      Attributes

      Primary prophylaxis

      Secondary prophylaxis

      Coefficient

      p value

      Coefficient

      p value

      Risk of febrile neutropenia

      0.039

      0.0152

      0.0939

      <10-4

      Biosimilar

      0.1446

      <10-4

      0.1102

      <10-4

      Cost/ cycle (€)

      0.1139

      <10-4

      0.1056

      <10-4

      Injection number

      0.212

      <10-4

      0.1368

      <10-4

      Injection site pain

      0.0768

      <10-4

      0.0463

      0.0054

      Bone pain

      -0.0402

      0.0123

      -0.072

      <10-4

      Influenza-like illness (ILI)/ fever

      -0.0366

      0.0228

      -0.0512

      0.0021

      Log-Likelihood

      -2130.81

      -2246.5

      Participant number

      205

      205

      Conclusion

      In primary prophylaxis, physicians’ preferences for G-CSF are based on patients’ comfort and costs more than efficacy which comes into play in secondary prophylaxis. Use of a biosimilar is well accepted in both settings.

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      FP06.02 - Treatment Decision-Making and Decisional Support Experiences Among Lung Cancer Patients and Survivors (ID 3401)

      00:00 - 00:00  |  Presenting Author(s): Kelly Clark  |  Author(s): Elissa C. Kranzler, Erica E. Fortune, Melissa F. Miller, Jemeille Ackourey, Linda Bohannon, Heather Badt, Corey J. Langer, Alexandra K. Zaleta

      • Abstract
      • Presentation
      • Slides

      Introduction

      With recent advances in early detection of lung cancer, biomarker testing, and personalized treatment planning, effective patient-provider communication is more important than ever for short- and long-term survivorship. Open communication between patients and clinicians about treatment options and cancer experience is a critical step toward collaborative treatment decision-making (TDM). We characterized lung cancer patient experiences regarding TDM and satisfaction with health care team (HCT) communication.

      Methods

      Eligible patients and survivors enrolled in Cancer Support Community’s online survey, the Cancer Experience Registry®. Survey items assessed participants’ knowledge about treatment options prior to decision-making, involvement in the TDM process, perceived preparation to discuss treatment options with their doctor, (response options for these three items: 0=Not at all to 4=Very much), and desire for additional support prior to treatment decision-making (Yes/No). Frequencies and correlations between these items and socio-demographic and clinical history measures were examined.

      Results

      Of 360 patients enrolled, 276 completed survey items pertinent to TDM. The sample was 67% female and 86% White. Mean age was 61.8 years (SD=10.9). 61% reported an annual household income of <$60,000; 73% indicated at least some college. 82% reported NSCLC and 19% had SCLC; mean time since diagnosis was 3 years (SD=5.1). 23% experienced a recurrence, and 39% were ever metastatic. 76% received chemotherapy, 28% immunotherapy, and 58% reported current treatment. 67% of participants reported they were quite a bit or very much involved in their TDM process; only 34% indicated they were quite a bit or very much knowledgeable about treatment options prior to TDM. 38% would have liked more support prior to TDM; only 40% indicated they felt quite a bit or very much prepared to discuss treatment options with their doctor. Preparation to discuss treatment options was correlated with greater knowledge about treatment options (r=.51, p<.001) and involvement in the TDM process (r=.52, p<.001). Higher income was correlated with greater preparation (r=.24, p<.01), knowledge (r=.27, p<.01) and involvement (r=.19, p<.01), and higher education was correlated with greater knowledge (r=.13, p<.05). Females reported greater preparation than males (t=2.69, p<.01). There were no significant differences in TDM by age, race, or lung cancer type.

      Conclusion

      Though most lung cancer patients and survivors reported considerable involvement in TDM, half as many reported high levels of knowledge about treatment options prior to TDM. Relatively few felt prepared to discuss treatment options with their doctor and many indicated a desire for additional support prior to TDM. Individuals with less education reported less TDM knowledge, and those with less income reported less TDM knowledge, preparation and involvement, suggesting that individuals with lower income may have less access to TDM resources compared to their economically advantaged counterparts. Results suggest involvement alone is insufficient for an informed TDM experience, and highlight a need for additional resources (e.g., TDM guides, in-person counseling) to enhance HCT communication surrounding TDM for individuals with lung cancer, particularly for economically disadvantaged individuals. Such efforts may provide patients better knowledge about treatment options, thus enhancing their preparation to discuss and select the appropriate treatment pathway.

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      FP06.03 - Treatment Past Progression with Second Line Nivolumab in Advanced Stage NSCLC (ID 1897)

      00:00 - 00:00  |  Presenting Author(s): Zamzam Salam Al-Hashami

      • Abstract
      • Slides

      Introduction

      Nivolumab is an accepted second line therapy in NSCLC regardless of PDL1 status. This retrospective study aims at evaluating the outcome of patients who were treated past progression with second line nivolumab in advanced NSCLC in British Columbia.

      Methods

      All patients with metastatic NSCLC referred to BC Cancer who received nivolumab in the second line setting were included in the study. Baseline characteristics, treatments and outcomes were collected retrospectively. Treatment response was assessed using RECIST 1.1.Treatment Past Progression (TPP) was defined as patients who had RECIST 1.1 radiological progression but continued on therapy. Pseudo-progression was defined as patients who experienced a response after progression. OS was calculated from the start of nivolumab therapy using the Kaplan-Meier method and compared using the log-rank test. Multivariate and univariate analysis for OS conducted using Cox regression.

      Results

      138 patients were treated with second line nivolumab. Baseline characteristics: median age 66 years, 52% male, 54% ECOG of 0-1, 62% non-squamous histology, 24% PD-L1<1%/24% PD-L1>1%/52% unknown. Best response: CR 1%, PR 13%, SD 26%, 36% PD and 24% unknown. 29/138 (21%) were treated past progression of which 4/21 (3%) had pseudo-progression, 14/21 (10%) had oligoprogression and 11/21 (8%) were treated for other resasons as per physician discretion. OS in patients who had TPP and received >5 cycles prior to progression had superior survival (20.5 months , HR 0.37) compared to patients who had TPP and received <5 prior to progression (6.0 months, HR 0.9) and to patients who did not have TPP 4.8 months (reference).

      In the univariate analysis, ECOG, best response, treatment past progression (TPP) and pattern of progression had a significant impact on OS (Table 1). On multivariate analysis, poor ECOG and SD or PD compared to CR/PR and pattern of progression were associated with a higher risk of death.

      Variables

      Univariate analysis

      Multivariate analysis

      HR (95% CI)

      p value

      HR (95% CI)

      p value

      Age

      0.98 (0.96-1.01)

      0.34

      Sex

      Female vs male

      1.47 (0.99-2.20)

      0.53

      Histology (vs non-squamous)

      Squamous

      NOS

      1.02 (0.63-1.65)

      0.83 (0.47-1.46)

      0.93

      0.52

      ECOG PS (vs 0-1)

      ≥ 2

      Unknown

      4.86 (3.11-7.59)

      2.4 (1.31-4.42)

      <0.001

      0.05

      2.77 (1.68-4.58)

      1.88 (0.99-3.57)

      <0.001

      0.052

      PD-L1 status (vs <1%)

      >1%

      Unknown

      0.69 (0.39-1.21)

      0.72 (0.45-1.16)

      0.20

      0.18

      Best response (vs CR/PR)

      SD

      PD

      Unknown

      5.79 (1.34-24.95)

      26.43 (6.33-110.34)

      72.61 (16.98-310.84)

      0.02

      <0.001

      <0.001

      4.88 (1.08-22.11)

      12.73 (2.51-64.62)

      9.43 (1.53-58.26)

      0.04

      0.002

      0.02

      Pattern of progression (vs no PD)

      Oligo-progression

      Multi-site progression

      New lesions only

      Unknown

      2.51 (0.82-7.66)

      9.67 (3.80-24.61)

      25.16 (9.59-66.04)

      8.56 (2.29-31.93)

      0.11

      <0.001

      <0.001

      0.001

      3.08 (0.87-10.87)

      3.71 (1.15-11.97)

      10.31 (1.97-54.00)

      6.37 (1.30-31.21)

      0.08

      0.03

      0.01

      0.02

      Treatment past progression (vs no treatment past progression)

      0.53 (0.32-0.87)

      0.010

      0.56 (0.29-1.08)

      0.08

      Conclusion

      In this cohort of second line NSCLC treated with nivolumab 21% of patients were treated past radiographic progression: 3% appropriately for pseudo-progression, 10% was for oligopregression. In patients who demonstrate early progression and receive ongoing nivolumab OS outcomes are similar to patients who are not treated past progression. In patients who demonstrate late progression and receive ongoing nivolumab OS outcomes are superior to patients who are not treated past progression. Given the rarity of pseudoprogression across tumor types (< 10%), continuation of treatment past progression (TPP) should be considered only in carefully selected patients whose clinical conditions have improved and who have not experienced severe toxicities.

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      FP06.04 - Psychological Distress in Outpatients with Lymphoma, Lung and Breast Cancer During COVID-19 Pandemic (ID 3676)

      00:00 - 00:00  |  Presenting Author(s): Domenico Galetta  |  Author(s): Annamaria Catino, Daniela Bafunno, Claudia Cormio, Francesca Romito, Carla Minoia, Giacomo Loseto, Miriam Dellino, Giusi Opinto, Erica Silvestris, Attilio Guarini, Francesco Giotta, Agnese Latorre, Michele Montrone, Pamela Pizzutilo, Vito Longo, Angelica Mastrandrea, Donata Ricci, Francesco Pesola

      • Abstract
      • Presentation
      • Slides

      Introduction

      The psychological impact of the lockdown experienced during the COVID-19 pandemic has been found detrimental for the general population, but it has still not been evaluated in cancer patients. We have investigated the psychological status of outpatients receiving anti-neoplastic treatmentduring the lockdown in a non-COVID Cancer Center, with the following aims: to measure the levels of post-traumatic stress symptoms, depression and anxiety, to compare patients with different diagnosis. A further objective was to compare the anxiety and depression levels between cancer patients before and after the emergency assuming an increase in distress in cancer patients in this period due to the health emergency.

      Methods

      Outpatients attending the IRCCS "Giovanni Paolo II" in Bari for their therapy were asked to complete these questionnaires: The Hospital Anxiety and Depression Scale (HADs) and the Impact of Event Scale-Revised (IES-r).Worries regarding the COVID-19 on patients’ lives, socio-demographic and clinical details were investigated using a brief structured questionnaire.

      Results

      One-hundred seventy-six outpatients (n.59 with lung cancer, n.40 with breast cancer, n.77 with lymphoma) were enrolled. Mean age was 57.9 y.o. (SD ±14); 48% were male. We found that 54,4% of patients were above the cut-off (score≥16) for HADS general scale. The mean-IES-R score of patients was 25 (SD±17), with 22.8% indicating severe level of PTDS. The HADS-D has been found significantly correlated with IES-R (r= 0.35; p<0.005). The 70% of patients declared that their worries have increased during the pandemic; their bigger concerns were: the risk of getting infected while at hospital (51.4%); the risk of infecting relatives coming back home (38.7%), andthe risk of delaying therapy (35.3%).When comparing the level of anxiety and depression in different diagnosis it has been found that patients with lung cancer have higher distress(HADs-general scale) than patients with lymphoma (F=17.3, p<0.005) and breast cancer (F=8.86, p<0.005). Finally, cancer patients who experienced the health emergency showed higher levels of anxiety Hads-A, t (237) = 3.73 p<0.001), and general distress (Hads-G, t (237) = 2.51) than those measured 2 years ago (fig 1).

      Conclusion

      This study focused on the psychological aspects of cancer patients during the COVID-19 pandemic, finding that one quarter of patients has severe post-traumatic stress symptoms, and has psychological distress. Patients with lung cancer have higher distress compared to the other groups. This condition risks being overlooked by clinical concerns, so we underline the importance to place even more attention to the psychological needs of patients.

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    FP07 - Pathology (ID 109)

    • Event: WCLC 2020
    • Type: Posters (Featured)
    • Track: Pathology, Molecular Pathology and Diagnostic Biomarkers
    • Presentations: 17
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
    • +

      FP07.01 - Dysbiosis of Gut Microbiota Suppress the Brain Metastasis of Non-Small Cell Lung Cancer (ID 1501)

      00:00 - 00:00  |  Presenting Author(s): Xiaorong Dong  |  Author(s): huanhuan Li, jiaojaio Wang, hao Zeng, yawen Bin, fan Tong

      • Abstract
      • Slides

      Introduction

      Brain metastasis (BM) is associated with poor prognosis in patients with advanced non-small cell lung cancer (NSCLC), gut microbiota have been reported involved in the development of NSCLC. However, the impact of the gut microbiota on BM of NSCLC is still vague to date. This study aimed to explore the potential mechanism of gut microbiota dysbiosis on BM of NSCLC.

      Methods

      We collected 85 fecal samples from NSCLC patients with or without BM, and performed 16S rRNA gene sequencing. Conventional C57BL/6 mice were treated with an antibiotic cocktail to deplete the gut microbiota. The effects of gut microbiota dysbiosis was investigated in vivo by using NSCLC BM mouse models.

      Results

      There are no obvious difference in the microbial diversity and composition between NSCLC patients with BM (BM+, n=25) and without BM group (BM-, n=60). However, several differentially abundant genera were identified between subject groups by LEfSe analysis and Wilcoxon rank-sum test. Blautia, the genus implicated in central nervous system disorder, significantly decreased in BM+ group comparing to BM- group. Furthermore, the tumor burden significantly reduced in antibiotics-treated BM mice model, along with increased microglia cells by flow cytometry analysis. Remarkably, fecal bacteria transplantation (FMT) reduced gut microbial dysbiosis, partially attenuate the antibiotic-mediated tumor inhibition.

      Conclusion

      These results indicate that gut microbiota dysbiosis modulate BM of NSCLC, and Blautia, was putative microbial biomarkers that exclusively associated with BM. Mice experiments suggest that gut microbial dysbiosis inhibit BM by increasing the number of microglia. FMT suggest that BM inhibition mediated by gut microbial disorder is weakened by restoring normal microbiota, and warrant further research on the function of microglia.

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      FP07.02 - Deep Learning Based Analysis of Multiplex IHC Accurately Interprets PD-L1 and Provides Prognostic Information in NSCLC (ID 1044)

      00:00 - 00:00  |  Presenting Author(s): Alexander Haragan  |  Author(s): Katharina Nekolla, Ansh Kapil, Nicolas Brieu, Moritz Widmaier, Alexei Budco, Ivan Kanchev, Marco Testori Testori, Jessica Chan, Katrin Schneider, Ana Hidalgo Sastre, Monika Baehner, Günter Schmidt, John K Field, Michael PA Davies, John R Gosney

      • Abstract
      • Slides

      Introduction

      Most assessment of PD-L1 expression by immunochemistry to guide immuno-modulatory (IM) therapy in non-small cell lung cancer (NSCLC) requires only tumour cells to be scored, the so-called ‘tumour proportion score’ (TPS). This narrow approach ignores what is almost certainly crucial information within the tumour microenvironment (TME), particularly the nature and distribution of tumour infiltrating lymphocytes (TILs). Such features of the TME are underutilised in the clinical setting and are strong candidates for improving the predictive power of PD-L1 assessment alone. We describe a novel approach to analysing the TME in this context.

      Methods

      Consecutive whole slide sections from 92 resected NSCLCs were stained with H&E and immunolabelled for PD-L1 alone using the SP263 clone (monoplex), PD-L1 using the SP142 clone, CD68 and CD3 (triplex), and FoxP3, PD-1 and CD8 (triplex). Monoplex PD-L1 expression was scored by two pathologists to generate a consensus TPS score and categorised as negative, weak or strong expression; <1%, 1-49% and ≥50% TPS respectively. An existing deep-learning based PD-L1 solution was used to automatically score PD-L1 TPS. For the triplex images, densities of ‘positive’ cells were computed automatically using assay-specific deep learning algorithms, with a separate deep learning algorithm used to segment epithelial regions. The density of PD-L1+ve/CD3-ve/CD68-ve cells was used as a surrogate PD-L1 TPS with 33rd and 66th quartiles defining clinical group categorisation. Survival data were used in Kaplan-Meier survival analysis of groups divided by PD-L1 expression and immune cell densities.

      Results

      TPS scores as a continuous variable correlated well between pathologist assessment and both monoplex (Pearson correlation coefficient 0.977) and triplex (Pearson CC 0.849) assessments. Automated interpretation via triplex was similar to monoplex for grouping samples by dichotomous division at a 50% cut-off (91.2% vs. 94.6% of cases) and for placement into clinically relevant categories (79.1%, Cohen’s kappa coefficient Κ = 0.687 vs. 85.9%, K = 0.786). Sub-group analysis of tumours divided by the median for each variable into ‘high’ or ‘low’ revealed no significant difference in overall survival (OS) when stratified by CD3, FoxP3, PD-1 or CD68. However, high CD8+ve TIL densities and strong PD-L1 expression both correlated with improved OS (56 vs. 39 months, p=0.028; 60 vs. 41 months, p=0.035 respectively). In addition, tumours with a PD-L1 high/CD8+ve high profile showed significantly better OS than those assessed as PD-L1 low/CD8+ve (57 vs. 36 months, p=0.019).

      Conclusion

      Automated, deep-learning based, algorithmic scoring of PD-L1 expression is a valid and accurate approach to its assessment, and utilising triplex data provides important prognostic information. Discrepancies between monoplex and triplex assessment might be attributed to the different anti-PD-L1 antibody clones used, but the automated nature of triplex that excludes macrophages and TILs still performs very well. Our study shows the power of using this approach to augment the power of PD-L1 expression alone as a predictor of response to IM therapy and to provide prognostic information.

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      FP07.03 - Landscape Heterogeneity of PD-L1 Expression and Immune Cells Predicts Prognosis of Metastatic Non-Small Cell Lung Cancer (ID 878)

      00:00 - 00:00  |  Presenting Author(s): Dong-Mei Lin  |  Author(s): Jianghua Wu, Wei Sun, Xin Yang, Haiyue Wang, Xinying Liu, Kaiwen Chi, Lixin Zhou, Xiaozheng Huang, Shuai Zhao, Tingting Ding, Bin Meng

      • Abstract
      • Presentation
      • Slides

      Introduction

      Immune microenvironment evolution may occur during tumor progression. The purpose of this study is to quantitatively access the heterogeneity and its significance of PD-L1 expression and immune cells (ICs) during the metastatic progression of non-small cell lung cancer (NSCLC).

      Methods

      Matched 64 resected specimens of paired primary tumors (PTs) and metastatic tumors (MTs) were obtained from 28 NSCLC patients. PD-L1 co-expression on tumor cells (TCs) and ICs (CD8+ cytotoxic T cells and CD68+ macrophages) as well as the density and spatial distance of ICs were analyzed by DNA-tagged multiplex staining on whole sections using HALO@ platform. The prognostic significance of the heterogeneity between MTs and corresponding PTs were concerned.

      Results

      Heterogeneity in the tumor proportion score (TPS) of PD-L1 expression on TCs, density of ICs, and spatial distance between ICs and TCs was observed between MTs and PTs. Importantly, subgroup analysis showed that significant discrepancies of TPS and ICs between MTs and PTs were associated with treatment (Figure 1). It was also novelty found that the alterations in PD-L1 expression on ICs during metastasis were closely associated with overall survival (OS) in NSCLC. Compared to corresponding PTs, an increase in TPS on MTs was slightly related to poor prognosis, while an increase in the density of PD-L1+ ICs and decrease in spatial distance between PD-L1+/CD8+ T cells and TCs was significantly correlated with prolonged OS as a positive immune response (Figure 2).

      Figure 1. Represented multiplex figures and quantitative analysis of the heterogeneity between MTs and PTs, Wilcoxon-signed-rank-test.

      figure 1.png

      Figure 2. The change status of PD-L1 expression and ICs on MTs compared to corresponding PTs was closely related with overall survival (OS).

      figure 2.png

      Conclusion

      Landscape of PD-L1 expression and ICs in MT and corresponding PT to highlight the change status of immune microenvironment predicts prognosis of metastatic NSCLC.

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      FP07.04 - Predictive Efficacy of Morphological Biomarkers Based on Digital Pathology for ICI Therapy of Non-Small Cell Lung Cancer (ID 3436)

      00:00 - 00:00  |  Presenting Author(s): Noriko Motoi  |  Author(s): Hiroshi Yoshida, Tomoharu Kiyuna, Hiroyasu Saiga, Hidehito Horinouchi, Tatsuya Yoshida, Shun-ichi Watanabe, Yuichiro Ohe, Atsushi Ochiai

      • Abstract
      • Slides

      Introduction

      PD-L1 IHC is a widely used biomarker for immune checkpoint inhibitor therapy (ICI), but it does not have high specificity. It is essential to establish more accurate biomarkers for modern medicine. Our previous preliminary study (presented at 2019 WCLC) indicated the morphological feature's substantial value as a biomarker for ICI therapy. The morphological biomarkers (MBM) using digital whole-slide images can be tested from archived FFPE specimens. Here, we report our study on the prediction potency of morphological biomarkers for lung cancer patients treated by anti-PD1 inhibitors.

      Methods

      255 NSCLC who received ICI therapy were recruited. Digital images of H&E and PD-L1 (22C3) IHC stained slides of pre-treatment biopsied or resected materials were examined by previously reported image analysis techniques (NEC, Japan). The morphological characteristics of cancer cells were also evaluated by the pathologist's eyeball (PPI, pathological prediction index score 1-3). PD-L1 IHC (22C3) and tumor mutation burden (TMB) by the NGS-based target sequence (NCC oncopanel ®) were examined. Using morphological characteristics of HE images, we build a prediction model using the decision tree method (MBM-DT) first, then applied a deep learning framework (MBM-DNN) to response prediction. We compared the prediction potency for the ICI-therapeutic response of each score. The relative area proportion of the seven-index spider plot using test quality indicators was measured. The logistic regression test was calculated (SPSS). A p-value of less than 0.05 was defined as statistically significant.

      Results
      Pathological prediction index (PPI) scores showed superior prediction ability to that of the PD-L1 test. The accuracy of PPI-score 3, PPI-score 2+3, PD-L1 with 1% cutoff (PD-L1-1%), PD-L1 with 50% cutoff (PD-L1-50%), TMB-high, and driver gene mutation-negative was 0.71, 0.64, 0.60, 0.66, 0.57 and 0.57, respectively. MBM_DNN had the highest accuracy, specificity, positive prediction value (PPV), and the lowest false-negative rate (FNR) among the tested biomarkers. PPI-(2+3) had the highest sensitivity and negative prediction value (NPV), and false-negative rate (FNR). The seven-index spider plot showed the superiority of PPI-score 3, PPI-score 2+3 to PD-L1. Both PPI and MBM showed superior accuracy to PD-L1, TMB, and gene mutation status. The area proportion of seven test-index spider plots was 50, 56, 45 for PPI-score 3, MBM_DNN, and PD-L1-50%. Accuracy of training, validation, and a test set of MBM-DNN resulted in 0.85, 0.61, and 0.64, respectively. The logistic regression analysis revealed that males, smokers, the absence of driver gene mutation, positive/high expression of PD-L1, high PPI-score, the positive MBM-DNN, and MBM-DT are likely to be non-responder by univariate analysis. PPI-score 2+3(0.31, <0.001), MBM-DNN (0.23, <0.001), and MBM-DT (0.32, <0.001) are the significant factors for prediction of ICI response, but others are not by multivariate analysis. Conclusion
      Our results showed the superior value of the morphological biomarker for ICI response prediction, compared to PD-L1 IHC and TMB. The morphological biomarker can be a useful biomarker for clinical therapeutic decisions.

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      FP07.05 - An Optimized Neoantigen Load Model Based on Immune Editing to Predict Response and Prognosis of Immune Checkpoint Therapy (ID 1776)

      00:00 - 00:00  |  Presenting Author(s): Haoxuan Jin  |  Author(s): Longyun Chen, Haoxuan Jin, Xiaofan Su, Zhobo Gao

      • Abstract
      • Presentation
      • Slides

      Introduction

      Only a minority of patients achieve clinical benefit from immune checkpoint therapy, how to distinguish responders and non-responders is still far from clearly understood. Recent studies have identified neoantigen reactive T cells in multiple tumors, such as non-small-cell lung cancer (NSCLC), melanoma and intrahepatic cholangiocarcinoma (ICC), and highlight their role of determining the responsiveness to immunotherapy. However, almost all the researches are focused on total neoantigen load at present, which predict immune response or prognosis only in small subset of tumors. Therefore, it is necessary to optimize the neoantigen load calculation to better predict clinical outcome of immune checkpoint therapy.

      Methods

      Tumor neoantigen load (oTNL) was optimized by counting neoantigen load selected from tumor clones which had ability of inducing immune elimination. We used a published method to quantify the DNA immune editing status for tumor clones, the number of neoantigen in the observed was lower than expected (immune editing score < 1) in a clone, suggesting immune-mediated elimination, and then neoantigen load was calculated. Tumor clonal architecture was calculated by PyClone. Three cohorts of immunotherapy-treated patients were collected from published and our own cohort. Clinical outcome including response and survival were compared between groups divided by oTNL score.

      Results

      We applied oTNL to three tumor immunotherapy cohorts, including 65 cases of NSCLC treated with anti-PD-1/PD-L1, 30 cases of melanoma treated with anti-PD-1 and 15 cases of ICC treated with anti-PD-1 plus lenvatinib. In the NSCLC cohort, the oTNL score of patients with durable clinical benefit (DCB, CR/PR/SD>6 month) was higher than those with non-durable clinical benefit (NDB, SD<6 month/PD) (median 62.62 vs 15.77, p = 0.025). The cut point of oTNL score was set at combined maximal sensitivity with best specificity. The DCB rate in oTNL-high patients was 55.00% versus 17.39% in oTNL-low patients (p = 0.0032). Progression-free survival (PFS) in patients with oTNL-high was longer than those with oTNL-low (median 146 vs 62 days, p = 0.00091). In the melanoma cohort, it was found that patients in oTNL-high group had higher objective response rate (ORR, CR/PR) than those in oTNL-low group (58.33% vs 5.56%, p = 0.026); the overall survival was longer (median 121 vs 39 weeks, p = 0.0062). Analysis of ICC cohort showed that longer PFS was also observed in oTNL-high group (median 7 vs 3.5 months, p = 0.023). For comparison, we also analyzed the correlation between total neoantigen load and clinical outcomes of three cohorts, but found no significant correlations.

      Conclusion

      It has been previously reported that tumor clones with neoantigen have immunogenicity and thus eliminated by T-cell-mediated immune editing. Moreover, genetic evidence of immune editing in lung cancer shows neoantigen may induce multiple routes to immune escape and affect tumor evolution. Therefore, not every neoantigen could induce immune elimination. Identifying neoantigen clones with the ability of inducing immune elimination would help to better predict the efficacy of immunotherapy. Our new optimized mathematical model could predict the response and prognosis of patients with lung cancer, melanoma and intrahepatic cholangiocarcinoma, and have better predicting value than prior's genetic method.

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      • Abstract
      • Presentation
      • Slides

      Introduction

      The Lung Immune Prognostic Index (LIPI) that combines the neutrophils/[leucocytes minus neutrophils] ratio (dNLR) and lactate dehydrogenase (LDH), is associated with outcomes in pretreated advanced NSCLC patients receiving single agent immune checkpoint inhibitors (ICI). However, its role in first line treatment of advanced NSCLC patients has not been explored yet. We assessed the value of baseline LIPI in the first line setting, for ICI-monotherapy, ICI-combination or platinum-based chemotherapy alone (CT).

      Methods

      We retrospectively collected data of patients treated with first-line ICI between 2016 and 2019 as single agent if PD-L1 ≥50% (ICI-cohort), or in combination with a CTLA4-inhibitor (ICI+ICI cohort), or with chemotherapy (ICI+CT cohort), from 18 centers worldwide. A control cohort of patients treated with platinum-based CT (CT-cohort) was also collected between 2011 and 2019 from 2 centers. Baseline LIPI was calculated as previously reported and correlated with overall survival (OS) and progression-free survival (PFS) in each treatment cohort.

      Results

      Overall, 930 patients were enrolled, 561 in the ICI-cohort, 186 in the combo ICI+CT, 55 in the ICI+ICI and 128 in the CT-cohort. Median (m) follow-up was 12.5 months. In the whole cohort, median age was 66 years, 70% male, 80% had non-squamous histology, and 84% had PS ≤1. Based on LIPI (available for 792 patients): 305 (38%) were considered good, 331 (42%) intermediate and 156 (20%) poor group.

      Treatment outcomes according to LIPI scores are depicted in Table 1. The LIPI poor population had significantly worse OS compared with other LIPI groups, in the whole cohort (P<0.001) as well as in the ICI monotherapy and combo ICI+CT cohorts (both P<0.0001); and in the CT cohort (P=0.004). In term of PFS, we observed correlation between LIPI groups and outcomes in the whole cohort (P<0.001) and in the ICI- monotherapy cohort (P=0.008); however, no differences were observed in the cohorts of patients receiving chemotherapy regimens, alone (P=0.08) or combined with ICI (P=0.08). The analysis by PD-L1 expression in 756 patients with available data will be presented in the Congress.

      Table 1: Median OS and PFS according to LIPI subgroups. NR = non reached.

      Outcomes

      LIPI

      subgroups

      Overall cohort

      N= 925

      ICI-cohort

      N=558

      ICI + CT-cohort

      N= 185

      ICI + ICI cohort

      N= 55

      CT-cohort

      N=127

      Median OS

      (95% CI)

      All

      16.3 (14.7-18.8)

      21.0 (17.1-NR)

      24.7 (16.9-27.1)

      20.5 (14.1-NR)

      9.79 (8.3-14.4)

      LIPI good, 38.5%

      19.8 (17.2-25.7)

      NR (NR-NR)

      25.7 (25.6-NR)

      33.6 (14.7-NR)

      14.42 (8.9-17.9)

      LIPI interm, 41.8%

      15.8 (14.3-20.3)

      21.2 (17.1-NR)

      20.3 (12.8-NR)

      14.6 (5.5-NR)

      9.30 (7.0-14.5)

      LIPI poor, 19.7%

      6.96 (5.6-12.5)

      8.5 (3.4-13.7)

      6.1 (4.9-NR)

      14.1 (10.3-NR)

      6.1 (5.0-NR)

      Global LogRank P value

      <0.0001

      <0.0001

      <0.0001

      0.4

      0.004

      Overall cohort

      N= 909

      ICI-cohort

      N=543

      ICI + CT-cohort

      N= 185

      ICI + ICI cohort

      N= 54

      CT-cohort

      N=127

      Median PFS

      (95% CI)

      All

      6.5 (5.9-7.1)

      6.3 (5.0-7.6)

      8.9 (6.80-10.9)

      7.2 (5.7-30.6)

      5.7 (5.3-6.4)

      LIPI good, 38.7%

      7.0 (5.9-8.5)

      6.4 (4.5-10.8)

      9.8 (7.8-13.0)

      9.2 (5.7-NR)

      6.0 (5.3-7.8)

      LIPI interm, 41.6%

      6.6 (6.1-7.6)

      6.6 (5.6-8.1)

      10.4 (6.4-12.4)

      5.5 (2.5-NR)

      6.1 (4.3-7.6)

      LIPI poor, 19.7%

      3.6 (3.1-5.6)

      3.3 (1.9-6.7)

      4.5 (2.8-8.2)

      7.1 (2.56- NR)

      3.7 (3.4-NR)

      Global LogRank P value

      <0.0001

      0.008

      0.08

      0.4

      0.08

      Conclusion

      Pretreatment LIPI was prognostic in untreated advanced NSCLC patients regardless of the type of therapy. However, LIPI was associated with PFS only in patients receiving ICI-monotherapy, with no statistically significant differences in CT-containing cohorts (alone or combined with ICI). This value of LIPI to guide treatment selection should be further explored in prospective studies.

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      FP07.07 - Value of the Lung Immune Prognostic Index (LIPI) As a Prognostic Tool for Real-World Patients Treated for Mutation-Positive Metastatic NSCLC (ID 3683)

      00:00 - 00:00  |  Presenting Author(s): Amanda Jane Williams Gibson  |  Author(s): Anifat Elegbede, Michelle Dean, Roxana Tudor, Adrian Box, Igor Stukalin, Daniel E. Meyers, D Gwyn Bebb

      • Abstract
      • Presentation
      • Slides

      Introduction

      LIPI is a prognostic index which has demonstrated strong utility in metastatic NSCLC (mNSCLC) patients when treated with immune checkpoint inhibitors (ICIs). Recent pooled analysis using clinical trial data suggests that LIPI scores may also be prognostic of outcome in patients with mNSCLC treated with non-ICI systemic therapies such as tyrosine kinase inhibitors (TKIs) and cytotoxic chemotherapy (CTx).

      Recognizing both the increasing number of patients with mNSCLC who possess mutation-positive tumours and the potential differences between clinical trial and real-world patient populations, we sought to explore the prognostic ability of the LIPI among real-world mutation-positive mNSCLC patients in receipt of palliative-intent systemic therapy.

      Methods

      Alberta patients diagnosed 2015-2019 with mutation-positive (KRAS, ROS1, EGFR or ALK) mNSCLC, in receipt of palliative-intent first-line TKI, CTx or ICI systemic therapy were identified. Demographic, clinical, treatment and outcome data were extracted from the institutional Glans-Look Lung Cancer Database. LIPI scores were calculated using blood component values taken ≤30 days prior to first-line systemic therapy initiation. Kaplan-Meier analysis assessed the impact of LIPI score on progression-free survival (PFS) and overall survival (OS), and Cox Proportional Hazards models were constructed to control for potential confounders and identify factors which had prognostic value.

      Results

      158 patients were identified (Table 1):

      lipi impact_table1.jpg

      Survival analysis revealed that LIPI was not significantly associated with outcome (PFS and OS) in the pooled cohort or by individual mutation, and only showed an association with outcome among the cohort of ICI-treated patients (all PD-L1 > 50%) where a previously established inverse relationship between LIPI score and median PFS/OS has been previously observed. ECOG was revealed to have better association with outcome, whereby ‘good’ ECOG (0 or 1) patients, when compared to ‘poor’ ECOG (2+) experienced significantly longer PFS (19.2 vs. 11.4 months p<0.001) and OS (34.4 vs. 12.1 months, p<0.001) in the pooled cohort, with this similar pattern observed within the ALK, EGFR and KRAS mutant populations.

      A Cox proportional hazards model, constructed for the pooled cohort and controlling for known confounders (age, sex, treatment, smoking history and mutation type) revealed that poor ECOG is prognostic of reduced PFS (HR: 3.6, p<0.001) and OS (HR: 3.6, p<0.001), while never-smoking history (HR: 0.26, p<0.001) and female sex (HR: 0.5, p=0.03) were prognostic of increased OS.

      Conclusion

      Among real-world mutation-positive mNSCLC, ECOG serves as a better prognosticator of outcome than LIPI score. The utility of LIPI in this population remains limited to those treated with ICI therapy.

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      FP07.08 - A Pan-Canadian Validation Study for the Detection of EGFR-T790M Mutations Using Circulating Tumour DNA (ctDNA) from Blood (ID 1294)

      00:00 - 00:00  |  Presenting Author(s): Shamini Selvarajah  |  Author(s): Sophie Plante, Marsha Speevak, Andrea Vaags, Elizabeth McCready, Daria Grafodatskaya, Normand Blais, Danh Tran-Thanh, Wenda Greer, Brian Lo, Douglas Demetrick, Bekim Sadikovic, Ryan Walton, Tracy Stockley, Harriet Feilotter, Philippe Joubert

      • Abstract
      • Presentation
      • Slides

      Introduction

      In advanced non-small cell lung cancer (NSCLC) patients with resistance to EGFR inhibitors, tumor genotyping to identify T790M resistance mutations is mandated. However, because of challenges such as tumour inaccessibility, tumour heterogeneity and patient morbidity, the measurement of circulating tumour DNA (ctDNA) in peripheral blood has emerged as a promising non-invasive clinical tool to detect this mutation. To facilitate standardization and clinical adoption of ctDNA testing across Canada, we developed a 2-phase multicentre RING study to standardize EGFR-T790M mutation detection using plasma ctDNA testing.

      Methods

      In Phase 1, commercially available cell-free DNA reference standards including a variety of clinically relevant variants were distributed to nine participating clinical molecular laboratories. Each site employed their existing platforms for mutation detection, including next generation sequencing (ThermoFisher Oncomine Lung cfDNA assay; Illumina TruSight Tumor 15 - TST15 panel), Bio-Rad digital droplet PCR, EntroGen ARMS-based ctEGFR mutation detection kit, Roche cobas EGFR mutation kit and the MassARRAY UltraSEEK Lung Panel). Baseline performance characteristics were established to ensure that the methods at each site were compatible with clinical application. Performance characteristics, including limit of detection, were further tested through distribution of blinded engineered plasma samples spiked with predetermined concentrations of T790M and L858R variants. Six of the labs proceeded to Phase II, where a series of blood samples, collected from local patients with known EGFR activating mutations progressing on treatment, were assayed for the presence of the primary mutation and the T790M variant. A blood sample was also sent out to the reference center using a clinically validated test (ddPCR, Bio-Rad). Blinded results were reported to a central repository to assess the concordance between the results.

      Results

      All labs in Phase I detected variants (T790M, L858R, Ex19 deletion alone or T790M/L858R) at allele frequencies of 0.5% and 5.0%. Four labs also reported detection of some variants at 0.05%. For the blinded samples, all labs identified the T790M and T790M/L858R variants at 0.5% and 5.0% (100% concordance). No false positives were reported for the EGFR wild type control.

      Six labs proceeded to Phase II using local patient-derived samples with the Cobas (Lab1), EntroGen (Labs 2, 4), NGS (Labs 3, 5) and ddPCR (Lab 6) platforms. The concordance between the reference and local labs for detection of both the sensitizing mutation and the resistance mutation was high, with NGS and ddPCR showing the best overall (~100%) concordance. The overall detection rate of T790M in this project was 22%. One lab using the EntroGen assay had lower concordance overall, but the other lab using the same kit had higher concordance, suggesting this could be a lab specific issue. These data suggest that the ability to detect EGFR resistance mutations at clinically relevant limits of detection is generally not only platform specific, but also impacted by lab specific practices.

      Conclusion

      These results indicate that the NGS and ddPCR platforms yielded the most concordant results for EGFR T790M detection in ctDNA when compared to a clinically validated reference lab. Discrepancies between sending labs using the same assay suggest that lab-specific factors may impact performance.

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      FP07.09 - Detection of Early Lung Cancer from Average-Risk Individuals and from Benign Nodule Carriers with a DNA Methylation Blood Test (ID 1845)

      00:00 - 00:00  |  Presenting Author(s): Baohui Han  |  Author(s): rong Qiao, rongxi Yang

      • Abstract

      Introduction

      Early detection is the key to reducing the death of lung cancer. An effective blood-based method for the early diagnosis of lung cancer has not yet been developed. Meanwhile, current strategies to differentiate benign and malignant lung nodules are also in lack of accuracy. Here we describe a blood test that can detect lung cancer early from average-risk individuals and from benign lung nodule carriers through assessment of a methylation panel of 8 genes in peripheral blood DNA.

      Methods

      Two independent retrospective studies were carried out to investigate the most distinguishable methylation loci among 38 candidate genes in peripheral blood DNA. All the blood was donated before surgery and before any cancer related treatment. The methylation levels of each CpG sites were semi-quantitatively measured by mass spectrometry.

      Results

      Out of the investigated 38 genes, 15 showed significant methylation difference between 161 lung cancer case (90.1% in Stage I) and matched 200 cancer free individuals in the discovery round. In the validation study, 8 genes had distinguishable methylation levels among 615 lung cancer case (92.2% in Stage I), 145 surgery confirmed benign lung nodule carriers, and 809 matched cancer free individuals. Taken together, for the average-risk individuals, when the specificity was 90%, the panel of 8 methylation genes had sensitivities around 70% for the detection of early stage lung cancer regardless of subtypes, stage and tumor size. Moreover, with the specificity of 90%, this panel had even higher sensitivities around 90% for the distinguishing benign lung nodule carriers from lung cancer, and this sensitivity was 83% for the very small nodules ≤1cm.

      Conclusion

      Together, these findings reveal in a large clinical cohort that the utility of DNA methylation markers in the peripheral blood for the effective early diagnosis of lung cancer even for the very small tumors ≤1cm.

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      FP07.10 - Circulating Tumor DNA Analysis in NSCLC with MET exon 14 Skipping Alterations (ID 3418)

      00:00 - 00:00  |  Presenting Author(s): Xiuning Le  |  Author(s): Lingzhi Hong, Haley Kemp, Jennifer Saam, Chuck Hensel, Victoria Raymond, Jianjun Zhang, John Heymach

      • Abstract
      • Slides

      Introduction

      MET exon 14 skipping alteration (METex14) is an established oncogene driver in non-small cell lung cancers (NSCLC). Small molecule inhibitors (crizotinib, tepotinib, capmatinib and savolitinib) have shown efficacy in this patient population. Circulating tumor DNA (ctDNA) is an effective approach to detect METex14, as utilized in the VISION trial, which showed comparable outcome to tissue biopsy in patients treated with tepotinib. Here, we present the mutation and co-mutation landscape of the METex14 NSCLC detected by ctDNA.

      Methods

      Guardant360® results (Guardant Health) from patients with a diagnosis of advanced lung cancer were retrospectively reviewed and treatment-naïve and previously treated patients were included. Each subject was counted once regardless of multiple ctDNA tests performed. METex14 was considered positive when a deletion or non-synonymous mutation flanking exon 14 of MET was identified.

      Results

      A total of 345 lung cancer patients with METex14 were identified, including adenocarcinoma (79.1%), squamous cell carcinoma (9.8%), NSCLC NOS (7.8%), small-cell lung cancer (2%), and large-cell lung cancer (1.2%). The median age was 77 (range: 41-94) years, and 59% were female. The prevalence by functional sites were: 5’ splice donor site (45.8%), 3’ splice acceptor site (31.0%), D1010 splice mutation (18.3%), Y1003 – CBL mediated MET degradation (4.0%), others (0.9%). No significant gender differences were observed regarding the functional sites. The most frequent mutation type was base substitution (58.4%), followed by indel (41.6%). Whole-exon deletion was not found in this dataset (Table 1). The most frequent oncogene co-alterations included MET amplifications (9.0%), EGFR (7.2%) amplifications, KRAS mutation (6.9%, 15/24 subclonal), CDK4 (4.3%) amplifications and BRAF mutation (4.0%, 11/14 subclonal), while ALK-, ROS1-, RET-, and NTRK-fusions (1.4%) were uncommon. Additionally, TP53 mutations were detected in 53.8% of cases.

      Table 1. Functional site by mutation types of METex14 in lung cancer (N=345)
      n (%)
      Acceptor site 107 (31.0)
      Indel 96 (27.8)
      Base substitution 11 (3.2)
      Donor site 158 (45.8)
      Indel 46 (13.3)
      Base substitution 112 (32.5)
      Y1003 14 (4.0)
      Insertion 1 (0.3)
      Base substitution 13 (3.8)
      D1010 63 (18.3)
      Base substitution 63 (18.3)
      Others 3 (0.9)

      Conclusion

      In this real-world cohort of 345 cases of METex14-mutant NSCLC, detected using Guardant360, up to 21% were non-adenocarcinomas. The distribution of alterations of METex14 identified using liquid biopsy were similar to previously reported cohorts from tissue biopsies. Other driver oncogene alterations co-occur with METex14 at a low frequency.

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      FP07.11 - Circulating Tumor DNA (ctDNA) Clearance as a Biomarker in Patients With Locally Advanced NSCLC Following Chemoradiation (ID 1432)

      00:00 - 00:00  |  Presenting Author(s): Brendan James Knapp  |  Author(s): Laura Mezquita, Siddhartha Devarakonda, Mihaela Aldea, Saiama Waqar, Kymberlie Pepin, Jeffrey Ward, Angela Botticella, Karen Howarth, Charle Knape, Clive Morris, Ramaswamy Govindan, Benjamin Besse, Daniel Morgensztern

      • Abstract
      • Presentation
      • Slides

      Introduction

      Circulating tumor DNA (ctDNA) testing has the potential to identify patients at high risk for recurrence following completion of concurrent chemoradiation (CRT) for locally advanced non-small cell lung cancer (LANSCLC). The objective of this analysis is to examine the feasibility of ctDNA testing on a commercially available focused gene panel to predict outcomes in patients with LANSCLC.

      Methods

      A total of 43 patients were prospectively enrolled between 09/2017 and 10/2019. Plasma for ctDNA testing was collected at the time of CRT initiation (D1), CRT completion (V1), quarterly follow up appointments for 12 months (FU1, 2, 3 and 4 respectively) after CRT completion, and at the time of relapse (R). ctDNA analysis was performed using InVisionFirst®-Lung, to detect the presence of SNVs, indels and CNAs in 37 cancer-related genes. ctDNA clearance was defined as the absence of D1 variants at V1. Patients without detectable D1 variants or in whom V1 samples were not collected were excluded from this analysis.

      Results

      Nineteen of 43 patients (44%) had detectable variants at D1. In this cohort of 19 patients, the median age at diagnosis was 65 years (range 43 - 82), with the majority of patients being smokers (16/19, 84%). The stage distribution was as follows: IIA (5%), IIIA (37%), IIIB (52%) and IIIC (5%). Nine patients (47%) had squamous cell carcinoma, 7 (37%) had adenocarcinoma, and 3 (16%) had poorly differentiated or NSCLC NOS. A median of 2 mutations per sample (range 1 - 5) were detected with a median of mean allelic frequency (AF) of 0.53 (range 0.05 - 16.28) at D1. Mutations in TP53 were the most commonly detected (17/19, 89%) at D1, followed by mutations in PIK3CA (5/19, 26%), CDKN2A (4/19, 21%), and EGFR (3/19, 16%). Two patients died from non-cancer related causes before FU1 and were excluded from further analysis (1 cleared ctDNA, another did not). All (3/3) patients who did not clear ctDNA had tumor relapse with a median time to relapse of 74 days (30-238), while 50% (7/14) of those who cleared ctDNA have not relapsed after a median follow-up of 469 days (range 130-710). Median time to relapse in patients who cleared ctDNA was 217 days (range 53-587 days).

      Conclusion

      Our results demonstrate that it is feasible to employ ctDNA testing to identify LANSCLC patients who are at high risk for disease recurrence following CRT. This finding requires validation in future studies.

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      FP07.12 - Underdiagnosis of EGFR Exon 20 Insertion Mutation Variants: Estimates from NGS-based Real-World Datasets (ID 3399)

      00:00 - 00:00  |  Presenting Author(s): Joshua M. Bauml  |  Author(s): Santiago Viteri, Anna Minchom, Lyudmila Bazhenova, Sai-Hong Ignatius Ou, Michael Schaffer, Nicholas Le Croy, Ralph Riley, Parthiv Mahadevia, Nicolas Girard

      • Abstract
      • Presentation
      • Slides

      Introduction

      Exon 20 insertion mutations (Exon20ins) account for up to 10% of all mutations in epidermal growth factor receptor (EGFR) mutant non-small cell lung cancers (NSCLCs). Exon20ins specific drugs are in development. Because Exon20ins are molecularly heterogenous, the ability to identify the range of variants is dependent on the test methods used. Real-time polymerase chain reaction (PCR) and next-generation sequencing (NGS) are two molecular tests widely used to identify mutations in the EGFR. We analyzed real-world genomic data to determine the frequency of Exon20ins variants and to assess the ability of PCR and NGS to comprehensively identify them.

      Methods

      Two US-based genomic databases were utilized for this analysis. NGS data from US institutions were extracted from the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) database, version 8.5 (The AACR Project GENIE Consortium. Cancer Discov. 2017;7(8):818-831). The FoundationInsights™ database (Foundation Medicine, Cambridge, MA) was used to obtain EGFR Exon20ins variants in real-world NSCLC samples. Coverage of Exon20ins from commercially available PCR tests (therascreen® and cobas®) was obtained from their instructions for use.

      Results

      The GENIE database included 12,497 patients with NSCLC. A total of 2,316 patients with EGFR mutant lung adenocarcinoma were identified and of these patients, 175 (7.6%) harbored Exon20ins. A total of 40 unique Exon20ins variants were identified. Of the 9 most common Exon20ins variants (≥5 patients), only 4 would have been identified at the protein level using commercially available PCR tests. PCR tests would have identified only 89 (50.9%) of the 175 patients with Exon20ins identified by NGS (Figure). The FoundationInsights™ database included 627 patients with lung adenocarcinomas who harbored Exon20ins and identified 102 unique Exon20ins variants. Of the 17 most common variants (≥5 patients), only 4 would have been identified at the protein level with commercially available PCR tests. PCR tests would have identified just 305 (48.6%) of the 627 patients with Exon20ins identified by NGS (Figure).

      Conclusion

      PCR methods are projected to miss 50% or more of Exon20ins. Reliance on commercially available PCR kit methods may provide insufficient information to support appropriate decision-making for emergent Exon20ins-directed therapies. The large number of insertion variants suggests that NGS platforms, academic or commercially available, would also improve their detection rate by capturing the full breadth of variants that have been identified.

      genie and fmi figure for submission.jpg

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      FP07.13 - Clinical Characteristics and Outcomes in Patients With KRAS G12C Mutated Non-Small Cell Lung Cancer (ID 1415)

      00:00 - 00:00  |  Presenting Author(s): Bruna Pellini  |  Author(s): Vishwanath Ganesan, Fei Wan, Sumithra Sankararaman, Sorrapong Manyanont, Neal Akhave, Maria Baggstrom, Jeffrey Ward, Saiama N Waqar, Daniel Morgensztern, Ramaswamy Govindan, Siddhartha Devarakonda

      • Abstract
      • Slides

      Introduction

      KRAS oncogenic mutations are the most common driver alterations in non-small cell lung cancer (NSCLC). Among these, G12C mutations are the most frequently encountered and targetable with currently available investigational therapies. Understanding the clinical characteristics and outcomes in patients with G12C mutated NSCLC has the potential to inform clinical testing in resource limited settings and facilitate the study of novel combination therapies.

      Methods

      KRAS-mutant NSCLC patients treated at Washington University in St. Louis were retrospectively identified through review of commercial target hybrid-capture next generation sequencing (NGS) test results (plasma and tissue). Clinical and demographic information was collected from electronic medical records. Patients were categorized into two groups based on the KRAS mutation: G12C and non-G12C. Fisher’s exact test was used for comparing categorical variables and log-rank test was used to test for differences in survival, between these categories.

      Results

      A total of 169 patients with KRAS mutations were identified for this study. Nearly a third of patients were G12C mutated (n=64,37.6%) (Table 1). The majority of patients in both groups were diagnosed with stage IV disease (68.7% [G12C] and 72.9% [non-G12C]). PD-L1 (22C3 antibody) status was available in 43.7% of patients and PD-L1 status did not significantly differ between both categories (p=0.772). G12C mutations were observed in patients of all races and predominantly in smokers (96.9%). Apart from adenocarcinomas (92.2%), G12C mutations were also observed in large cell carcinomas (n=5), poorly differentiated carcinomas (n=3), NSCLC-NOS (n=1) and combined adenocarcinoma-small cell lung cancer (n=1). Pattern of metastasis at presentation did not differ between G12C and non-G12C patients. Overall, 28 KRAS mutated patients received immunotherapy as single agent or in combination with chemotherapy in the first-line setting (n=10 [G12C] and n=18 [non-G12C]). While no statistically significant difference in PFS and OS were found between these categories (median PFS 6.24 [G12C] vs 6.27 months [non-G12C], log rank p=0.899; median OS 21.0 [G12C] vs 21.8 months [non-G12C], log rank p=0.992), G12C mutated NSCLC was associated with a better PFS than non-G12C NSCLC (p=0.0384), when the analysis was restricted to patients achieving a durable response to immunotherapy (PFS>3.5 months, corresponding to first 4 cycles).

      TABLE 1. Patients Characteristics

      Characteristic

      KRAS G12C (n=64)

      Non-KRAS G12C (n=105)

      p-valuea

      Median Age (range)

      64.5 (47-89)

      63.0 (46-89)

      Gender, n (%)

      0.626

      Male

      22 (34.4)

      40 (38.1)

      Female

      42 (65.6)

      65 (61.9)

      Race, n (%)

      0.156

      Caucasian

      54 (84.4)

      82 (78.1)

      African American

      7 (10.9)

      22 (21.0)

      Asian

      2 (3.1)

      1 (1.0)

      Hispanic

      1 (1.6)

      0 (0)

      Smoking history, n (%)

      0.08

      Ever

      62 (96.9)

      94 (89.5)

      Never

      2 (3.1)

      11 (10.5)

      Histology, n (%)

      0.146

      Adenocarcinoma

      59 (92.2)

      83 (77.6)

      Squamous cell

      0 (0)

      6 (5.6)

      Large cell

      5 (8.0)

      18 (16.8)

      NSCLC-NOS

      3 (4.7)

      10 (9.5)

      Sarcomatoid

      0 (0)

      3 (2.9)

      Poorly differentiated carcinoma

      1 (1.6)

      0 (0)

      Adenosquamous

      0 (0)

      1 (1.0)

      NSCLC with NET differentiation

      0 (0)

      1 (1.0)

      Adenocarcinoma with SCLC component

      1 (1.6)

      0 (0)

      Carcinoma of the lung

      0 (0)

      1 (1.0)

      Clinical stage*, n (%)

      0.942

      I

      6 (9.3)

      8 (7.4)

      II

      4 (6.4)

      5 (4.8)

      III

      10 (15.6)

      16 (14.9)

      IV

      44 (68.7)

      78 (72.9)

      PD-L1 status, n (%)

      0.704

      <1%

      13 (20.3)

      20 (19.0)

      1-49%

      7 (10.9)

      11 (10.5)

      >50%

      11 (17.2)

      12 (11.4)

      Missing

      33 (51.6)

      62 (59.0)

      Initial Therapy, n (%)

      0.772

      Surgery +/- Chemotherapy

      10 (18.2)

      12 (12.9)

      Radiation

      5 (9.1)

      9 (9.7)

      Concurrent chemoradiation

      7 (12.7)

      14 (15.1)

      Chemoimmunotherapy

      6 (10.9)

      12 (12.9)

      Platinum-doublets

      14 (25.5)

      27 (29.0)

      Pembrolizumab

      4 (7.3)

      6 (6.5)

      Docetaxel

      1 (1.8)

      0 (0)

      Vinorelbine

      0 (0)

      1 (1.1)

      Gemcitabine

      0 (0)

      1 (1.1)

      Pemetrexed

      6 (10.9)

      7 (7.5)

      Targeted therapy

      0 (0)

      3 (3.2)

      Clinical Trial

      2 (3.6)

      1 (1.1)

      aFisher’s exact test p-value; NSCLC-NOS: non-small cell lung cancer, not otherwise specified; NET: neuroendocrine tumor; SCLC: small cell lung cancer; *stage at diagnosis; PD-L1: programmed death ligand-1

      Conclusion

      Although outcomes and demographics in KRAS G12C and non-G12C mutant NSCLCs appear to be largely comparable, our analyses suggest an association between the presence of G12C mutations and durable responses to immunotherapy. These findings will require validation in larger, prospective studies.

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      FP07.14 - Implementation of a Lung Biopsy Histology Protocol Supports Successful Cancer Biomarker Testing (ID 3744)

      00:00 - 00:00  |  Presenting Author(s): Sarah Wu  |  Author(s): Delia Liepins, Lynette M. Sholl

      • Abstract
      • Presentation
      • Slides

      Introduction

      Non-small cell lung cancer (NSCLC) management increasingly relies on biomarker testing, which presents a logistical challenge for utilization of lung biopsy specimens beyond routine diagnosis. Appropriate allocation of tissue from small biopsies is critical in order to permit for accurate histologic diagnosis while preserving tissue for ancillary studies such as PD-L1 testing and next generation sequencing (NGS). International surveys show that satisfaction with molecular testing is less than ideal, driven in part by inadequacy of formalin-fixed paraffin embedded (FFPE) tumor tissue for biomarker testing in over a quarter of clinical cases by some reports. We developed a histology protocol (LUNGCOR) that generates multiple unstained FFPE slides up front in order to increase tissue yields for pathologic diagnosis and ancillary testing. We examined the efficacy of this protocol in regards to molecular testing success rates.

      Methods

      Biopsy samples (e.g. transbronchial or fine needle biopsies) were flagged for the LUNGCOR protocol based on a clinical indication of "lung mass" or need for genomics. Proceduralists were requested to prospectively specify when samples were obtained for the purposes of biomarker testing. Per protocol, after embedding, 2 H&E slides with 18 intervening 4-micron unstained FFPE slides were prepared and reserved for immunohistochemistry or molecular studies. We performed a retrospective review of consecutive LUNGCOR specimens within the pathology information system and electronic medical record to determine the usage patterns for the unstained slides and success rates of molecular testing.

      Results

      This analysis is restricted to the first 2 years (2015-2016) following protocol initiation. 300 specimens were designated for the LUNGCOR protocol in this time period. Of these specimens, 84% resulted in a malignant diagnosis and 175 (58%) were non-squamous NSCLC. Of these, 87 (50%) of NSCLC underwent molecular profiling of some kind, either in house NGS, single gene PCR assays, or send-out NGS. For cases undergoing in house next generation sequencing (447-gene panel), 61 of 69 (88%) cases generated complete genotyping for all required and emerging biomarkers for targeted therapy. Sequencing failures were most commonly due to inadequate tumor content in the biopsy specimen, rather than inadequate size of the overall sample.

      Conclusion

      Generation of unstained slides during upfront histologic processing of known or suspected NSCLC increases availability of tissue for molecular testing and reduces risk of sample inadequacy due to specimen loss during routine handling steps, such as "refacing" the block. This straightforward process improvement can improve the yield of invasive biopsies for essential biomarker testing and contribute to improved patient outcomes.

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      FP07.15 - Real-world ALK Testing Trends and Patterns in Patients with Advanced NSCLC in the United States (ID 3333)

      00:00 - 00:00  |  Presenting Author(s): Christine M. Lovly  |  Author(s): Huamao M Lin, Yanyu Wu, Yu Yin, Huifeng Niu, Michael J Humphries

      • Abstract
      • Slides

      Introduction

      Patients whose lung cancers harbor anaplastic lymphoma kinase (ALK) rearrangements are sensitive to treatment with ALK tyrosine kinase inhibitors (TKIs). Several treatment guidelines recommend molecular testing to identify ALK-positive patients who are eligible for ALK TKI therapy. This study assessed real-world ALK testing patterns among community practices in the United States in patients with advanced non-small cell lung cancer (NSCLC) and explored treatments received prior to receiving test results in patients with ALK-positive NSCLC.

      Methods

      This retrospective analysis used data extracted from the Flatiron Health electronic health record-derived deidentified database. Patients ≥ 18 years old with a diagnosis of advanced NSCLC (clinical stage IIIB or IV as determined by pathologic and radiologic findings) and ≥ 2 clinic visits within the Flatiron Network between 01/01/2011 and 12/31/2019 were included.

      Results

      Overall, 60,025 patients with advanced NSCLC were identified, including 41,496 patients with non-squamous cell carcinoma and 15,291 patients with squamous cell carcinoma. Between 2011 and 2019, 36,691 (61.1%) patients with advanced NSCLC were ever tested for ALK by various diagnostic tests. Of these, 1,042 patients were ALK-positive. In patients with advanced NSCLC, ALK testing rates increased from 33.1% in 2011 to 73.0% in 2019. Considering histological subtype, ALK testing rates increased from 41.6% in 2011 to 81.6% in 2019 in patients with non-squamous cell carcinoma and from 13.6% in 2011 to 50.4% in 2019 in patients with squamous cell carcinoma. The proportion of ALK testing conducted by fluorescence in situ hybridization (FISH) declined from 68.3% in 2011 to 32.1% in 2019, while the use of next-generation sequencing (NGS) increased from < 1% in 2011 to 52.2% in 2019. Overall, tissue samples were most commonly used for testing (85.1%), followed by blood samples (13.5%), and the use of blood samples for ‘liquid biopsy’ increased from < 1% in 2011 to 28.2% in 2019. Among 983 patients who tested ALK-positive with a non-missing test result date, 24.7% of patients initiated therapy before receiving their first ALK-positive test results, with immuno-oncology (IO) therapies the most common treatments initiated since 2017. Among those who tested ALK-positive, the proportion of patients who started IO therapies before receiving ALK test results increased from 4.8% in 2016 to 17.8% in 2019. Median time from diagnosis of advanced NSCLC to first ALK-positive result date was 23 days. This included a laboratory turnaround time of 9 days from the date specimens were received by the laboratory to the test report date.

      Conclusion

      Over time, ALK testing rates have increased, reaching over 70.0% since 2017. There was increased use of NGS and a concurrent decrease in the use of FISH as the primary testing method. Despite this increase, over a quarter of patients with advanced NSCLC were not tested for ALK, indicating that many patients are not receiving recommended biomarker testing. Furthermore, 24.7% of patients who tested ALK-positive initiated therapy before receipt of ALK test results, which indicates that treatment decisions are sometimes being made in the absence of recommended biomarker data.

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      FP07.16 - Trends in Biomarker Testing Among Advanced NSCLC Patients in Oncology Practice Settings in the US (ID 3325)

      00:00 - 00:00  |  Presenting Author(s): Lauren Bartolome  |  Author(s): Rebecca Levin, Amy Sullivan, Benjamin Li, Vilasini Shetty, Stan Krulewicz

      • Abstract
      • Slides

      Introduction

      The NCCN guidelines for non-small cell lung cancer (NSCLC) state that testing for gene alterations is important to identify patients where targeted therapies may be efficacious, and to avoid therapies that are unlikely to provide clinical benefit. With the availability of genomic biomarker therapies that have shown prolonged median overall survival, there is a need to ensure that patients with NSCLC who may receive targeted biomarker therapies are identified.

      The objective of this study is to understand ALK, BRAF, EGFR, and ROS1 genomic biomarker testing and treatment initiation trends among individuals diagnosed with advanced stages of NSCLC in real-world oncology practice settings.

      Methods

      This retrospective analysis of data from the ConcertAI Patient 360 electronic health record database focused on adult patients diagnosed with advanced (stage IIIb-IV) NSCLC (aNSCLC) from January 2013 – December 2019. Study metrics included the proportion of patients with any biomarker test and specific biomarker tests stratified by year of aNSCLC diagnosis, the time between aNSCLC diagnosis and first biomarker test result, and the time between first biomarker test result to initiation of treatment. The time between aNSCLC diagnosis and biomarker testing were reported as continuous and categorical variables. The time between biomarker testing to initiation of treatment are reported among patients who received their first biomarker test before starting their first line treatment and were tested 30 days prior or 360 days post aNSCLC diagnosis date.

      Table 1: Biomarker testing trends overtime by year of aNSCLC diagnosis

      table 1.png

      Results

      Among 6,876 aNSCLC patients diagnosed from 2013-2019, 3,301 had first line (1L) treatment of which 54.26% were tested for at least one of ALK, BRAF, EGFR, or ROS. Annual trends are presented in Table 1: Biomarker testing trends overtime by year of aNSCLC diagnosis. EGFR testing data were most prevalent overall (49.56%) followed by ALK (40.84%), ROS (27.51%), then BRAF (13.97%). Testing rates increased for all biomarkers over time, with the largest increase observed in BRAF testing. About half of patients were tested within 30 days of aNSCLC diagnosis. Median days from test to treatment were between 15-16 days for ALK, BRAF, EGFR, and ROS1.

      Conclusion

      This snapshot of biomarker testing shows that progress has been made in the proportion of patients tested, however biomarker testing rates in US oncology practices are still suboptimal. Additional research is needed on the reasons or barriers to ordering timely biomarker testing among advanced and metastatic stage NSCLC patients.

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      FP07.17 - The Impact of Blood Based Host Immune Profile to Identify Aggressive Early Stage NSCLC   (ID 3600)

      00:00 - 00:00  |  Presenting Author(s): Eric Schaefer  |  Author(s): Paul Walker, R. Brian Mitchell, David Oubre, Nagaprasad Nagajothi, Jiahuai Tan, Mazen Khalil, John Dubay, James Orsini, Wallace Akerley

      • Abstract
      • Presentation
      • Slides

      Introduction

      Early detection of non-small cell lung cancer (NSCLC) provides the greatest opportunity for a cure. However, even when NSCLC is identified early, 30-60% of patients diagnosed with stage I-IIIA disease will experience local and/or distant recurrences, respectively. More precise tools are needed to refine lung cancer staging and identify patients that have a more aggressive disease who may benefit from additional treatment or enhanced disease surveillance following curative intent. The Host Immune Classifier (HIC) is a clinically validated, blood-based proteomic test designed to identify an inflammatory disease state associated with aggressive cancer. Here we report the results of a prospectively designed observational study evaluating the ability of the HIC to predict the survival outcomes of patients with early stage NSCLC.

      Methods

      The INSIGHT study (NCT03289780) has enrolled over 3,500 patients with NSCLC, regardless of stage, at 33 sites throughout the U.S. All subjects are tested and designated HIC-Hot (HIC-H) or HIC-Cold (HIC-C) prior to treatment initiation. An interim analysis of secondary and exploratory endpoints was performed after 12-18 months (mo) follow-up with the first 2,000 enrolled patients. We report the overall survival (OS) of HIC-defined subgroups comprising patients with stage I through stage IIIA (defined by the AJCC seventh edition staging system) NSCLC treated according to standard of care practice.

      Results

      At the time of database lock, 335 patients with newly diagnosed early stage NSCLC were included in the analysis. Disease stage at study entry was: 20% Stage IA (N=68, 3% HIC-C), 13% Stage IB (N=45, 11% HIC-C), 11% Stage IIA (N=37 (14% HIC-C), 13% Stage IIB (N=44, 21% HIC-C), 32% Stage IIIA (N=141, 34% HIC-C). Without biomarker stratification, landmark 15 mo OS was 85% (95% CI 78-90%) for patients with localized disease (Stage I-IIA) and 73% (95% CI 65-79%) for patients with regional disease (Stage IIB-IIIA), respectively. When patients with localized disease were evaluated with the HIC test, 15 mo landmark OS was significantly decreased for patients classified as HIC-C (HIC-C 55% (95% CI 23-78%) vs. HIC-H 87% (95% CI 80-92%), HR 3.68 (95% CI 1.38-9.87), p value 0.01). Similarly, 15 mo landmark OS for regionally advanced NSCLC was also significantly reduced for patients classified as HIC-C (HIC-C 60% (95% CI 45-72%) vs. HIC-H 79% (95% CI 70-85%), HR 1.77 (95% CI 1.02-3.06), p value 0.04). HIC remained prognostic for OS when adjusted for other covariates such as stage, ECOG performance status, histology, and treatment type in a multivariate analysis (HR of 1.89 (95% CI 1.15-3.12), p value 0.012).

      Conclusion

      The use of blood-based immune profiling may identify early stage lung cancer patients with aggressive disease that could potentially benefit from enhanced disease surveillance or additional treatment. Furthermore, the inclusion of blood-based biomarkers such as the HIC into the anatomic TNM staging system may help improve prognostication and aid in refining stage classification.

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    FP09 - Screening and Early Detection (ID 175)

    • Event: WCLC 2020
    • Type: Posters (Featured)
    • Track: Screening and Early Detection
    • Presentations: 5
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      FP09.01 - Economic Impact of Screening Selection with the PLCOm2012 Risk Model Versus USPSTF-Guidelines in the International Lung Screening Trial (ILST)  (ID 2400)

      00:00 - 00:00  |  Presenting Author(s): Sonya Cressman  |  Author(s): Martin Carl Tammemagi, Renelle Myers, John Yee, John English, John Mayo, Sukhinder Atkar-Khattra, Ren Yuan, Aleisha Fernandes, Stephen Lam

      • Abstract
      • Slides

      Introduction

      Screening protocols that use model-estimated risk for selection are thought to improve the efficiency of lung cancer screening by reducing the number needed to screen and detecting more lung cancers. Since risk selection enriches screening populations with greater age and tobacco smoke exposure, some hypothesize that screening with model-based risk selection would be less cost-effective than more broadly defined selection criteria such as those defined by the USPSTF. The objective of this study is to examine the costs and cost-effectiveness of selection with the PLCOm2012 risk model versus USPSTF-based selection in the International Lung Screening Trial (ILST).

      Methods

      The International Lung Screening Trial offered enrollment to participants that either had a PLCOm2012 lung cancer risk ≥1.51%/6 years or met the USPSTF criteria for screening selection. A cohort-based simulation model was developed to estimate the lifetime economic impact of screening PLCOm2012+ve but not PLCOm2012-ve/USPSTF+ve compared with screening USPSTF+ve but not PLCOm2012+ve/USPSTF-ve. We used risk-matched screening costs from the PanCan Early Detection of Lung Cancer study (PanCan) to calculate the post-baseline annual screening costs for each of the selection subgroups in the ILST and estimated the additional costs per quality adjusted life years (QALYs) with a published simulation model based on the NLST and PanCan screening studies.

      Results

      At the time of analysis 11,166 individuals registered in the study, with an interest in participating in lung cancer screening at one of seven coordinating sites in Canada, Australia and Hong Kong. Of these, 4282 enrolled in the study; 991 (23.1%) were exclusively selected by the PLCOm2012 criteria, 597 (13.9%) were exclusively selected by the UPSPSTF criteria and 2694 (62.9%) were selected by both criteria. The annual screening costs for the USPSTF-exclusive group were slightly higher than the rest of the cohort ($514 versus $508; p<0.05) and were thus held constant for simulation of the base-case scenario in the cost-effectiveness analysis. Compared with the PLCOm2012-selected cohort, the risk ratios for developing lung cancer were significantly lower for the proportion of the ILST that only met the USPSTF selection criteria (0.22; 95%CI: 0.07-0.71) and PLCO-exclusive subgroup had similar lung cancer risk ratios as the rest of the cohort (1.31; 95%CI: 0.82-2.08). Under the assumption that the early-stage lung cancers detected in the PLCOm2012-exclusive cohort would go undetected in the USPSTF-guided strategy – and the published modelling assumptions – the PLCOm2012-guided selection strategy is estimated to cost an additional $170 and result in an additional 0.3 QALYs over the comparator. The incremental cost-effectiveness ratio appears to be cost-effective at $561/QALY. The results were sensitive to lung cancer treatment costs and modifiable heart and lung health risks such as prevention and improved quality of life through earlier and better management of COPD; while insensitive to annual screening costs.

      Conclusion

      When risk-model informed screening selection is compared to the USPSTF selection guidelines, risk-model selection introduces minor costs but may prove cost-saving in the long-term, and lead to improved QALY gains. Updates to immunotherapy treatment costs are likely to counterbalance any additional costs associated with model-based risk selection.

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      FP09.02 - Calibration of the LLP Lung Cancer Risk Stratification Model: Prospective Validation in the UKLS Cohort of 76,000 People (ID 3137)

      00:00 - 00:00  |  Presenting Author(s): John K Field  |  Author(s): Daniel Vulkan, Michael PA Davies, Stephen W. Duffy, Rhian Gabe

      • Abstract
      • Presentation
      • Slides

      Introduction

      Introduction: Evidence from two large randomised trials estimates a significant 20% -24% reduction in lung cancer mortality in the low dose CT screening arm.

      Future lung cancer screening programmes require identification of high-risk populations to optimise detection in those who would benefit from screening for lung cancer and provide a cost-effective programme. The Liverpool Lung Project risk model (LLPv1) was first developed in 2008, validated in three international datasets in 2012 and amended in the UKLS trial (LLPv2). We report on further amendments to the model (LLPv3), where it is calibrated to the whole of England and more recent lung cancer incidence data.

      Methods

      75,958 participants responded to the first approach UKLS trial questionnaire. We obtained cancer registration data from Public Health England, linked through a third party, providing at least 5 years of follow-up data. A ROC curve was plotted to assess ability of the LLP model to distinguish between those individuals who went on to develop lung cancer. In order to assess the calibration of the predictive model, we ranked the LLPv3 risk scores, assigned decile groups, and carried out a linear regression of the log-odds () of the rate of observed cancers in each group against the log-odds of the mean of the risk scores in the group (See Figure1).

      Results

      The ROC curves for LLPv2 and LLPv3 are almost identical, as would be expected, since the coefficients pertaining to the risk factors are the same; ranking of most individuals is unchanged from LLPv2 to LLPv3, thus, the discrimination is very similar. The AUC in each case was 0.81 (95% CI 0.79 - 0.82). After excluding individuals allocated to the UKLS trial intervention arm, the AUC and 95% confidence interval were also unchanged.

      The LLPv3 model also provided a very good estimation of future risk through comparison of observed and expected lung cancer outcomes. However, without the calibration to the current England population in terms of age and sex specific lung cancer risk, there would have been considerable overestimation of risk. This is consistent with the findings of Katki et al. [Ann Intern Med 2018;169(1):10-19], who concluded that previous versions of the LLP model overestimated future incidence.

      figure 1.png

      Conclusion

      The discrimination of LLPv2 and LLPv3 was excellent. LLPv3, which was calibrated to contemporary, English incidence, achieved more accurate prediction of absolute incidence, and would be more effective in selecting a high-risk group for surveillance in England today.

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      FP09.03 - Circulating Nucleosomes in Lung Cancer Diagnosis Following Low-Dose Computed Tomography (ID 3748)

      00:00 - 00:00  |  Presenting Author(s): Tung Ming Tsai  |  Author(s): Dorian Pamart, Nathalie Hardat, Marielle Herzog, Mong-Wei Lin, Hsao-Hsun Hsu, Jin-Shing Chen

      • Abstract
      • Slides

      Introduction

      Low-Dose Computed Tomography (LDCT) is the widely accepted standard for screening of individuals at high risk of lung cancer (LC). However, LDCT has several limitations including the high prevalence of non-malignant pulmonary nodules detected leading to overdiagnosis, the potential harms of cumulative radiation dose and poor adherence to recommended follow-up. Therefore, novel blood-based tests could offer a simple follow confirmation approach or front-line stratification test to help discriminate between lung cancer and non-malignant nodules noted by LDCT.

      Nucleosomes are DNA fragments wrapped around a histone core and have been associated with tumour burden and malignancy progression. We used a Nu.Q™ immuno-assay to investigate the clinical performance of circulating nucleosome levels containing the histone H3.1 alone and in combination with carcinoembryonic antigen (CEA) in blood from subjects referred to LDCT to evaluate their discriminant power towards LC and non-malignant nodules.

      Methods

      We measured H3.1 variant nucleosome levels and CEA in 220 patients referred for CT at National Taiwan University Hospital. The patients were later confirmed to have either a LC (n=100) (70 early stage, 30 late stage), or non-malignant nodules (n=50), or no-nodules (n=30). Whole blood was collected in EDTA plasma tubes for analysis by Nu.Q™ immunoassay. Plasma samples were analyzed in duplicate for nucleosome levels using a quantitative immunoassay for H3.1 nucleosomes (Nu.Q™-H3.1) developed and validated to CLSI guidelines using a recombinant nucleosome standard curve. CEA was analysed using a chemiluminescent magnetic microparticle immunoassay on the Abbott ARCHITECT analyzer. We evaluated circulating Nu.Q™-H3.1 and CEA levels individually for their performance in discriminating subjects into the following groups: cancer vs non-malignant nodule and no nodules (group A) or cancer vs non-malignant nodules (group B). A decision tree analysis was performed for combinatorial performance in discriminating group B.

      Results

      Nu.Q™-H3.1 gave an area under the curve (AUC) of 0.60 and 0.59 for group A and B, respectively, with a sensitivity at 90% specificity of 16% and 23% for group A and B, respectively. CEA gave an AUC of 0.65 and 0.60 and a sensitivity at 90% specificity of 28% and 26% for group A and B, respectively. A decision tree combining Nu.Q™ H3.1 with CEA resulted in improved discrimination between LC and non-malignant nodules (group B) relative to CEA marker alone, achieving a sensitivity of 41% at 90% specificity for the key clinical question faced by physicians utilizing LDCT. In addition, we observed that whereas CEA detect mostly late stage cancer, H3.1 levels detect better early stage cancer.

      Conclusion

      Our results indicate that nucleosome levels, as measured by Nu.Q ™-H3.1, are elevated in LC. Combining analysis with CEA exceeds the performance either biomarker alone and provides a discrimination power between LC vs non-malignant nodules in LD-CT screen positive individuals. These promising initial results suggest that the Nu.Q™ H3.1 assay may be a useful alternative blood-based test in addition to LD-CT for early identification of lung cancer and warrants further study.

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      FP09.04 - Association Between Family History and Other Risk Factors for Lung Cancer: Analysis of an Internet-Based Risk Assessment (ID 1145)

      00:00 - 00:00  |  Presenting Author(s): Ryan O'Keefe  |  Author(s): Michael Lariviere, Carolyn Vachani, Margaret Hampshire, Christina Bach, Karen Arnold-Korzeniowski, Marisa Healy, James Metz, Christine Hill-Kayser

      • Abstract
      • Slides

      Introduction

      While smoking and asbestos exposure are strongly associated with lung cancer (LC), associations between diet/obesity, alcohol consumption, and marijuana smoking have also been reported. Individuals with a family history (FH) of cancer are more likely to be smokers but are also more likely to be in contemplation/preparation stages of smoking cessation. The CDC recommends integrating FH of cancer into prevention and control programs. Current smokers appreciate that they are at an increased risk for LC; however, they do not appreciate the impact of FH and genetics on this risk. The association between FH of LC and behavioral risk factors for developing cancer is not well understood. While smoking cessation remains the most important preventive measure to reduce the risk of LC, mitigation of other behaviors may reduce the risk of LC and other cancer types as well.

      Methods

      The OncoLink Reduce My Risk tool is an Internet platform created in 2009 to provide personalized information regarding cancer risk, available at OncoLink.org. Voluntary participants were asked about risk factors and risk-associated behaviors. Differences between respondents with v. without FH of LC were analyzed using chi-square test.

      Results

      Among 28,001 respondents, 5,326 (19%) reported FH of LC. Those with FH of LC were more likely to be current cigarette and marijuana smokers and to smoke > 1 pack per day (Table). However, respondents with household income >$75,000 who had FH of LC were not more likely to be current smokers compared to those without FH (Table). Those with FH of LC were more likely to drink alcohol regardless of demographic factors, and to drink both 8+ and 11+ drinks per week (Table). Those with FH of LC were more likely to be obese regardless of demographic factors, and less likely to exercise 2+ times per week (Table). Those with FH of LC were more likely to have received 10+ imaging scans and to have been exposed to hydrocarbons compared to those without FH (Table). There were no reported differences in any other occupational or home exposures, including asbestos and radon in those with v. without FH of LC (Table).

      Family History (FH) of Lung Cancer and Associated Risk Factors and Demographics
      Behavior/Risk Factor Pos FH Neg FH P-value Behavior/Demographic Pos FH Neg FH P-value Behavior/Demographic Pos FH Neg FH P-value Behavior/Demographic Pos FH Neg FH P-value
      Current Smoker 15.3% 12.0% <0.001 Current Smoker Current Alcohol Obese
      > 1 Pack Per Day 4.9% 3.4% <0.001 Rural 17.6% 13.6% 0.001 Rural 51.1% 49.1% 0.2654 Rural 38.1% 28.6% <0.001
      Current Marijuana 13.6% 11.9% 0.003 Suburban 13.0% 9.6% <0.001 Suburban 61.2% 53.9% <0.001 Suburban 27.5% 22.8% <0.001
      Current Alcohol 59.6% 53.5% <0.001 Urban 17.9% 15.0% <0.001 Urban 62.5% 55.7% <0.001 Urban 26.2% 22.8% 0.016
      8+ Drinks/Week 23.3% 18.5% <0.001 $ 0 - 75,000 20.4% 15.3% <0.001 $ 0 - 75,000 56.6% 51.0% <0.001 $ 0 - 75,000 33.9% 28.9% <0.001
      11+ Drinks/Week 14.5% 11.3% <0.001 $75,000 + 9.8% 8.6% 0.082 $75,000 + 66.9% 62.5% <0.001 $75,000 + 26.5% 21.2% <0.001
      Obese 29.2% 23.8% <0.001 White 15.4% 12.5% <0.001 White 61.0% 57.3% <0.001 White 29.5% 24.2% <0.001
      Exercise 2+/Week 60.7% 65.1% <0.001 Non-White 12.4% 9.4% 0.057 Non-White 50.6% 41.3% <0.001 Non-White 27.7% 22.0% 0.028
      10+ Imaging Scans 9.0% 6.0% <0.001 < Full College 18.8% 14.3% <0.001 < Full College 51.7% 44.5% <0.001 < Full College 30.3% 24.2% <0.001
      Asbestos Exposure 1.5% 1.9% 0.417 College + 11.5% 9.4% 0.001 College + 68.1% 64.0% <0.001 College + 27.9% 23.3% <0.001
      Radon Exposure 4.2% 3.4% 0.101
      Hydrocarbon Exposure 3.4% 2.6% 0.001
      Heavy Metal Exposure 2.2% 2.0% 0.405
      Mustard Gas Exposure 0.3% 0.4% 0.698
      Industrial Dye Exposure 2.3% 2.2% 0.633
      Occup Radiation Exposure 1.3% 1.0% 0.782
      Conclusion

      FH of LC is associated with higher-risk behaviors that increase the likelihood of developing both lung and other cancers. As such, FH can be used in cancer prevention and control programs to identify higher-risk patients and educate patients that FH of lung cancer is associated with risk-increasing behaviors that are nonetheless modifiable.

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      FP09.05 - Driver Oncogenic Alterations and Indoor Radon in NSCLC Patients From the IFCT Biomarker Cohort: Bioradon France Study (ID 1176)

      00:00 - 00:00  |  Author(s): Fabrice Barlesi, Geraldine Ielsch, J Merlio, D Debieuvre, J Mosser, Charles Ricordel, L Ouafik, I Rouquette, I Monnet, F Escande, Alexandra Langlais, Frank Morin, C Vignaud, Edouard Auclin, Jose Carlos Benitez, David Planchard, Klervi Leuraud, Dominique Laurier, Benjamin Besse, Virginie Westeel

      • Abstract
      • Presentation
      • Slides

      Introduction

      Radon is a radioactive gas, considered as the leading cause of lung cancer in non-smokers. In a previous work, we studied the correlation between the estimation of radon concentration from the French Indoor Radon Map (Institut de Radioprotection et de Sûreté Nucléaire, IRSN) and the regional prevalence of driver alterations in a cohort of 116.424 NSCLC patients in France (Mezquita et al, WCLC 2018). The prevalence of driver oncogene alterations was significantly higher in high-radon areas but clinical data were not available. We aim to confirm this hypothesis in an annotated database of NSCLC patients with matched molecular data available for adjustment (Barlesi et al, Lancet 2016).

      Methods

      Retrospective assessment of patients with NSCLC tested for EGFR/BRAF/HER2/KRAS mutations (m) and ALK fusion from the 28 Platform led by the National Cancer Institute between Apr.2012 and Apr.2013, and included in the Biomarkers France dataset. We studied the association between the prevalence of driver oncogenic alterations (EGFR/ALK/BRAF/HER2/KRAS) and the radon mean concentration in the area where the patient was born according to the IRSN Map. Adjustment on age, gender and smoking was performed.

      Results

      Out of 17664 patients, we analyzed 3994 with birthplace available: 63% males, 82% smokers, with a median age of 64 years [18-94]. Lung cancer tumors were mostly adenocarcinoma (76%), followed by other histologies (18%) and squamous (6%). By molecular alterations: 468 tumors harbor EGFRm (12%), 129 ALK (3%), 89 BRAFm (2%), 32 HER2m (1%), 985 KRASm (25%); 2273 wildtype or harbor other non-driver alterations (control; 57%). Adenocarcinoma histology (83.7% vs. 80.2%, p=0.0034), and non-smoker habit (19.5% vs. 16.5%, p=0.0251) were more common in radon high-risk group (comparatively at the low risk group). The mean radon concentration by birthplace was 74.36 Bq/m3 ±53.28SD [range 16.6-622.3], and by molecular groups: EGFRm 72.49 Bq/m3 ± 47.98 SD [16.6-461.4], ALK 80.24 Bq/m3 ±55.22SD [19.3-384.7], BRAFm 73.22 Bq/m3 ±47.86SD [19.3-319.3], HER2m 72.74 Bq/m3 ±39.51SD Bq/m3 [27.8-231.3], KRASm 71.79 Bq/m3 ±53.32SD [16.6-576.8] and control group 75.67 Bq/m3 ± 54.5SD [16.6-622.3] (p=0.20). The prevalence of driver alterations was higher in high-radon areas (table 1; p=0.0472); but no significant difference was observed after adjustment on age, gender and smoking.

      Low radon
      <50 Bq/m3

      High radon
      50 Bq/m3

      P value

      P value adjusted*

      EGFR

      Mutation

      N (%)

      155 (11.4%)

      313 (13.2%)

      0.1218

      0.3024

      Control (1)

      N (%)

      1199 (88.6)

      2059 (86.8)

      ALK

      Fusion

      N (%)

      42 (3.4%)

      87 (4.1%)

      0.3272

      0.4708

      Control (1)

      N (%)

      1199 (96.6)

      2059 (95.9)

      BRAF

      Mutation

      N (%)

      32 (2.6%)

      57 (2.7%)

      0.8708

      0.9865

      Control (1)

      N (%)

      1199 (97.4)

      2059 (97.3)

      HER2

      Mutation

      N (%)

      7 (0.6%)

      25 (1.2%)

      0.0880

      0.1781

      Control (1)

      N (%)

      1199 (99.4)

      2059 (98.8)

      KRAS

      Mutation

      N (%)

      375 (31.3%)

      610 (29.6%)

      0.3227

      0.3478

      Control (2)

      N (%)

      824 (68.7)

      1449 (70.4)

      DRIVER

      Positive

      N (%)

      236 (16.4%)

      482 (19%)

      0.0472

      0.2128

      Control (1)

      N (%)

      1199 (83.6)

      2059 (81)

      (1) population no EGFRm, noBRAFm, no HER2m and no ALKr
      (2) population no EGFRm, noBRAFm, no HER2m, no ALKr and no KRASm

      *adjustment on age, gender and smoking

      Conclusion

      We observed a higher prevalence of driver oncogenic alterations in NSCLC patients born in high radon areas; but no significant difference was observed after adjustment on age, gender and smoker. This study warrants further research on radon gas and driver oncogenes.

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    FP10 - Small Cell Lung Cancer/NET (ID 231)

    • Event: WCLC 2020
    • Type: Posters (Featured)
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 5
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      FP10.01 - Survival in Advanced SCLC: Projected Impact of Immuno-Oncology-Associated Durable Response on Population Health Gains in US (ID 1557)

      00:00 - 00:00  |  Presenting Author(s): Jason Gordon  |  Author(s): Phil McEwan, Rob Young, Polly Kirkness, John R Penrod, Yong Yuan

      • Abstract
      • Presentation
      • Slides

      Introduction

      Historically, prognosis for patients with metastatic small cell lung cancer (SCLC) treated with chemotherapeutic agents has been poor. Immuno-oncology (I-O) therapies, such as nivolumab and ipilimumab, have been associated with improved response and durable survival in SCLC. Healthcare decision-makers considering reimbursement are required to balance expected treatment costs with predicted lifetime costs and health outcomes. These predictions are sensitive to the proportion of I-O treated patients achieving a durable response; however, this information is typically unavailable at the time of decision-making. Consequently, the objective of this study was to quantify historical age-specific US SCLC survival rates and compare these with expected I-O survival for a range of clinically plausible durable response rates.

      Methods

      Overall survival (OS) for patients with metastatic SCLC between 2010-2015 were derived from the Surveillance, Epidemiology, and End Results (SEER) database stratified by age at diagnosis (40-90 years). OS for patients receiving I-O therapy was based on those with recurrent SCLC from the nivolumab arm of the Checkmate-032 study. Mean OS was estimated using a delayed mixture model, applying a piecewise exponential and assuming a fraction of patients surviving at the end of the 26 month follow-up period (~21% patients) achieved a durable response. A plausible base case fraction was derived using long term follow-up of patients treated with nivolumab in NSCLC, indicating a 10% durable response fraction. For those achieving a durable response background general population mortality was applied. Incremental survival was estimated by comparing historical outcomes (SEER) to long-term survival estimates for patients receiving I-O therapy. Estimates of incremental survival benefit were extrapolated to the US population using age-adjusted incidence data for patients with advanced (stage III/IV) disease. Age-adjusted incidence data was applied to all incident patients to assess the potential population health gains associated with I-O therapy.

      Results

      Historic diagnosis with advanced SCLC (SEER) was associated with an expected survival of 8.4 months (baseline age: 70 years). By contrast, mean OS in I-O treated patients was estimated to be 29.5 months, equivalent to incremental survival gains of 21.2 months. At ages 40 and 90 real-world benchmark expected survival was 12.3 months and 4.0 months respectively, I-O-treated mean OS ranged between 62.2 months (49.9 month gain at age 40) and 13.3 months (9.3 month gain at age 90) for the 10% of patients surviving and achieving a durable response after 26 months of follow up. Applying age-adjusted incremental survival estimates to the incident SCLC population (13,570 patients) was associated with a potential gain of 27 thousand life years, with more pronounced gains in life expectancy in younger compared with older cohorts.

      Conclusion

      Patients with recurrent SCLC have historically experienced few treatment options and poor outcomes. Potential health gains associated with I-O therapies are significant at both the patient and population level but should account for age to avoid bias and improve accuracy. This study quantifies expected OS gains associated with I-O therapy using a remission rate based on trial data designed to assist decision-makers’ expertise when considering the robustness of predicted survival estimates.

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      FP10.02 - Investigating the Immunophenotype of Small Cell Lung Cancer to Improve Immunotherapeutic Targeting (ID 1686)

      00:00 - 00:00  |  Presenting Author(s): Kate Sutherland  |  Author(s): Sarah Best, Jonas Hess, Fernando Souza-Fonseca Guimaraes, Joe Cursons, Ariena Kersbergen, Yue You, Jin Ng, Melissa Davis, Tracey Leong, Louis Irving, Matt Ritchie, Daniel Steinfort, Nick Huntington

      • Abstract
      • Presentation
      • Slides

      Introduction

      Small cell lung cancer (SCLC) is the most aggressive subtype of lung cancer and although most patients initially respond to platinum-based chemotherapy, resistance rapidly develops. Immunotherapy has promise in the treatment of lung cancer, however SCLC patients exhibit poor overall responses. This highlights the necessity for alternative treatment approaches. Recently, SCLC has been divided into four subtypes based on the expression of key transcription factors, ASCL1, NEUROD1, POU2F3 and YAP1. Though it has been speculated that these subtypes may respond differentially to therapeutic interventions, response to cytotoxic immune cell killing has not been investigated.

      Methods

      We have investigated the immune microenvironment (IM) profiles of human SCLC patients on freshly obtained endobronchial ultrasound biopsies. We characterized the IM through antibody panels (flow cytometry) and unbiased hierarchal clustering (single-cell sequencing). Immune cell signatures were also interrogated in publicly available human SCLC datasets. Subcutaneous transplantation studies utilizing syngeneic SCLC cell lines were performed to functionally validate the role of cytotoxic immune cell populations. Tumor growth, metastatic dissemination and the activation of CD8+ T and natural killer (NK) cells were evaluated by histology and flow cytometry.

      Results

      Transcriptomic analysis of treatment naïve human SCLC samples revealed heterogeneous immune checkpoint and cytotoxic signature profiles. We identified that immune cell infiltration scores stratified the four subtypes of SCLC, suggesting immunotherapeutic targeting may be prognostic in some patient cohorts. To functionally evaluate the role of cytotoxic immune cells in the surveillance of SCLC, we demonstrated that the absence of NK cells, but not CD8+ T cells, significantly enhanced metastatic dissemination of SCLC in vivo.

      Conclusion

      These proof-of-principle findings provide a rationale for exploiting the anti-tumor functions of NK cells in the treatment of SCLC patients. Critically, the distinct IM profiles of SCLC subtypes reveal an unappreciated level of heterogeneity that warrants further investigation in the stratification of patients for immunotherapy.

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      FP10.03 - Multi-Region Exome Sequencing Reveals the Intratumoral Heterogeneity of Surgically Resected Small Cell Lung Cancer (ID 2079)

      00:00 - 00:00  |  Presenting Author(s): Huaqiang Zhou  |  Author(s): Yaxiong Zhang, Yuanyuan Zhao, Liyan Ji, Mengmeng Song, Pansong Li, Yanfang Guan, xuefeng Xia, Ningning Zhou

      • Abstract
      • Slides

      Introduction

      Small cell lung cancer (SCLC) is a highly malignant tumor with extensive genomic alterations detected by single-region sequencing. But the intratumoral heterogeneity (ITH) of SCLC remains unknown. Elucidating the heterogeneity of SCLC by multi-region sequencing help the understanding of disease and the improvement of clinical outcomes.

      Methods

      Multi-region exome sequencing was performed on 120 FFPE samples from 40 staged I-III SCLC patients (three regions for each patient). All the tissue samples were collected by surgical resection from Sun Yat-sen University Cancer Center and confirmed as SCLC by immunohistochemistry. Intratumoral heterogeneity (ITH) was defined as percentage of branch/subclonal somatic non-silent mutations or copy number variations. We further analyzed the correlation of ITH and clinical phenotype to evaluate the impact of genomic alterations on outcome, including disease-free survival and overall survival.

      Results

      We subjected 120 FFPE SCLC samples to multi-regional whole-exome sequencing. In total, 48818 somatic mutations were identified with average 239x sequencing depth. The most significantly and frequently mutant genes were TP53 (88%) and RB1 (70%), which dominate truncal mutations (Fig.1A). In addition to a medium tumor mutation burden (TMB, 15/Mb range 2~66), SCLC exhibited somatic copy number variation (CNV) across all patients. Using CNV ITH, an average of 0.49 (range 0.22~1 per sector) was found in SCLC (Fig.1B). The age-associated, tobacco-associated, and aflatoxin-associated signatures were major mutational signatures in these patients (Fig.1C). We found a medium mutational heterogeneity (0.50, range 0.22~1) in our SCLC cohort, in contrast to low ITH in previous reported NSCLC and LUAD cohort (Fig.1C). Combined SCLC patients behaved in much the same way as pure SCLC patients, both in terms of mutation distribution, ITH, TMB, mclone (number of tumor molecular clones) and gene signatures (Fig. 1D). This condition is also present in smoker patients and those with EGFR mutations. A higher CNV ITH was observed in stage I-II of SCLC than stage III (p < 0.001) (Fig.1E). Less mClone were associated with better DFS of SCLC (Fig. 1E).

      wclc2020-2079-submit-image.jpg

      Conclusion

      Despite moderate mutation burden, SCLC showed a medium intratumoral heterogeneity with high genomic instability. CNV exhibited a high heterogeneity at early stage and mclone may serve as a prognostic biomarker for SCLC.

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      FP10.04 - RESILIENT Part 1: Safety and Efficacy of Second-Line Liposomal Irinotecan in Patients with Small Cell Lung Cancer (ID 3657)

      00:00 - 00:00  |  Presenting Author(s): Luis G. Paz-Ares  |  Author(s): David R. Spigel, Yuanbin Chen, Maria Jove, Oscar Juan-Vidal, Patricia Rich, Theresa Hayes, Vanesa Gutiérrez Calderón, Reyes Bernabe Caro, Alejandro Navarro, Afshin Dowlati, Bin Zhang, Yan Moore, Xiaopan Valerie Yao, Jaba Kokhreidze, Santiago Ponce, Paul Bunn

      • Abstract
      • Presentation
      • Slides

      Introduction

      Many patients with small cell lung cancer (SCLC) develop drug resistance to first-line platinum-based chemotherapy, and second-line therapies are limited. RESILIENT (ClinicalTrials.gov identifier NCT03088813) is a two-part phase 2/3 study assessing the safety, tolerability and efficacy of liposomal irinotecan monotherapy as second-line treatment for patients with SCLC. Here we report data from part 1 of the RESILIENT study (data cut off, 2 December 2019).

      Methods

      RESILIENT part 1 was an open-label, single-arm study comprising dose-exploration and dose-expansion phases. Eligible patients with SCLC were aged ≥ 18 years, had progressed with platinum-based first-line therapy, had an Eastern Cooperative Oncology Group performance status score of 0 or 1, and had adequate organ function; prior exposure to immunotherapy was permitted. During dose exploration, participants received liposomal irinotecan 85 mg/m2 or 70 mg/m2 free base administered every 2 weeks; the identified recommended dose was used during dose expansion. Primary endpoints were safety and tolerability. Efficacy assessments included objective response rate (ORR), best overall response (BOR), progression-free survival (PFS), and overall survival (OS).

      Results

      In total, 30 patients received liposomal irinotecan in RESILIENT part 1 (women, 56.7%; median age, 61.5 years). During dose exploration, four patients who received liposomal irinotecan 85 mg/m2 experienced dose limiting toxicities, including diarrhea (n = 3) and abnormal liver function test (n = 1). Thus, this dose was not considered tolerable and enrollment into the 70 mg/m2 cohort was initiated; a total of 25 patients (platinum resistant, 40%) received liposomal irinotecan 70 mg/m2 (dose exploration, 12 patients; dose expansion, 13 patients). Among the 25 patients who received the recommended dose of 70 mg/m2, 40% had one or more grade ≥ 3 treatment-related treatment-emergent adverse events (TEAEs), most commonly diarrhea (20%), neutropenia (16%), and anemia, thrombocytopenia, asthenia and abdominal sepsis (each 8%); 8% of patients discontinued treatment owing to TEAEs. Median (95% CI) PFS was 3.98 (1.45–4.24) months and OS was 8.08 (5.16–9.82) months. ORR (complete response + partial response) was 44% and BOR was: complete response, 4%; partial response, 40%; stable disease, 28%; progressive disease, 20%; non-evaluable, 8%.Thirty patients were treated in RESILIENT part 1. Full results to be presented in the updated abstract.

      Conclusion

      In participants with SCLC who had progressed with platinum-based first-line therapy, liposomal irinotecan at the recommended dose of 70 mg/m2 showed promising antitumor activity and safety findings were aligned with the known safety profile. RESILIENT part 2, an ongoing, phase 3, randomized controlled trial versus topotecan will provide further data regarding the efficacy and safety of liposomal irinotecan 70 mg/m2 for the second-line treatment of patients with SCLC.

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      FP10.05 - A Prospective Phase II Study of Apatinib Plus Chemotherapy for Pretreated Patients With Advanced Small Cell Lung Cancer (ID 2045)

      00:00 - 00:00  |  Presenting Author(s): Kewei Ma  |  Author(s): Yinghui Xu, Yangyang Cai, Xu Wang, Chao Sun, Ye Guo, Shi Qiu

      • Abstract
      • Slides

      Introduction

      Small-cell lung cancer (SCLC), which accounts for ∼15% of all lung cancers, is characterised by its rapid proliferation. The clinical outcomes of second-line and above treatments are unsatisfactory, resulting in a median progression-free survival (PFS) of less than 3 months. There is currently none targeted drugs or new chemotherapeutic drugs that can achieve breakthroughs in advanced SCLC. This study aims to observe whether apatinib in combination with chemotherapy can be a new choice for pretreated patients with advanced SCLC. This clinical trial has presented initial results in 2019 WCLC abstract 1788. This has updated the new data.

      Methods

      This is a prospective, single-center, single-arm clinical study designed to evaluate the efficacy and safety of apatinib plus chemotherapy for second-line and above treatment of advanced SCLC ((NCT03547804)). The dose of apatinib was 500mg per day in the initial protocol, and the treatment plan was adjusted due to tolerance of patients later and lower dose of apatinib 250mg once daily was applied. The dose of apatinib could be further reduced to 250mg every other day if the patient was observed with a grade 3/4 adverse effect. Chemotherapeutic agents were limited to irinotecan or docetaxel alone. The primary endpoint was the progression-free survival (PFS). The secondary endpoints included overall survival (OS), disease control rate (DCR), objective response rate (ORR), and adverse events (AEs).

      Results

      31 patients were enrolled from March 2018 to Oct 2019. 28 patients were available for response evaluation. The ORR and DCR were 25.00% (7/28) and 100% (28/28), respectively. The median PFS and OS were 7.43 months and 12.50 months, respectively (Fig 1a-1b). For subgroup analyses, we found that limited-stage disease had a longer PFS comparied with that of extensive-stage disease (9.17m vs 4.33m, P=0.0013) (Fig 1c). There were no significant differences in efficacy in subgroups of different initial dose (500mg vs 250mg) and age (<60y vs ≥60y). The most common treatment-related AEs were neutropenia, thrombocytopenia, hypertension, hand-foot syndrome, proteinuria, diarrhea, abnormal liver function and mucitis. However, the incidence of grade Ⅲ-Ⅳ adverse reactions was lower and the patients had a better tolerance with an initial dose of apatinib 250mg plus chemotherapy.未标题-1.jpg

      Conclusion

      Apatinib plus single agent chemotherapy showed a promising efficacy and a good tolerance in patients with pretreated SCLC. Especially, apatinib 250mg per day was recommended in this clinical trial.

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    FP12 - Tumor Biology and Systems Biology - Basic and Translational Science (ID 188)

    • Event: WCLC 2020
    • Type: Posters (Featured)
    • Track: Tumor Biology and Systems Biology - Basic and Translational Science
    • Presentations: 12
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
      • Abstract
      • Slides

      Introduction

      Survival data supports the use of first-line osimertinib as standard of care for EGFR positive non-small lung cancer (NSCLC). However, it remains unclear whether upfront osimertinib is superior to sequential first- or second-generation tyrosine kinase inhibitor (TKI) followed by osimertinib for all patients. The impossibility of predicting which patients are at high risk of progression constitutes a major limitation of the sequential TKI approach.

      Methods

      Seven hundred and forty-five plasma samples from 192 stage IV, EGFR positive NSCLC patients who were treated with first-line TKI were analysed by digital PCR.

      Results

      Patients with EGFR sensitizing mutations in plasma with mutant allele frequency (MAF) <7% before treatment initiation had median OS 37.9 months (25.3-NR), compared 17.5 (95%CI: 11.3-25.5) months for patients with MAF≥7% (adjusted HR=0.43; 95%CI: 0.25-0.76, respectively). OS was achieved with 53.1% of the patients treated with a 2nd line treatment other than osimertinib. In the multivariable analysis, undetectable levels of circulating tumour DNA (ctDNA) after 3 and 6 months of treatment were associated with improved PFS and OS (P<0.001 in all cases). Patients who became ctDNA negative after 3 or 6 months of treatment with MAF<7% at diagnosis had more than two-thirds lower risk of progression and death compare to the rest of patients (adjusted HR=0.28; 95%CI: 0.17-0.46 and HR=0.24; 95%CI: 0.12-0.48 for PFS and OS, respectively).

      Conclusion

      Pre-treatment ctDNA levels identify patients at low risk of progression and death who could benefit from sequential TKI treatment. Information regarding EGFR sensitizing mutation clearance could improve patient selection.

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      FP12.03 - SRC-Homology 2 Domain-Containing Phosphatase 2 (SHP2) in Resected Lung Adenocarcinoma (LUAD) (ID 992)

      00:00 - 00:00  |  Presenting Author(s): Masaoki Ito  |  Author(s): Jordi Codony-Servat, Ana Giménez-Capitán, Mireia Serra-Mitjans, Francisco Pérez-Ochoa, David Lligé, Imane Chaib, Ramon Rami-Porta, Carme Obiols, Sergi Call, José Belda-Sanchís, Xavier Tarroch-Sarasa, Niki Karachaliou, Miguel Angel Molina-Vila, Morihito Okada, Rafael Rosell

      • Abstract
      • Slides

      Introduction

      Epidermal growth factor (EGFR)-mutant lung adenocarcinomas (LUADs) display impaired phosphorylation of extracellular signal-regulated kinase (ERK) and SRC-homology 2 domain-containing phosphatase 2 (SHP2) in comparison with EGFR wild-type LUADs. However, the function of SHP2 in early EGFR-mutant LUADs and EGFR wild-type LUADs has not been reported. We posit that SHP2 mRNA expression could be a predictive marker in resected EGFR-mutant LUADs versus EGFR wild-type patients (pts).

      Methods

      We examined 267 resected LUADs from Japan and Spain. mRNA expression levels of AXL, MET, CDCP1, STAT3, YAP1 and SHP2 were analyzed by quantitative reverse transcriptase polymerase chain reaction (PCR). EGFR mutant cell lines were investigated for their activity of SHP2.

      Results

      Among the 267 enrolled pts, 100 (37.3%) were EGFR-mutant LUADs. Five-year recurrence-free survival (RFS) and overall survival (OS) were lower for EGFR-mutant LUADs with high SHP2 mRNA levels (hazard ratio= 1.83 and 2.28, respectively. p= 0.03 and p=0.04). However, SHP2 was not associated with RFS nor OS in the 167 wild-type EGFR LUADs. In EGFR-mutant cells, RMC-4550 (SHP2 inhibitor) plus erlotinib showed synergism via inhibition of AKT (S473) and ERK1/2 (T202/Y204). While erlotinib displaces SHP2 into the nucleus, either RMC-4550 alone, or in combination with erlotinib, restores SHP2 into the cytoplasm membrane, limiting AKT and ERK activation.

      Conclusion

      High SHP2 mRNA is related to shorter RFS and OS in EGFR-mutant LUADs, but not in EGFR wild-type LUADs. The findings indicate that the addition of SHP2 inhibitors could improve adjuvant therapy in EGFR-mutant LUADs.

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      FP12.04 - Intelligent Label-Free Image-Based Profiling for Lung Cancer Cell Detection and Classification (ID 1930)

      00:00 - 00:00  |  Presenting Author(s): Michelle Chi Kiu Lo  |  Author(s): Dickson Man Dik Siu, Michael Hsin, Chung Man James Ho, Kevin Kin Man Tsia

      • Abstract
      • Presentation
      • Slides

      Introduction

      Ample evidence shows that the biophysical properties of cells (e.g. size, mass density, structural complexity etc.) are as effective descriptors of cellular heterogeneity, dysfunctional/malignant changes, compared to the conventional fluorescence markers. Because of its label-free nature, biophysical phenotyping of cells could also augment the adaptability and cost-efficiency of diagnosis. However, its widespread utility, particularly in lung cancer diagnosis/treatment monitoring, requires both high- throughput and high statistical power that are unattainable currently. To close this gap, we present an integrative strategy that extracts high-dimensional biophysical single- cell information and processes with millions of quantitative images at sub-cellular resolution assisted by deep learning. This advance provides sufficient discrimination power to delineate the biophysical phenotypes of lung cancer subtypes, and sensitively detect rare lung cancer cells spiked in human blood in a completely label-free manner.

      Methods

      We developed a microfluidic imaging flow cytometer, called multi-ATOM, which captures single-cell quantitative phase images (QPI) at an ultrahigh-throughput beyond 10,000cells/sec. We parameterized >80 label-free biophysical phenotypes from QPI and molecular-specific fluorescent markers simultaneously on the same cells. Further using deep neural-network with transfer learning, we investigated the feasibility of using these single-cells phenotypic profiles for (I) classification of three major lung cancer subtypes (adenocarcinoma, squamous cell carcinoma and small cell carcinoma) from 7 cell lines (H358, H1975, HCC827, H520, H2170, H526 and H69, all from ATCC) with a total population of >2,000,000cells; (II) detection of rare lung cancer cells (H2170) spiked in the human peripheral blood mononuclear cells (PBMCs) at ratios of 1:1,000, 1:10,000 and 1:100,000.

      Results

      wclc2020_resultsimage.png

      We demonstrated that this profiling strategy achieves the overall accuracy of ~90% to predict the three lung cancer subtypes. We further confirmed that lung cancer subtypes exhibit their distinct label-free phenotypic “fingerprint-like” profiles distilled from 7 cell lines. In the spiked-in tests, this method also achieves high sensitivity of >96% and specificity of 98%. In contrast to the detection method using cell size, our approach with the entire biophysical profile greatly improved the specificity of rare H2170 detection in PBMCs (increased from 89% to 98% at spike ratio of 1:10,000;and from 91% to 98% at spike ratio of 1:100,000.)

      Conclusion

      Massive label-free image-based profiling of single-cell showed the feasibility for rare lung cancer cells detection in blood, and lung cancer subtypes classification with the sensitivity and specificity which are otherwise challenging in the current label-free technologies. It could open a new avenue for exploiting cost-effective methods for cancer diagnosis and treatment monitoring.

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      FP12.05 - Molecular Landscape of Primary and Acquired Resistance to Immune Checkpoint Inhibitors in Chinese Advanced Non-Small Cell Lung Cancer (ID 3529)

      00:00 - 00:00  |  Presenting Author(s): Xiaomin Niu  |  Author(s): Zhen Zhou, Yongfeng Yu, Lan Shen, Ke Liu, Jian Bai, Airong Yang, Lin Wu, Shun Lu

      • Abstract
      • Slides

      Introduction

      Immune checkpoint inhibitors (ICIs) have improved the prognosis of non-small cell lung cancer (NSCLC) patients. However, about 80% of patients do not respond at all ("primary resistance"), whereas others initially respond to immunotherapy, later relapse and develop therapy resistance ("acquired resistance"). Absence of PD-L1 expression is well regarded as a biomarker of primary resistance to ICIs, and tumor mutation burden (TMB), microsatellite instability (MSI), HLA genotype and tumor neoantigen burden (TNB) have also been reported in recent studies to be related to the resistance of immunotherapy. This research is to explore the molecular landscape of primary and acquired resistance in Chinese advanced NSCLC treated with anti-PD-L1/PD-1 antibodies based on results of whole exome sequencing (WES) and targeted sequencing (TS) containing comprehensive immune molecular markers.

      Methods

      WES (~39Mb CDS of over 18,000 genes) or TS (~1.6Mb CDS of 654 genes) were conducted on 50 samples from 45 patients received anti-PD-L1/PD-1 antibodies, including 18 baseline pretreatment and 32 resistant tumor samples (Figure 1A). The primary endpoints include objective response rate (ORR) and progression-free survival (PFS), and statistics was analyzed using Fisher’s exact test and Kaplan-Meier analysis.

      Results

      About 31% of patients (N=14) responded to anti-PD-L1/PD-1 antibodies in Chinese advanced NSCLC (Figure 1A, 1B), and 40% (N=18) had stable disease. TNB was a stronger prognosis predictor of ICIs than TMB in pretreatment samples (N=18, Figure 1C, 1D). Patients with high TNB had a significantly better objective response (P=0.007) and longer PFS (P=0.003) (Figure 1C). HLA supertype B27 (HR=0.350, P=0.021) and HLA B*15:02 (HR=0.330, P=0.018) were individually associated with a poor prognosis in total 45 patients received ICIs (Figure 1E, 1F). These results indicate that low TMB or presence of HLA B27 and HLA B*15:02 were associated with primary resistance to ICIs. For acquired resistance to ICIs, known mutations were found when disease progressed on ICIs (3/25), including B2M p.W80*, B2M p.L15Ffs*41 and JAK1 p.L235I (Figure 1G). One patient had PFS of 11.2 months with acquired B2M mutation p.L15Ffs*41 detected only in post-progression sample (Figure 1H).

      figure1_update20200827.png

      Conclusion

      In Chinese advanced NSCLC, low TNB and presence of HLA B*15:02 and supertype B27 are biomarkers of primary resistance to ICIs, implying TNB and HLA genotypes can help screen patients with greater clinical benefit from immunotherapy in addition to PD-L1. Known mutations of acquired resistance to ICIs are found in few samples, other molecular mechanisms need to be explored to understand acquired resistance to ICIs.

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      FP12.06 - GRIm-Score Variations Predict Outcome in Metastatic NSCLC Patients Treated with First-Line Pembrolizumab (ID 3363)

      00:00 - 00:00  |  Presenting Author(s): Edoardo Lenci  |  Author(s): Luca Cantini, Silvia Rinaldi, Federica Pecci, Valeria Cognigni, Veronica Agostinelli, Giulia Mentrasti, Nicoletta Ranallo, Alessio Lupi, Francesco Paoloni, Alessio Cortellini, Corrado Ficorella, Rita Chiari, Massimo Di Maio, Joachim Aerts, Anne-Marie Dingemans, Linda Nicolardi, Andrea Caglio, Sophie Aerts, Rossana Berardi

      • Abstract
      • Slides

      Introduction

      Prompt identification of metastatic non-small cell lung cancer patients (NSCLC) who benefit from first-line pembrolizumab is crucial in clinical practice. The Gustave Roussy Immune Score (GRIm-score) takes into account neutrophil-to-lymphocyte ratio (NLR), serum albumin concentration and lactate dehydrogenase (LDH) and its prognostic score has been investigated in patients treated with immune check-point inhibitors (ICIs). To further assess the predictive value of baseline GRIm-score (GRImT0), we separately investigated two cohorts of metastatic NSCLC patients treated with first-line pembrolizumab immunotherapy or chemotherapy (CHT). We also investigated whether GRIm-score at 45 days since treatment initiation (GRImT1) and GRIm-score deterioration between the two time points may better predict clinical outcomes.

      Methods

      We retrospectively evaluated 222 metastatic NSCLC patients: 135 treated with pembrolizumab and 87 treated with chemotherapy. NLR, serum albumin and LDH concentrations were assessed at T0 and at T1. According to the GRIm-score, patients were assigned 1 point if they had NLR > 6, LDH > upper limit normal or albumin < 3.5 g/dl, for a total of 3 points. Patients with a GRIm-score <2 were considered as having a low Score. Chi-squared test was used to evaluate the association between variables. Median overall survival (OS) and progression free survival (PFS) were estimated by Kaplan-Meier method and log-rank test was used to assess differences by subgroups. The independent prognostic and predictive role of the scores was further analysed by multivariate logistic regression and Cox proportional hazard analyses.

      Results

      Median follow up of the whole population was 24.0 months, median OS and PFS were 12.0 months and 6.5 months, respectively. In both cohorts, no difference in terms of OS between patients with low and high GRImT0 was found. Otherwise, median OS and PFS of the low GRImT1 group were significantly longer than those of the high GRImT1 group in pembrolizumab-treated patients, but not in the CHT cohort (pembrolizumab cohort: low vs. high; median OS not reached vs. 9.2 months, p = 0.004 and median PFS 10.8 vs. 2.3 months, p = 0.002). The outcome of patients receiving pembrolizumab with no GRIm deterioration was better compared to patients with GRIm deterioration in terms of OS (median OS not reached vs. 12.0 months, p < 0.001), PFS (median PFS 20.6 vs. 2.6 months, p < 0.001) and objective response rate (58.2% vs 7.6%, p = 0.003). The prognostic and predictive role of GRImT1 and of GRIm deterioration in the pembrolizumab-cohort was also confirmed at multivariate analyses, after adjusting for performance status (PS), smoking and disease burden (high GRImT1 HR for death: 2.63, 95% CI 1.18-5.86, p = 0.01, GRIm deterioration HR for death: 3.28, 95% CI 1.39-7.74, p = 0.006).

      Conclusion

      Our data shown that GRImT1 and GRIm deterioration are more reliable predictors of outcome compared to GRImT0 in NSCLC patients treated with pembrolizumab. Their prognostic and predictive value was independent of PS, smoking and disease burden. Both GRImT1 and GRIm deterioration represent useful and easy-to-access early indicators of treatment response in metastatic NSCLC patients treated with first-line pembrolizumab and might help guiding clinicians’ choices in this setting.

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      FP12.07 - Prognostic Value of HLA-I Homozygosity in Non-Small Cell Lung Cancer Patients Treated with Single Agent Immunotherapy (ID 1069)

      00:00 - 00:00  |  Presenting Author(s): Afaf Abed  |  Author(s): Leslie Calapre, Johnny Lo, Suzana Correia, Samantha Bowyer, Abha Chopra, Mark Watson, Muhammad Khattak, Michael Millward, Elin Gray

      • Abstract
      • Slides

      Introduction

      HLA plays a key role on the orchestration of the immune response. In particular, HLA downregulation is a well-established mechanism in cancer immune evasion. On the other hand, the role of HLA homozygosity in cancer control and response to immunotherapy is less well understood. We aimed to assess the impact of genomic HLA-I/II homozygosity in the survival benefit of patients with unresectable locally advanced, metastatic non-small lung cancer treated by single-agent PD1/PDL1 inhibitors.

      Methods

      We collected blood from 170 advanced lung cancer patients treated with immunotherapy at two major oncology centres in Western Australia. Genomic DNA was extracted from white blood cells and used for HLA-I/II high-resolution typing. HLA-I/II homozygosity was tested for association with survival outcomes. Univariate and multivariate Cox regression models were constructed to determine where HLA homozygosity was an independent prognostic factor affecting Overall Survival (OS) and Progression Free Survival (PFS). We also investigated the association between individual HLA-A and -B supertypes with OS.

      Results

      Homozygosity at HLA-I loci, but not HLA-II, was a statistically significant associated with shorter OS (HR=2.17, 95%CI 1.13-4.17, P=0.02) in both univariate and multivariate analysis. The effect HLA-I homozygosity in OS was particularly relevant for patients with tumours expressing PDL1 ≥50% (HR=3.93, 95%CI 1.30-11.85, P<0.001). The adverse effect of HLA-I hhomozygosity on PFS was only apparent after controlling for interactions between PD-L1 status and HLA-I genotype (HR= 2.21, 95%CI 1.04 – 4.70, P=0.038). The presence of HLA-A02 supertype was the only HLA-I supertype to be associated with improved OS (HR=0.56, 95%CI 0.34-0.93, P=0.023)

      figure 1.jpg

      table multivariate.png

      Conclusion

      Our results suggest that homozygosity at ≥1 HLA-I loci is associated with short OS and PFS in patients with advanced NSCLC with PDL1 ≥50% treated with single-agent immunotherapy. Carriers of HLA-A02 supertype reported better survival outcomes in this cohort of patients.

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      FP12.08 - The Survival Impact of Circulating T Regulatory Cells Subsets in Patients with Untreated Lung Cancer (ID 3425)

      00:00 - 00:00  |  Presenting Author(s): Dahiana Amarillo  |  Author(s): Andreina Brugnini, Natalia Trias, Maria Clara Rodríguez, Virginia Rodríguez, Siul Salisbury, Mauricio Cuello, Daniela Lens

      • Abstract
      • Slides

      Introduction

      Regulatory T Cells (Tregs) play an important role in carcinogenesis and tumor escape from immunosurveillance by suppressing effector cells. The number of circulating Tregs are increased in patients with cancer, included lung cancer. However, the prognosis impact of different subsets in lung cancer prognosis it is limited and controversial. This study aimed to investigated survival impact of different circulatory Tregs subsets in patients with lung cancer

      Methods

      We analyzed the frequency of circulating CD4, CD8 and Tregs lymphocytes in 66 patients with lung cancer and 32 healthy controls using flow cytometry. Circulating Tregs subtypes: naïve, memory and the expression of the activation marker HLA-DR were correlated with overall survival. Statistical analysis was performed using the software SPSS 25.

      Results

      Sixty-six treatment-naïve lung cancer patients and 32 controls were enrolled to the study. The percentage of Tregs was significantly increased in lung cancer patients compared to healthy controls (7.23 vs 3.5 %, p<0,0001). There was significant difference between the percentage of memory Tregs (CD45RO+) in patients and controls (86.41 vs 43.21%; p<0.0001). Median Overall survival (OS) for all patients was 5,6 months, with a 12-months overall survival rate of 32,8%. We found that patients levels of Tregs above the 75th percentile (5.4 %) had a significantly worse OS than patients with levels below the 75th percentile (median OS 6.0 months vs 11.7 months; p 0.005; fig 1). Patients with more than 20% of activated Tregs (TRegs DR+) had worse OS than patients with lower levels (median OS 6.4 vs 11.8 months; p 0.003; Fig. 2). No association was found between memory Tregs (CD45 RO+) levels and survival.

      Conclusion

      Tregs and activated Tregs (DR+) are potential prognostic factors in patients with lung cancer and could be considered a predictive biomarker in future clinical trials.

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      • Abstract
      • Slides

      Introduction

      Many studies have demonstrated that chemo-immunotherapy is a promising approach for NSCLC patients but still exists a lack of prediction biomarkers of survival. We have recently showed that pathological response is a surrogate of progression free survival (PFS) including infiltrating immune cells as potential biomarker of pathological response in NADIM clinical trial (Provencio et al., 2020. Lancet Oncology, in press).

      New biomarkers in peripheral blood are being described, focused on the immune system response. Preliminary data was presented at WCLC 2019 however additional results are included in this report. Here we describe the effect of chemo-immune neoadjuvant treatment on resectable NSCLC stage III patients’ immune system and describe blood biomarkers that could help to identify responders to this combination therapy.

      Methods

      Peripheral mononuclear cells (PBMCs) and plasma from NADIM clinical trial patients before and after chemo-immune neoadjuvant treatment were used. Phenotyping and activation levels of immune cell populations were analyzed by flow cytometry, focused on CD4 T cells, CD8 T cells, T cells NK like and NK cells. Moreover, characterization of the immune response was evaluated by a cytokine array.

      Clinical evaluation of pathological response, classified patients in 3 groups, complete (CPR, 0% tumor cells), major (MPR, <10% viable tumor) and incomplete (IPR, >10% viable tumor). Wilcoxon and Kruskall-Wallis statistic tests were used.

      Results

      Even though we have previously described a decrease of T lymphocytes on tissue after treatment, we do not see these changes on blood. Thus, percentages of PBMCs (T cells, B cells, NK cells and macrophages) did not vary after neoadjuvant treatment. However, lower levels of activated CD4 T cells and NK cells were observed. Interestingly, this decrease was exclusively statistically significant for patients who achieved a CPR, but no differences were observed for MPR or IPR. As expected, detection of PD1+ cells after neoadjuvant Nivolumab (anti-PD1) treatment was almost completely abrogated, however, a trend for higher PD1+ cell proportions was observed in patients achieving CPR at diagnosis.

      Furthermore, many cytokines involved in immune response and described as putative biomarkers for immunotherapy in NSCLC as IL-2, IL-15, IL-6, IL-13 or IFN-gamma, among others, were decreased after neoadjuvant treatment. Notably, stratifying by pathological responses, this decrease was statistically significant only for non-complete responses.

      Conclusion

      The analysis of immune cell markers on blood samples could be a source for potential surrogate markers of pathological response to neoadjuvant treatment on NSCLC patients.

      Similarly, to what occurs in tissue, CPRs showed differences compared to MPR or IPR in some blood markers, both at the cellular and cytokine level. Thus, after treatment, patients achieving CPRs do not seem to reduce their levels of cytokines such as IL-2, IL-15, IL-6, IL-13 or IFN-g associated with anti-tumor response, but they do reduce their levels of activated CD4 and NK cells

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      FP12.10 - IGF-1R Inhibition in Small Cell Lung Cancer: Role of Brigatinib (ID 1953)

      00:00 - 00:00  |  Presenting Author(s): Apar Kishor Ganti  |  Author(s): Imayvaramban Lakshmanan, Sanjib Chaudhary, Naveen Kumar Perumal, Surinder Batra

      • Abstract
      • Slides

      Introduction

      Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine tumor characterized by early distant spread and chemoresistance. The overall 5-year survival rate has remained a dismal 7% over the last 25 years, and systemic treatment options for patients with relapsed SCLC have remained unchanged. Even though patients often initially respond to chemotherapy, they routinely relapse. Relapsed SCLC is often chemorefractory, resulting in poor survival. Brigatinib (AP26113) is a selective anaplastic lymphoma kinase-positive (ALK) inhibitor; however, besides ALK inhibition, brigatinib inhibits IGF-1R signaling. IGF-1R is thought to be a key target in SCLC. The objective of this project is to identify the mechanism and therapeutic efficacy of brigatinib along with currently available chemotherapeutic drugs in SCLC.

      Methods

      We used various SCLC cell lines and normal human bronchial epithelial cells (NHBE) for the screening of IGF-1R by quantitative real-time PCR and western blotting. MTT assays were performed to identify the inhibitory role of brigatinib on IGF-1R positive and negative SCLC cells. We have also performed apoptosis and cell cycle experiments to identify the effect of brigatinib on apoptosis and cell growth, respectively. Further, we have formed CRISPR-Cas9 based IGF-1R, and IGF-1 knockout. These isogenic cells were used to identify the chemoresistance mechanisms.

      Results

      We chose five SCLC cell lines based on IGF-1R level (SBC-5 high, H82high, H526basal, SBC-3 basal and H69basal). The IC50 of brigatinib ranged from 50 nM to 100 nM in H526 and H69 cells lines and from 750 nM to 1 µM in SBC-3, SBC-5, and H82 cell lines. IGF-1R knockdown SCLC cells showed enhanced sensitivity to cisplatin and etoposide, as compared to control clone cells. We observed that combination of brigatinib and etoposide increased apoptosis. SBC-3 and SBC-5 cells ware treated with brigatinib alone, etoposide alone and combination of brigatinib and etoposide. The percentage of apoptotic cells was significantly higher in cells treated with combination etoposide and brigatinib (SBC-3 - 54.1 %; SBC-5 - 37.5%) compared to brigatinib alone (12.9%; 37.8%), etoposide alone (31.2%; 14.9%) and untreated controls (3.7%; 8.1%).

      Conclusion

      Brigatinib induced IGF-1R inhibition may have therapeutic implications in SCLC. Targeting IGF-1R signaling and identifying possible mechanisms of IGF-1R mediated chemoresistance in SCLC can potentially reduce the SCLC associated mortality. Clinical trials of brigatinib in patients with SCLC and high IGF-1R expression are warranted.

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      FP12.11 - Single-Cell RNA Sequencing Analyses Distinguishes Transcriptional Activity of c-Myc and L-Myc in Small Cell Lung Cancer (ID 2495)

      00:00 - 00:00  |  Presenting Author(s): Ayushi S Patel  |  Author(s): Ranran Kong, Takashi Sato, Seungyeul Yoo, Abhilasha Sinha, Charles A Powell, Jun Zhu, Hideo Watanabe

      • Abstract
      • Slides

      Introduction

      Small cell lung cancer (SCLC) accounts for 15% of all lung cancer with a dismal prognosis, where the 5-year overall survival is 6%. The genomic landscape of primary SCLC tumors has revealed universal loss of RB1 and TP53 and frequent genomic amplification of oncogenes; specifically, MYC family members that are mutually exclusive of each other. Prior works have revealed that c-Myc and L-Myc expression is observed in distinct histopathological murine tumors with unique expression of neuroendocrine markers. Furthermore, we previously characterized their role as lineage factors, where c-Myc induces trans-differentiation across SCLC subtypes while L-Myc fails to convert the fate of the cell to neuroendocrine SCLC subtype (Patel et al., 2020 AACR). Together implying intrinsic differences between c-Myc and L-Myc. However, the molecular mechanisms underlying the differences still remain unexplored. Here, we apply single-cell technology to investigate the redundant and unique transcriptional activities of L-Myc and c-Myc in SCLC.

      Methods

      We generated a cell-based model to engineer the swapping of c-Myc and L-Myc in NCI-H82, a c-Myc amplified SCLC using overexpression and CRISPR/Cas9 systems. We performed bulk RNA-seq and single-cell RNA sequencing (scRNA-seq) on genetically engineered control NCI-H82 cells (LacZ/sgNT), NCI-H82 with L-Myc overexpression only (L-Myc/sgNT) and replaced NCI-H82 with L-Myc overexpression and c-Myc deletion (L-Myc/sgMYC).

      Results

      UMAP analysis of the single-cell transcriptome of these cells revealed unique clusters for control NCI-H82 (LacZ/sgNT) cells and NCI-H82 (L-Myc/sgMYC) cells. These unique clusters were differentiated by the expression of several neuronal associated genes and metabolic associated genes. This was consistent with our findings from bulk RNA-seq, where we found L-Myc induces the expression of genes that are enriched for neuronal- and neurogenesis- associated pathways. We identified specific co-regulated modules for only c-Myc expressing cells (NCI-H82 LacZ/sgNT), cells expressing both c-Myc and L-Myc (NCI-H82 L-Myc/sgNT), and only L-Myc expressing cells (NCI-H82 L-Myc/sgMYC), that distinguished c-Myc and L-Myc transcriptional activity. Furthermore, inferred regulatory relationships for c-Myc and L-Myc was supported by our previous findings that c-Myc and L-Myc have unique transcriptional networks. Additionally, unsupervised pseudotime ordering of combined genetically engineered cells revealed a lineage hierarchy that reflected the dynamic changes in the cellular state corresponding with the changes in c-Myc and L-Myc expression.

      Conclusion

      Collectively, we leveraged single-cell technologies and identify the molecular differences and similarities between c-Myc and L-Myc in the context of SCLC, a long-standing question in the field.

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      FP12.12 - Lung Cancer in Women Never-Smokers: A Genomics Perspective of the Women’s Health Initiative (WHI) Cohort (ID 3531)

      00:00 - 00:00  |  Presenting Author(s): Sitapriya Moorthi  |  Author(s): Amy Paguirigan, Garnet Anderson, Peggy Porter, Megan Herndon, Esther Jhingan, Gavin Ha, Alice Berger

      • Abstract
      • Presentation
      • Slides

      Introduction

      Lung cancer is the leading cause of cancer-related deaths worldwide. Although lung cancer is primarily attributed to tobacco consumption, the number of lung cancer cases in never-smokers (LCNS), defined as lifetime consumption of less than 100 cigarettes, is increasing. Currently, 24% of lung cancer cases in women and 17% of lung cancer cases in men are in individuals who have never smoked, the majority of which are adenocarcinomas. In fact, if considered as a separate class of cancer, LCNS would be the 7th highest cause of cancer related mortality worldwide. LCNS is more common among women and is 3-4-fold more common among Asian women (age-adjusted). Thus far, the majority of tumor genome-wide sequencing efforts in lung cancer have been focused on patient cohorts with a smoking history. We know that LCNS is distinct from lung adenocarcinoma found in smokers at the genetic level, however large gaps in our understanding of this population persist. Through a unique collaboration with the Women’s Health Initiative (WHI) we now have access to a large repository of tumor tissue from LCNS patients. We have performed exome-sequencing on this cohort and here we describe novel mutations, structural variants and copy number changes in this cohort.

      Methods

      Whole-exome sequencing of 75 tumor-normal pairs was performed. Mutations were identified for the entire cohort using a consensus dual-caller and filtering methodology. Variants were then analyzed to identify genes with significant mutations using MutSig2CV. Structural variant analysis was performed using SvABA and copy number analysis was performed using TITAN. Finally, we perform correlative analysis of mutations with the metadata curated by the WHI and highlight key features of this cohort.

      Results

      Our mutational analysis reveals showed that there is an enrichment of known oncogenes including KRAS, EGFR and TP53. Additionally, we identified mutations in STK11. Here we describe novel genes and mutations previously unknown to occur in LCNS cohort and describe their potential functional implications. We also report novel structural variants and copy number alterations.

      Conclusion

      Mutational analysis of our LCNS cohort reveals that this cohort in general has a lower tumor mutational burden compared to their control cohort with a history of smoking. Additionally, we find that this cohort has mutations that have been previously reported in studies in LCNS patients. However, the existence of novel mutations and structural alterations may offer a unique opportunity for future target identification and therapeutic intervention.

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      FP12.13 - Therapeutic Index Predicts Clinical Outcome of both Treated and Treatment-Naïve NSCLC Patients Receiving Targeted- and Immune-Therapy (ID 1931)

      00:00 - 00:00  |  Presenting Author(s): Xiaomin Niu  |  Author(s): Zhen Zhou, Zhiwei Chen, Yongfeng Yu, Lan Shen, Ziming Li, Ke Liu, Jian Bai, Airong Yang, Lin Wu, Shun Lu

      • Abstract
      • Slides

      Introduction

      Recent studies have reported that the more molecular matches, the better prognosis of clinical treatments is. “Matching score” based on a targeted panel is such an index to evaluate the prognosis of previously treated cancer patients receiving targeted- and immune-therapy, while no similar scoring system has been established for treatment-naïve patients. This research aims to construct a new therapeutic index (T-Index) to predict clinical prognosis for both treatment-naïve and treated NSCLC patients receiving targeted- and immune-therapy.

      Methods

      Whole exome sequencing (WES, ~39Mb CDS of over 18,000 genes) and targeted sequencing (TS, ~1.1Mb CDS of 457 genes) were conducted on tumor samples from 102 stage IV NSCLC patients (treated N=32, treatment-naïve N=70) before targeted- (N=84) and immune-therapy (N=18) from 2018 to 2019. Molecular feature shared by WES and TS (SNV/Indel, CNV and tumor mutation burden (TMB)), and WES-specific molecular features (HLA genotyping, tumor neoantigen burden (TNB), loss of heterozygosity (LOH) and intra-tumoral heterogeneity (ITH)) were analyzed to identify prognostic predictors, and T-Index of WES and TS was each calculated. The association of both T-Indexes with objective response rate (ORR) and progression-free survival (PFS) were analyzed and compared. The cutoff of 0.5 was chosen according to the minimum P value approach.

      Results

      ORR and PFS were significantly higher and longer in patients with T-Index>0.5 than those with T-Index<=0.5 in previously treated patients (N=39) using WES (p=7e-0.4 for ORR, p=0.005 for PFS), but not using TS (p=0.388 for ORR, p=0.119 for PFS) (Figure 1A and 1C). In the treatment-naïve patients (N=70, targeted N=62, immunotherapy N=8), ORR in patients with T-Index>0.5 was significantly higher than those with T-Index<=0.5 using both WES (73.5% vs. 31.8%, p=0.002, Figure 1B)and TS (73.9% vs. 36.4% p=0.004, Figure 1D). A higher T-Index was also an independent predictor of longer PFS in WES(8.4mo vs. 5.5mo,p=0.012)and TS(9.5mo vs. 7.4mo,p=0.035)for treatment-naïve patients (Figure 1B and 1D).figure-20200825.png

      Conclusion

      Our results showed that T-Index by WES including non-canonical biomarkers, TNB, HLA genotyping, LOH and ITH, is significantly associated with clinical outcome whether in treatment-naïve or previously treated patients. Since TS are more practical for companion diagnostics in clinical, a new version of sequencing panel which covers non-canonical biomarkers related to immunotherapy listed above is needed to be developed and tested with the study going forward.

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