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Daniel SW Tan

Moderator of

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    ES24 - Diagnosis and Management of Side Effects of Immunotherapy (ID 363)

    • Event: WCLC 2019
    • Type: Educational Session
    • Track: Immuno-oncology
    • Presentations: 3
    • Now Available
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      ES24.01 - Recognizing Toxicities in an Early Phase in PDL1 Treatment (Now Available) (ID 3905)

      11:30 - 13:00  |  Presenting Author(s): Hossein Borghaei

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      ES24.02 - Renal Toxicities in Combination I/O Chemotherapy Treatment (Now Available) (ID 3906)

      11:30 - 13:00  |  Presenting Author(s): Joachim G.J.V. Aerts

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      ES24.03 - Management of Immunerelated Toxicities Unresponsive to Steroids (Now Available) (ID 3907)

      11:30 - 13:00  |  Presenting Author(s): Anne Tsao

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    PL04 - Food for Thought in the Management of Thoracic Malignancies (ID 91)

    • Event: WCLC 2019
    • Type: Plenary Session
    • Track: Advanced NSCLC
    • Presentations: 4
    • Now Available
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      PL04.01 - Epidemiology and Clinical Characteristics of Lung Cancer in Women (Now Available) (ID 3595)

      16:15 - 17:00  |  Presenting Author(s): Enriqueta Felip

      • Abstract
      • Presentation
      • Slides

      Abstract

      "Non applicable"

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      PL04.02 - What Does Survivorship Mean in the World of Immunotherapy (Physical and Financial)? (Now Available) (ID 3596)

      16:15 - 17:00  |  Presenting Author(s): Michelle Turner

      • Abstract
      • Presentation
      • Slides

      Abstract

      With improvements in diagnostic, therapeutic, and supportive therapies, the number of cancer survivors

      continues growing with over 20 million cancer survivors worldwide and an estimated 2/3 of adults with

      a cancer diagnosis who are anticipated to be alive in 5 years1. Due to this increase in survivors, major

      medical societies such as American Society of Clinical Oncology (ASCO), Institute of Medicine (IOM), and

      the Society for Immunotherapy of Cancer’s (SITC) have highlighted the need for strategies to improve

      the ongoing care of survivors and survivorship plans.2

      The 4 basic tenets of a survivorship plan are surveillance, prevention, intervention and coordination.

      Surveillance is aimed at monitoring for recurrence, second cancers, and long term toxicities, prevention

      of these sequelae if possible, intervention if they are found, and lastly coordination between hospital

      and community‐based doctors is essential for this plan to be effective.3 These needs are typically

      communicated to the patient’s general practitioner (GP)/primary care physician (PCP) by a “care plan”

      that outlines the patient’s oncology treatment course, potential long‐term toxicity, the

      frequency of follow up visits, scans and links to community resources.

      New cancer therapies such as immunotherapy has resulted in significantly improved overall survivals in

      many advanced cancers, including those that had formerly been considered refractory.6,7,8 However, the

      short‐, intermediate‐, and long‐term complications of these therapeutic agents are still being identified.

      Immune‐mediated events, for example, can occur immediately after therapy initiation or even up to two

      years post treatment as a consequence of overstimulation of the immune system leading to

      autoimmunity with the potential for permanent or long‐term sequelae.4,5

      References:

      1. https://cancercontrol.cancer.gov/ocs/statistics/statistics.html

      2. https://www.canceradvocacy.org/

      3. Denlinger, CS et. Al. Survivorship: Introduction and Definition. J Natl Compr Canc Netw. 2014 Jan; 12(1): 34–45.

      4. Sheela S, Kim ES, Mileham KF. Moving away (finally) from doublet therapy in lung cancer: immunotherapy and KEYNOTE‐189J Thorac Dis. 2018 Sep;10(9):5186‐5189.

      5. Weber JS, Hodi FS, Wolchok JD, et al. Safety Profile of Nivolumab Monotherapy: A Pooled Analysis of Patients With Advanced Melanoma. J Clin Oncol 2017; 35:785.

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      PL04.03 - The Relevance of an International Database for the Study of Thymic Neoplasms (Now Available) (ID 3597)

      16:15 - 17:00  |  Presenting Author(s): Vanessa Bolejack

      • Abstract
      • Presentation
      • Slides

      Abstract

      Introduction

      Until the 8thedition of the AJCC/UICC TNM classification of malignant tumours went into effect, no official stage classification was available for thymic malignancies. Some classification systems had been proposed but were generally developed from a limited number of patients and not usually tested in an independent dataset. The system developed by Dr. Akira Masaoka in 1981 did undergo external validation and was widely adopted. However, the adoption of these proposed systems in different institutions and regions was hampered by a lack of uniform nomenclature and varying interpretations of definitions. The current (8thedition) TNM stage classification for thymic malignancies endorsed by AJCC and UICC was informed by a database with 10,808 cases of thymic malignancies from 105 sites worldwide, compiling cases contributed by ITMIG (including patients from North and South America, European, and Korean (KART) and Chinese (ChART) institutions), Japan (JART), and Europe (ESTS) with funding and coordination by IASLC and Cancer Research and Biostatistics (CRAB), with the specific intent of developing a TNM based staging system for these malignancies.

      Methods and materials

      The IASLC Stating and Prognostic Factors Committee - Thymic Domain (SPFC-TD) conducted a web-based cross-sectional survey to assess the implementation of the 8thEdition TNM staging system in the thoracic community. The survey was sent to the major thymic organizations (ITMIG, ESTS, KART, ChART, RYTHMIC, JART) in addition to IASLC membership. A new database to inform the 9thedition TMN staging system is under development to provide updated follow-up from the institutions contributing to the 8thedition database, add additional institutions, and add new cases collected prospectively.

      Results

      According to the survey results, the TNM stage classification of thymic tumors has gained a reasonable acceptance in the scientific community, while the Masaoka stage system remains widely employed. An increased attention to the N descriptor seems to have been incorporated. There is high awareness of the new staging system. The current efforts of the Thymic Domain of the IASLC Staging and Prognostic Factors Committee focus on expanding and updating the database used for the 8thedition to further refine the stage definitions and includes updated follow-up on patients from Turkey, the ESTS, JART, ChART and KART, plus data collected prospectively from ChART.

      Conclusion

      The database created to inform the 9thedition of TNM staging for thymic malignancies will allow for refinement and adjustment of the 8thedition system and attempt to address any perceived deficiencies of the current system. An overview of the current state of the database will be presented at the meeting in Barcelona.

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      PL04.04 - Prognostic Factors in Malignant Pleural Mesothelioma (Now Available) (ID 3598)

      16:15 - 17:00  |  Presenting Author(s): Michaela B Kirschner

      • Abstract
      • Presentation
      • Slides

      Abstract

      Malignant pleural mesothelioma (MPM) is a disease for which we are facing difficulties and challenges at many levels from diagnosis over treatment selection and prediction of treatment response to prediction of the prognosis of individual patients. Besides the necessities to obtain an accurate and early diagnosis and to be able to predict the response to a specific treatment, it is equally important to be able to estimate the overall prognosis of a patient as this will also affect treatment decisions.

      Looking at the research efforts of the last two decades, we see an abundance of studies investigating prognostic markers for MPM, yet to date the most reliable predictors of disease outcome are still the clinical and pathological parameters, which have been used in the past. Probably the most accurate prognostic factor for MPM is the histopathological subtype, with epithelioid MPM being associated with the best prognosis followed by the biphasic subtype and sarcomatoid histology. In addition, it is well recognised that patients presenting with less advanced disease, of younger age and female gender are generally doing better. Some of these factors were combined with additional proposed predictors of outcome into scoring systems suggested by the European Organization for Research and Treatment of Cancer (EORTC, [1]) and the Cancer and Leukemia Group B (CALGB, [2]). Both scores have been subsequently validated and still hold true today, over 20 years later.

      Since then, many studies have attempted to identify additional prognostic biomarkers. One area of extensive research is the investigation of changes in blood cell ratios, which can be linked to the inflammatory and/or nutritional status of the patients [3, 4]. In terms of inflammation-related indicators of poor outcome, elevated C-reactive protein (CRP), a high neutrophil-to-lymphocyte ratio, and a low lymphocyte-to-monocyte ratio (LMR) have been proposed. Some of these inflammatory markers have also been combined with factors reflecting the nutritional status of patients. For example, has the combination of CRP and albumin been suggested to have prognostic value, as shown in the CRP-to-albumin ratio (CAR) and the modified Glasgow Prognostic Score (mGPS). Another proposed combination is that of albumin and lymphocytes into the Prognostic Nutritional Index (PNI). Additionally, radiological factors, such as tumour volume or pleural thickness measured by CT or MRI alone or as part of prognostic scores (e.g. in combination with other factors such as in the multimodality prognostic score [5]), as well as radiomics approaches have shown prognostic potential [6]. While many of these proposed prognostic factors are often routinely collected during standard clinical work-up and blood tests, prospective testing in a clinical setting has yet to be attempted.

      A second area of extensive research in the last decade has been molecular factors, namely the expression of proteins, genes, and microRNAs [3]. Initially, the majority of studies focused on the potential prognostic role of protein expression in tumour tissue. Here, rather frequently, the expression of tyrosine kinases such as epidermal growth factor receptor (EGFR) and c-Met has been investigated, due to the additional potential of targeting those using tyrosine kinase inhibitors. In addition, many cell cycle and apoptosis-related proteins such as p21, p53, survivin or PTEN were evaluated, but in many cases these proteins did not reach significance in multivariate analyses, highlighting that they do not represent independent markers. Other proteins, such as ERCC1 and TS, the target of the antimetabolite drug pemetrexed, did not show consistent results between various studies, hence none of these proteins are used routinely in the clinic. On the level of gene expression, already 15 years ago a 4-gene signature was proposed, which was subsequently independently validated, but never in a prospective fashion. In addition to gene expression, microRNAs have also been proposed to hold prognostic value, but again, independent validation is thus far lacking.

      While many candidate prognostic biomarkers have been proposed, these tend to be dependent on the histological subtype, and the identification of factors predictive of outcome within the individual histological subgroups of MPM patients remains a major challenge. However, with more genetic profiling of larger datasets becoming available also in MPM, investigators have started to address this issue. By aiming to genetically subclassify pathologically purely epithelioid or sarcomatoid tumours, this resulted in the C1/C2 classification [7] and the e-score and s-score classification [8], as well as the 4 cluster iCluster classification generated based on TCGA data [9]. Besides providing potential novel prognostic factors, the molecular characterization of MPM can also provide us with urgently needed deeper insights into the biology of the different subgroups of MPM, which is likely to allow us to identify novel treatment targets together with respective markers predictive of response.

      Nevertheless, these exciting recent findings remain to be independently validated, most importantly in a prospective fashion. A closer look at the literature of the last two decades, however, shows us that rather than aiming at validation of proposed prognostic factors, we are inclined to identify novel candidates. In order to move these promising novel candidates from the bench to the bedside, international collaboration to increase cohort sizes as well as prospective validation will be crucial.

      References:

      1. Curran, D., et al., J Clin Oncol, 1998. 16(1): p. 145-52.

      2. Herndon, J.E., et al., Chest, 1998. 113(3): p. 723-31.

      3. Davidson, B., Hum Pathol, 2015. 46(6): p. 789-804.

      4. Yamagishi, T., et al., Lung Cancer, 2015. 90(1): p. 111-7.

      5. Opitz, I., et al., J Thorac Oncol, 2015. 10(11): p. 1634-41.

      6. Armato, S.G., 3rd, et al., Lung Cancer, 2019. 130: p. 108-114.

      7. de Reynies, A., et al., Clin Cancer Res, 2014. 20(5): p. 1323-34.

      8. Blum, Y., et al., Nat Commun, 2019. 10(1): p. 1333.

      9. Hmeljak, J., et al., Cancer Discov, 2018. 8(12): p. 1548-1565.

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Author of

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    ES01 - What Is the Role of Chemotherapy in the Era of Immunotherapy in Advanced NSCLC? (ID 4)

    • Event: WCLC 2019
    • Type: Educational Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      ES01.03 - Chemotherapy Directly Targets the Immune System to Improve Efficacy  (Now Available) (ID 3151)

      10:30 - 12:00  |  Presenting Author(s): Daniel SW Tan

      • Abstract
      • Presentation
      • Slides

      Abstract

      Multiple phase III trials support the use of combination chemotherapy with immune checkpoint inhibitors in the first line setting. Yet the exact mechanism of synergy is poorly understood. In this third instalment of three talks dissecting this topic, the focus will be on the impact of chemotherapy on the immune system, ranging from its effect on recognition of tumor antigens, circulating immune cells and/or cytokines, as well as on immune cells in the tumor microenvironment. Elucidating the mechanism of action can delineate more tailored approaches to first line therapy, including the use of single agent checkpoint inhibitors or alternative/ additional combinations that further enhance the immune response.

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    MA09 - EGFR & MET (ID 128)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
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      MA09.09 - Long-Term Outcomes to Tepotinib Plus Gefitinib in Patients with <i>EGFR</i>-Mutant NSCLC and MET Dysregulation: 18‑Month Follow-Up (Now Available) (ID 1783)

      15:15 - 16:45  |  Author(s): Daniel SW Tan

      • Abstract
      • Presentation
      • Slides

      Background

      In EGFR-mutant NSCLC, MET amplification may cause resistance to EGFR tyrosine kinase inhibitors (TKIs). In a Phase Ib/II study in EGFR TKI-resistant patients with EGFR-mutant MET+ NSCLC, progression-free survival (PFS) and objective response rate (ORR) after ≥6 months of follow-up were improved with tepotinib (a highly selective MET TKI) plus gefitinib, compared with chemotherapy, particularly in patients with MET amplification. Here we present data at ≥18 months of follow-up.

      Method

      Asian patients with advanced, EGFR+, T790M-, MET+ NSCLC with resistance to prior EGFR TKIs were randomized to receive oral tepotinib 500 mg/day+gefitinib 250 mg/day or ≤6 cycles of cisplatin/carboplatin+pemetrexed chemotherapy±pemetrexed maintenance until confirmed progression, unacceptable toxicity, or withdrawal. Primary endpoint was investigator-assessed PFS. Secondary endpoints included ORR, overall survival (OS) and safety. Subgroup analyses were preplanned in MET IHC3+ and MET amplification populations (NCT01982955).

      Result

      Low recruitment halted full enrolment with 55 of 156 planned patients enrolled.

      As of 12-Dec-2018, median (range) duration of treatment with tepotinib+gefitinib was 21.4 (4.6, 110.9) weeks, with 3 patients still receiving treatment; and with pemetrexed was 18.0 (3.0, 60.4) weeks. 15 patients (62.5%) received ≥4 cisplatin/carboplatin cycles.

      Better outcomes were reported with tepotinib+gefitinib vs chemotherapy (Table), particularly in patients with MET IHC3+ (PFS: HR 0.35 [90% CI 0.17–0.74], OS: 0.32 [0.14–0.75]) or MET amplification (PFS: HR 0.13 [90% CI 0.04–0.43], OS: 0.08 [0.01–0.51]).

      Drug-related grade ≥3 adverse events (AEs) occurred in 17 (54.8%) patients receiving tepotinib+gefitinib and 12 (52.2%) patients receiving chemotherapy. Any-cause AEs leading to discontinuation occurred in 3 (9.7%) patients receiving tepotinib+gefitinib and 1 (4.3%) receiving chemotherapy. Dose reductions due to AEs were reported in 5 (16.1%) vs 4 (17.4%) patients.

      Conclusion

      Tepotinib+gefitinib has durable antitumor activity in patients with EGFR-mutant NSCLC with MET IHC3+ or MET amplification, and was generally well tolerated. MET amplification will be further explored as a biomarker for tepotinib.

      Table: Summary of efficacy data

      Population

      Tepotinib + gefitinib

      Chemotherapy

      HR/OR
      (90% CI)

      Overall MET+*

      Patients, n

      31

      24

      mPFS, months (90% CI)

      4.9 (3.9, 6.9)

      4.4 (4.2, 6.8)

      0.67 (0.35, 1.28)

      mOS, months (90% CI)

      17.3 (12.1, 37.3)

      18.7 (15.9, 20.7)

      0.67 (0.33, 1.37)

      ORR, n (%) [90% CI]

      14 (45.2) [29.7, 61.3]

      8 (33.3) [17.8, 52.1]

      1.99 (0.56, 6.87)

      MET IHC3+

      Patients, n

      19

      15

      mPFS, months (90% CI)

      8.3 (4.1, 21.2)

      4.4 (4.1, 6.8)

      0.35 (0.17, 0.74)

      mOS, months (90% CI)

      37.3 (24.2, 37.3)

      17.9 (12.0, 20.7)

      0.32 (0.14, 0.78)

      ORR, n (%) [90% CI]

      13 (68.4) [47.0, 85.3]

      5 (33.3) [14.2, 57.7]

      4.33 (1.03, 18.33)

      MET amplification

      Patients, n

      12

      7

      mPFS, months (90% CI)

      21.2 (8.3, NE)

      4.2 (1.4, 7.0)

      0.13 (0.04, 0.43)

      mOS, months (90% CI)

      37.3 (NE, NE)

      13.1 (3.3, NE)

      0.08 (0.01, 0.51)

      ORR, n (%) [90% CI]

      8 (66.7) [39.1, 87.7]

      3 (42.9) [12.9, 77.5]

      2.67 (0.37, 19.56)

      CEP-7, centromere protein 7; CI, confidence interval; EGFR, epidermal growth factor receptor; GCN, gene copy number; HR, hazard ratio; IHC, immunohistochemistry; IRC, independent review committee; ITT, intention to treat; MET, mesenchymal-epithelial transition factor; NE, not estimable; OR, odds ratio; ORR, objective response rate; OS, overall survival; PFS, progression-free survival

      All efficacy outcomes are investigator-assessed by RECIST v1.1.

      *IHC2+/IHC3+/gene amplification.

      MET amplification is defined as GCN ≥5 and/or MET/CEP-7 ratio ≥2. 17 of 19 patients with MET amplification have MET overexpression (IHC3+).

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    P1.01 - Advanced NSCLC (ID 158)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.01-107 - KEYNOTE-495/KeyImPaCT: Phase 2 Biomarker-Directed Study of Pembrolizumab-Based Therapy for Non–Small Cell Lung Cancer (ID 1355)

      09:45 - 18:00  |  Author(s): Daniel SW Tan

      • Abstract

      Background

      Immune checkpoint–based therapy has revolutionized the care of patients with non–small cell lung cancer (NSCLC). Pembrolizumab-based combination therapy aims to improve clinical outcomes over pembrolizumab monotherapy. Identification of biomarkers associated with improved response to different combination therapies may improve overall outcomes and yield a more precise approach to the use of immunotherapies in NSCLC. To test the clinical usefulness of a biomarker-informed, pembrolizumab-based combination therapy, this phase 2 KEYNOTE-495 trial (NCT03516981) will be carried out in patients with treatment-naive, advanced NSCLC.

      Method

      KEYNOTE-495 is a randomized, multicenter, open-label, phase 2 trial. Tumor tissue from patients with treatment-naive, advanced NSCLC will be initially screened for 2 validated, independent, next-generation biomarkers: T cell–inflamed gene expression profile (GEP) and tumor mutational burden (TMB). Based on the results of this biomarker screening, patients will be assigned to 1 of 4 groups: TMBlowGEPlow, TMBhighGEPlow, TMBlowGEPhigh, and TMBhighGEPhigh. Within each group, patients will be randomly assigned to receive pembrolizumab combined with MK-4280 (anti–LAG-3), lenvatinib, or MK-1308 (anti–CTLA-4). This is a group-sequential, adaptive randomization trial. Patients will be randomly assigned to MK-4280 or lenvatinib first, after which MK-1308 will be introduced; randomization has been modified to accommodate the delayed introduction of MK-1308. Response will be assessed by tumor imaging every 9 weeks for the first year, then every 12 weeks thereafter using RECIST v1.1. Treatment will continue for 35 cycles (~2 years). Patients in the pembrolizumab + lenvatinib arm who complete 35 treatments may continue with lenvatinib monotherapy until disease progression or toxicity. After a patient experiences disease progression or starts new anticancer therapy, the patient will be followed up and contacted every 12 weeks until death, withdrawal of consent, or study end, whichever occurs first. Safety will be monitored throughout the study and for 30 days after treatment or before initiation of a new anticancer treatment, whichever occurs first. Treatment arms may be terminated during the interim analysis because of safety, prespecified futility criteria, or both. The primary end point is investigator-assessed objective response rate (RECIST v1.1). Secondary end points are progression-free survival, overall survival, and safety. Recruitment and screening are ongoing in more than 14 countries and will continue until ~288 patients are randomly assigned across the biomarker-defined groups to determine the optimal treatment for each subgroup.

      Result

      Section not applicable

      Conclusion

      Section not applicable

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    P1.09 - Pathology (ID 173)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Pathology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.09-19 - High-Throughput Next Generation Sequencing of Treatment-Naïve Non-Squamous NSCLC: The Singapore National Lung Profiling Study (ID 68)

      09:45 - 18:00  |  Author(s): Daniel SW Tan

      • Abstract
      • Slides

      Background

      Scaling traditional single biomarker assays are hampered by the need to evaluate an expanding list of therapeutically relevant biomarkers in small biopsies. We sought to compare the performance of targeted NGS panels with traditional assays, and correlate the mutational landscape with PD-L1 status in Singaporean lung cancer patients (pts).

      Method

      We identified consecutive pts diagnosed between Jan 2016 to Sep 2017 with residual tissue after standard molecular testing (for EGFR, ALK, ROS1, MET, RET alterations). Tissue samples were tested using a targeted NGS panel (29 selected genes including BRAF, ERBB2, KRAS/NRAS, TP53) and an RNA fusion panel (ALK, ROS1, RET). PD-L1 immunohistochemistry (E1L3) was also performed (TPS: <1%, 1-49%, >50%).

      Result

      A total of 174 samples were evaluated: PD-L1 (n=170), NGS DNA panel (n=161) and RNA fusion panel (n=118). Median age was 68 years, 53% were male, 58% were non-smokers, 85% were Chinese, 66% had metastatic disease and 95% had adenocarcinoma histology. In NGS DNA profiled pts, EGFR (55%), KRAS (16%), ERBB2 (4%) and BRAF (2%) alterations were found. RNA fusion testing revealed ALK (6%), RET (3%) and ROS1 (1%) fusions. The sensitivity and specificity for NGS versus standard molecular testing was >90% for all subtypes of EGFR mutation. Only 11% of the cohort had both no detectable actionable alteration on NGS (with targeted agents that are approved or in ongoing clinical trials) and PD-L1 <1%. Median turnaround time for NGS was 10 days (range 6-30). Cost-effectiveness analysis demonstrated that current standard testing was less effective and more costly than the other three testing strategies. Compared to sequential testing of NGS in EGFR negative pts only, upfront NGS testing resulted in an additional 1% of pts receiving targeted therapy for an additional SGD$110 and compared to upfront NGS testing, hotspot testing (NGS in EGFR, ALK/RET/ROS1 FISH negative pts only) resulted in an additional 4% of pts receiving targeted therapy for an additional SGD$1044. In the subset of pts with metastatic EGFR mutant NSCLC after first-line therapy with EGFR TKI (n=64), PFS was worse in patients with EGFR and TP53 co-mutation (n=32) compared to EGFR mutation alone (n=32; HR 0.54, 95%CI 0.30-0.98, p=0.042).

      Conclusion

      We demonstrated that even in an EGFR mutant predominant population, upfront NGS and PD-L1 testing represents a feasible, cost-effective method of diagnostic molecular profiling. The additional information from NGS in characterizing the wider genomic profile may also have prognostic significance in EGFR mutant pts. More broadly, our results support the implementation of NGS in non-squamous NSCLC to allow pts access to the most appropriate personalized therapy.

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    P1.17 - Treatment of Early Stage/Localized Disease (ID 188)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Treatment of Early Stage/Localized Disease
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.17-07 - Neoadjuvant Gefitinib in Resectable Early Stage EGFR Mutant Non-Small Cell Lung Cancer (NSCLC): A Window-of-Opportunity Study (ID 754)

      09:45 - 18:00  |  Author(s): Daniel SW Tan

      • Abstract
      • Slides

      Background

      EGFR TKI therapy is standard of care in metastatic EGFR mutant NSCLC, however its role in resectable NSCLC remains unclear. Furthermore, although EGFR TKIs elicit tumor shrinkage in 60% of patients, determinants of response are poorly understood. This was a window-of-opportunity study of neoadjuvant gefitinib prior to surgery for resectable NSCLC with serial plasma and tissue sequencing.

      Method

      From Feb 2015 to Nov 2018, stage IA-IIIA EGFRmt NSCLC pts received minimum 4 weeks oral gefitinib 250mg daily before surgery. Biomarkers for TKI sensitivity were correlated with RECIST response, pharmacodynamic changes with serial PET-CT scans and pathologic response. Safety and feasibility were determined. Translational studies included multiregion whole exome sequencing (WES, n=44 sectors total) and RNAseq (n=39 sectors).

      Result

      14 pts were treated, 1 pt withdrew consent prior to surgery without toxicity or progression. Gefitinib (median exposure 1.4 mths) was well tolerated, 1 (8%) pt had ≥G3 AE, with G3 AST/ALT elevation leading to gefitinib cessation. ORR was 62% and DCR was 100%. 13/13 pts underwent resection, 6 (46%) pts had pathological downstaging, 4 (31%) pts had nodal pathCR and 1 (8%) pt had a major pathological response (<10% residual viable tumor cells). There was no correlation between CT response or residual FDG uptake post TKI with % residual viable tumor. WES (up to 370x) showed low tumor purities (median 0.17, range 0.1-0.37) across sectors. Purity correlated with number of coding mutations (r2=0.29, p<0.01) but not ploidy (r2=0.04, p=0.2). Compared to a matched treatment naïve cohort (n=18), phylogenetic analysis showed higher proportions of private driver mutations (p=0.04) and sub-clonal copy number variations. The presence of co-occurring truncal drivers did not account for the 5 pts with SD. On RNAseq, all pts had upregulation of immune regulatory and inflammatory response related genes, with significantly higher GEP score (median score; -0.17 vs -1.06, p=0.01) compared to the treatment naive cohort, although with heterogeneity across sectors. EPIC and xCell de-convolution showed high residual FDG uptake may be due to CAFs or infiltrating T-cells. After median 23 mths follow-up, 7/13 pts recurred, median RFS was 20.2 mths. Of 4 evaluable pts re-treated with palliative EGFR TKI, 3 had PR, 1 had PD (leptomeningeal only recurrence).

      Conclusion

      Neoadjuvant gefitinib is safe, feasible and effective. Post EGFR TKI treatment samples had low tumor purities influencing genomic and transcriptomic analyses. Percentage residual disease did not correlate with residual FDG uptake or tumor response. There was pervasive upregulation of immune regulatory and inflammatory response genes, indicating infiltration of fibroblasts and T cells, providing unique insight into adaptive response and for the development of rational combination approaches in EGFR mutant NSCLC.

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    P2.01 - Advanced NSCLC (ID 159)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.01-17 - CANOPY-1: Phase 3 Study of Canakinumab/Placebo+Pembrolizumab+Platinum-Chemotherapy in Untreated Stage IIIB-IV NSCLC Pts (ID 1209)

      10:15 - 18:15  |  Author(s): Daniel SW Tan

      • Abstract

      Background

      Interleukin-1β (IL-1β) inhibition with canakinumab reduced the incidence of and mortality due to lung cancer among patients with atherosclerosis in CANTOS trial. Inhibition of IL-1β driven inflammation may lead to a tumor microenvironment more susceptible to anti-PD-(L)1 therapies. Recent studies have shown that low levels of CRP at baseline or decreased levels over time correlated with improved responses to anti-PD-(L)1 agents, providing rationale for combination of canakinumab and Pembrolizumab (PEM).

      Method

      CANOPY-1 (NCT03631199) is a double-blind, randomized, placebo (Pb)-controlled, phase III trial to determine efficacy and safety of PEM + platinum-based chemotherapy (Ctx) ± canakinumab in untreated stage IIIB/IIIC-IV squamous and non-squamous NSCLC pts. It is a 2 part study- In Part 1 [open-label safety run-in with 3 cohorts of ~9 pts each to confirm recommended phase 3 canakinumab regimen], pts will receive canakinumab 200 mg s.c (Q3W) + PEM 200 mg i.v (Q3W) + platinum-based Ctx [Cohort A (non-squamous), carboplatin (CBCDA) + pemetrexed (PTX); Cohort B (non-squamous), cisplatin + PTX; Cohort C (squamous or non-squamous), CBCDA + paclitaxel]. In Part 2 [with ~600 pts) to evaluate efficacy and safety of canakinumab combination], pts will be randomized to receive canakinumab/Pb + PEM + platinum-based Ctx (non-squamous, CBCDA or cisplatin + PTX; squamous, CBCDA + paclitaxel or nab-paclitaxel). PEM and platinum-based Ctx will be administered at their approved doses. Randomization (1:1) will be stratified by PD-L1 status, region and histology. In both parts, pts will receive 4 cycles of induction therapy (canakinumab/Pb + PEM + Ctx) followed by maintenance therapy (PEM + canakinumab/Pb +/- PTX) until progressive disease. Primary objectives: confirm recommended phase 3 regimen for canakinumab combination (Part 1), compare PFS and OS between treatment arms (Part 2). Secondary objectives (Part 1 and 2): ORR, DCR, safety, PK and DOR.

      Result

      Section not applicable

      Conclusion

      Section not applicable

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    P2.14 - Targeted Therapy (ID 183)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.14-20 - ATORG-003: Dacomitinib With or Without Dose Titration as First-Line Therapy for Metastatic EGFR Mutant Non-Small Cell Lung Cancer (NSCLC) (ID 67)

      10:15 - 18:15  |  Author(s): Daniel SW Tan

      • Abstract
      • Slides

      Background

      Dacomitinib is a second generation EGFR tyrosine kinase inhibitor (TKI) with irreversible pan-HER inhibitory activity. In the phase III ARCHER 1050 trial, median PFS was improved from 9.2 months to 14.7 months in the gefitinib and dacomitinib groups respectively. Significantly, median overall survival (OS) was also improved from 26.8 months to 34.1 months. However, dacomitinib commenced at 45 mg orally daily was associated with increased toxicity, higher rates of dose reductions and treatment discontinuation. Despite this, post-hoc analysis revealed the efficacy of dacomitinib (PFS and OS) was similar in dose-reduced patients and the overall study population. This investigator-initiated trial aims to evaluate an alternative dose titration strategy to improve the safety and tolerability of dacomitinib while maintaining treatment efficacy. The trial is being conducted by the Asian Thoracic Oncology Research Group (ATORG) – a co-operative lung cancer trials group in Asia.

      Method

      ATORG-003 is a multi-national, multi-centre, single-arm, open-label, phase 2 clinical trial of dacomitinib in newly diagnosed stage IIIB/IV or recurrent EGFR mutant (exon 19 deletion or L858R mutation) NSCLC patients. Importantly, subjects with asymptomatic central nervous system (CNS) metastases will be eligible. Patients will be administered dacomitinib 30 mg orally daily for one cycle (4 weeks), after which subjects with <G1 toxicity attributable to dacomitinib may escalate to 45 mg with shared investigator and patient decision. Dose reductions to 30 or 15 mg daily will be permitted. The primary objective is to evaluate PFS rate at 12 months. Key secondary objectives include OS, objective response rate (ORR), time to treatment failure (TTF) and intracranial objective response rate (iORR). Exploratory objectives include evaluation of dacomitinib resistance mechanism(s) using next-generation sequencing (NGS) on tissue and plasma circulating tumour DNA (ctDNA). Across 15 sites in six Asian countries (Hong Kong, Korea, Malaysia, Singapore, Taiwan, Thailand), a planned 118 subjects will be enrolled. Primary analysis will be conducted on subjects without CNS metastases only, with 94 subjects required to achieve a one-sided significance level of 5% and 90% power to detect a 15% improvement in 12 month PFS rate for dacomitinib versus historical control for gefitinib (i.e. 55% versus 40%) using the intent-to-treat (ITT) analysis population. Enrollment is due to begin in July 2019.

      Result

      Section not applicable.

      Conclusion

      Section not applicable.

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