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    OA01 - Improving Outcomes in Locoregional NSCLC I

    • Type: Oral Abstract Session
    • Track: Treatment of Locoregional Disease - NSCLC
    • Moderators:
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      OA01.01 - 10-Year Updated Analysis of NRG Oncology/RTOG 0214: A Phase III Comparison of PCI vs. Observation in Patients with LA-NSCLC.

      10:30 - 10:40  |  Presenting Author(s): Alexander Sun  |  Author(s): Chen Hu, Elizabeth Gore, Stuart Wong, Gregory M.M. Videtic, Swati Dutta, Mohan Suntharalingam, Yuhchyau Chen, Laurie Gaspar, Hak Choy

      • Abstract

      Background

      To determine if prophylactic cranial irradiation (PCI) improves survival in locally advanced non–small-cell lung cancer (LA-NSCLC), we conducted a prospective randomized phase III trial. Previously we reported that compared to observation, PCI significantly increased disease-free survival and reduced brain metastases. With extended follow-up, we sought to determine whether PCI conferred an overall survival benefit.

      Method

      Patients with stage III NSCLC without disease progression after treatment with surgery and/or radiation therapy (RT) with or without chemotherapy were eligible. Participants were stratified by stage (IIIA v IIIB), histology (nonsquamous v squamous), and therapy (surgery v none) and were randomly assigned to PCI or observation. PCI was delivered to 30 Gy in 15 fractions. The primary end point of the study was overall survival (OS). Secondary end points were disease-free survival (DFS), neurocognitive function (NCF), and quality of life. Kaplan-Meier and log-rank analyses were used for OS and DFS. The incidence of brain metastasis (BM) was evaluated with the logistic regression model.

      Result

      Among 356 patients entered to this study, 340 are eligible for analysis. The median follow-up time was 2.1 years for all patients, and 9.2 years for living patients. The survival estimates and hazard ratio indicate that there appears to be no improvement in survival with the use of PCI (p=0.12, HR=1.23, 95% CI: 0.95-1.59). Of note, with the current data there is only 45% power to detect the hypothesized difference HR=1.25 at 1-sided significance level of 0.025. The DFS estimates are better in the PCI arm (p=0.03, HR=1.32, 95% CI: 1.03-1.69). Patients in the observation arm were 2.33 times more likely to develop BM than those in the PCI arm (p= 0.004). On multivariate analysis PCI was significantly associated with decreased BM and improved DFS, but not OS. However, among the 225 non-surgical patients, use of PCI was associated with higher OS (p=0.026, HR=1.42, 95% CI: 1.04-1.94) and DFS (p=0.014), and lower BM (p=0.003). NCF was previously published (Sun, JCO 2011 and Gondi, IJROBP 2013), however, with longer follow-up, there is insufficient data for further analysis.

      Conclusion

      In this 10-year updated analysis, use of PCI continued to significantly improve DFS and reduce brain metastases. However, the early accrual closure failed to provide adequate power to detect the hypothesized difference in OS and the survival rates were not significantly different between PCI and observation. Subgroup analyses based on stratification factors suggest that PCI may improve survival among non-surgical patients.

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      OA01.02 - The Estimate of Shrinking Field and SIB Radiotherapy Guided by 18F-FDG PET/CT in Locally Advanced NSCLC Patients: A Phase 2 Randomized Clinical

      10:40 - 10:50  |  Presenting Author(s): Yaping Xu  |  Author(s): Yaoyao Zhu, Chenxue Jiang, Feiying Gu, Qingren Lin, Xiaojiang Sun

      • Abstract

      Background

      Tumor control remains suboptimal in locally advanced lung cancer. Radiation dose acceleration has a positive effect to local tumor control, but is limited by radiation-induced lung injury (RILI). The aim of this study was to evaluate the safety and efficacy of adaptive radiation therapy guided by functional imaging 18F-FDG PET/CT in patients with locally advanced non-small lung cancer.

      Method

      A total number of 72 patients with locally advanced NSCLC were enrolled between November 2012 and June 2017. After signing the inform consent form, 36 patients were randomized into the shrinking field and simultaneous integrated boost radiotherapy group, others were in the conventional radiotherapy group. The Objective Response rate (ORR), progression-free survival (PFS) and overall survival (OS) were compared, as well as the safety of shrinking field and simultaneous integrated boost radiotherapy (radiological dosimetry parameters and the incidence of grade 2 or higher radiotherapy-related toxicity). T-test was utilized to compare the differences between the quantitative data of two groups, while chi-square test or Fisher exact test were utilized to compare the differences between the count data of two groups. Kaplan-Meier curve was utilized to show PFS and OS, and the log-rank test analysis was utilized to compare the survival difference between two groups. P value less than 0.05 was considered statistical difference.

      Result

      All the patients in both two groups had completed their treatment according to the study protocol. The shrinking field and simultaneous integrated boost radiotherapy group was significantly greater than the conventional radiotherapy group in ORR (77.8% vs. 52.8%, P=0.026). The median OS and PFS in shrinking field and simultaneous integrated boost radiotherapy group was 22.0 months (95%CI:18.1~25.9) and 12.4 months (95%CI:10.4~14.3), which is significantly longer than 18.1 months (95%CI:12.4~23.8) and 8.2 months (95%CI:5.2~11.2) in the conventional radiotherapy group (P=0.045 and P=0.013). There was no significant difference between the two groups in radiological metrological parameters and organ at risk (OAR). The incidence of grade 2 or higher RILI, radiation-induced esophagitis, radiation-related myocardial damage and myelosuppression between two groups has no statistically significant difference.

      Conclusion

      Shrinking field and simultaneous integrated boost radiotherapy guided by function imaging 18F-FDG PET/CT is a safe and operable technique in practice. It can improve ORR, OS and PFS without increasing the risk of radiotherapy-related toxicity in patients with locally advanced NSCLC.

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      OA01.03 - Interaction Between Dose and Calcifications Is a Predictor for Overall Survival in Lung Cancer Patients Receiving Radiotherapy

      10:50 - 11:00  |  Presenting Author(s): Alan McWilliam  |  Author(s): Eliana Vasquez Osorio, Frank Brewster, David Catharina Petrus Cobben, Corinne Faivre-Finn, Anna Scaife, Marcel Van Herk

      • Abstract

      Background

      Recently, incidental dose to the heart was found to be predictive for overall survival in lung cancer patients receiving radiotherapy [McWilliam et al EJC 2017, Johnson et al Radiother Oncol 2018]. These patients often present with multiple comorbidities that should be incorporated in survival analysis. However, such data is often missing. We investigated whether calcifications, identified on the radiotherapy planning CT, can be used as a surrogate for cardiac health. In particular, we investigated the interaction between calcifications, dose and survival.

      Method

      Data from 814 unselected non-small cell lung cancer patients was used, all treated with 55Gy in 20 fractions. Methodology was developed to automatically segment calcifications within the heart, the aortic arch and their surroundings. The 3D planning CT scans, and the associated lung and spinal cord delineations were processed using well-established image processing algorithms, e.g., convex hull, thresholding, morphological operations, connected pixel analysis and flood filling to detect calcifications. Moreover, shape analysis was included to enhance regions that presented tubular or plate-like appearance. The detection algorithm was validated in a small subset of 10 patients, and this group was used to determine the success and error rate of the automatic segmentation. Finally, a Cox-proportional hazards multivariate analysis was performed for overall survival of all patients accounting for tumour size, total calcification volume, mean dose across all identified calcifications, and interaction between calcification volume and dose.

      Result

      The success rate of the algorithm for identifying calcifications was 81.8%, its error rate was 8.8%. The multivariate survival analysis identified tumour size (continuous, p<<0.0001) and the interaction of calcification volume and their mean dose (continuous, p=0.029) as significant. Calcification volume (p=0.57) or mean calcification radiation dose alone (p=0.269) were not found to be significant.

      Conclusion

      Multivariate analysis shows a significant interaction between volume of the identified calcifications and their mean radiotherapy dose predicting survival. Further improvements to identify calcifications in the descending thoracic aorta and validation of our methodology are required. Further work linking our results with the established Agatston or Coronary Artery Calcium score is in progress.

      * EVO-FB share first authorship

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      OA01.04 - Discussant - OA 01.01, OA 01.02, OA 01.03

      11:00 - 11:15  |  Presenting Author(s): John Armstrong

      • Abstract

      Abstract not provided

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      OA01.05 - Phase II Study of Neo-Adjuvant Chemo/Immunotherapy for Resectable Stages IIIA Non-Small Cell Lung Cancer- Nadim Study-SLCG

      11:15 - 11:25  |  Presenting Author(s): Mariano Provencio  |  Author(s): Ernest Nadal, Amelia Insa, Rosario García Campelo, Gerardo Huidobro, Manuel Domine, Margarita Majem, Delvys Rodríguez-Abreu, Virginia Calvo, Alex Martinez-Marti, Javier De Castro, Manuel Cobo Dols, Guillermo Lopez-Vivanco, Elvira Del Barco, Reyes Bernabé, Nuria Vinolas, Isidoro Barneto, Bartomeu Massuti

      • Abstract

      Background

      The combination of chemotherapy and immunotherapy (CT-IO) has a high response rate and longer survival in unselected patients (pts) with metastatic non-small cell lung cancer (NSCLC). There are no data about this combination in the neoadjuvant setting.

      Method

      A Phase II, single-arm, open-label multicenter study of local-advanced resectable stage IIIA N2-NSCLC adult patients with CT plus IO (nivolumab (NV)) followed by adjuvant treatment for 1 year. Neoadjuvant treatment: Three cycles of NV 360mg IV Q3W + paclitaxel 200mg/m2 + carboplatin AUC 6 IV Q3W. After completing neoadjuvant therapy, tumor assessment is performed in patients prior to surgery. Surgery is performed in the 3rd or 4th week after day 21 of the third cycle of neoadjuvant treatment. Adjuvant treatment: NV 240mg IV Q2W for 4 months and NV 480mg IV Q4W for 8 months (total one year) after surgical resection. The study aims to recruit 46 pts. The primary endpoint is Progression-Free Survival (PFS) at 24 months. Efficacy is explored using objective pathologic response criteria. We present preliminary data on patients that completed 3 cycles and underwent surgical resection.

      Result

      At the time of submission, 46 pts had been included and 20 underwent surgery. CT-IO was well-tolerated and surgery was not delayed in any patient. None of the pts was withdrawn from the study preoperatively due to progression or toxicity.

      Twenty surgeries had been performed and all tumors were deemed resectable. The overall clinical response rate was 5% complete (CR) and 65% PR. The pathological response evaluated after surgery: 13 cases (65.0%) achieved CR (CPR) (95% CI 40.8-84.6%), and 3 (15.0%) had a major pathologic response (MPR), defined as <10% viable tumor cells in the resection specimen. Considering both CPR and MPR, the overall response rate was 80.0% (95% CI 56.3-94.3%) and 60% of complete responses were unsuspected

      Conclusion

      This is the first multicentric study testing CT-IO in the neoadjuvant setting with promising antitumor activity in locally advanced, potentially resectable NSCLC yields an unprecedented complete pathologic response rate. The data will be updated at the time of the congress. EudraCT Number: 2016-003732-20

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      OA01.06 - DETERRED:  Phase II Trial Combining Atezolizumab Concurrently with Chemoradiation Therapy in Locally Advanced Non-Small Cell Lung Cancer

      11:25 - 11:35  |  Presenting Author(s): Steven H Lin  |  Author(s): Xiuyan Lin, Debora Clay, Luyang Yao, Isabel Mok, Daniel Gomez, Jonathan M Kurie, George R. Simon, George R Blumenschein, Jenean Young, See Phan, Alan Sandler, Vassiliki A Papadimitrakopoulou, John V Heymach, Anne S. Tsao

      • Abstract

      Background

      While consolidation immunotherapy after chemoradiation (CRT) is the current standard of care for locally advanced NSCLC (LA-NSCLC), the effectiveness of immunotherapies may be enhanced when combined concurrently with CRT. We report on the safety and preliminary efficacy of combining PD-L1 blockade using atezolizumab (atezo) and concurrent CRT followed by consolidation full dose carboplatin/paclitaxel (CP) with atezo and maintenance atezo up to 1 year for LA-NSCLC.

      Method

      This is a single institution phase II study in LA-NSCLC assessing the safety and feasibility of adding atezo to CRT in two parts: I) sequentially (N=10) with CP after completing CRT, or II) concurrently (N=30) with CRT followed by consolidation atezo with CP. Atezo was given at 1200 mg IV Q3 weeks for up to one year from the first dose. Radiation dose at 60-66 Gy in 30-33 fractions was combined with weekly low dose CP, followed by 2 cycles of full dose CP. Severe adverse events (AEs) ≥ grade 3 are defined within 15 weeks of start of therapy or any immune-related AEs during atezo treatment. Evaluable patients (pts) have received at least one dose of atezo.

      Result

      From February 2016 to April 2018, we accrued 40 evaluable pts. For part 1, any grade 3+ AEs was seen in 6 pts (60%), with most common being pneumonia (2 of 10, 20%). Three grade 3+ AEs (30%) were attributed to atezo, including dyspnea, arthralgia and a grade 5 TE fistula. Grade 2 radiation pneumonitis (RP) was seen in 3 pts. Four progressed with disease during atezo maintenance and have died, ranging from 0.93 to 1.86 years. Four pts completed atezo and are in follow up without recurrence. For part 2, 17 of 30 pts had any grade 3+ AEs (57%), with pneumonia being the most common (6 of 30, 20%). Three (10%) were attributed to atezo (dyspnea, fatigue and heart failure). RP was seen in 3 pts, with 2 grade 2 and 1 grade 3, which led to atezo discontinuation. So far, 4 pts have progressed and 4 have died, 2 due to disease and 2 due to treatment (neutropenic sepsis and gastric hemorrhage). All others have completed CRT and are on maintenance atezo, ranging from 5 to 19 doses. Updated efficacy results will be presented.

      Conclusion

      Concurrent atezo with CRT followed by consolidation and maintenance atezo appears safe without increased toxicities compared to CRT alone followed by consolidation and maintenance atezo.

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      OA01.07 - Updated Results of a Phase II Trial of Concurrent Chemoradiation with Consolidation Pembrolizumab in Patients with Unresectable Stage III NSCLC

      11:35 - 11:45  |  Presenting Author(s): Greg Durm  |  Author(s): Sandra Althouse, Ahad Sadiq, Shadia Jalal, Salma Jabbour, Robin Zon, Goetz H Kloecker, William Fisher, Karen L. Reckamp, Ebenezer Kio, Robert Langdon, Bamidele Adesunloye, Ryan Gentzler, Nasser Hanna

      • Abstract

      Background

      Concurrent chemoradiation (CRT) has been the standard Rx for pts with unresectable stage III NSCLC. A recent phase III trial (PACIFIC) of consolidation durvalumab [PDL-1 inhibitor] demonstrated improved median PFS vs. placebo (16.8 vs. 5.6 mo, HR 0.52, p<0.001). 12-mo (55.9% vs. 35.3%) and 18-mo (44.2% vs. 27%) PFS were also improved. Toxicity was manageable with a grade 3-4 pneumonitis rate of 3.4%, and 4 patients experienced grade 5 pneumonitis. We report updated results of a phase 2 trial of consolidation pembrolizumab [PD-1 inhibitor] following concurrent CRT in patients with unresectable stage III NSCLC.

      Method

      After completion of CRT with carboplatin/paclitaxel, cisplatin/etoposide, or cisplatin/pemetrexed + 59-66.6 Gy XRT, those pts w/o PD after 4-8 weeks off CRT received pembro 200 mg IV q3wk for up to 1 yr. The primary endpoint was time to metastatic disease or death [TMDD]. Key secondary endpoints included PFS, OS, and toxicity.

      Result

      93 pts enrolled [92 eligible for efficacy analysis]. Median f/u was 18.6 mo and median age 66 (45-84). 64.1% male and 35.9% female. Stages were 59.8% IIIA and 40.2% IIIB. 55.4% non-SqCC and 43.5% SqCC with 1 mixed histology. 94.6% were current/former smokers. Chemo regimens included carbo/pac (71.7%), cis/etop (26.1%), cis/pemetrexed (2.2%). Median number of cycles of pembro was 13.5 [1-19]. 16% received < 4 cycles; 84% received > 4 cycles; 37% completed 1 yr pembro. Median TMDD was 22.4 months (95% CI 17.9-NR). Median OS was NR (95% CI 22.4-NR), and the estimates of 1-yr and 2-yr OS were 81% and 61.9% respectively. Median PFS was 17 months (95% CI 11.9-NR). 12, 18, and 24-month PFS were 60.2%, 49.9%, and 44.6% respectively. 16 (17.2%) pts developed G2 pneumonitis, 5 (5.4%) had G3-4 pneumonitis. There was 1 pneumonitis-related death. In those developing G2 pneumonitis, the median time was 8.4 wks [1.1-48.3]. No other G 3/4 toxicities exceeded 5% except dyspnea (5.4%).

      Conclusion

      Consolidation pembrolizumab following CRT substantially improves TMDD and PFS compared with historical controls. Prelim OS data is promising and suggests a substantial gain in outcomes of patients with stage III NSCLC is possible with consolidation pembrolizumab. These data will be updated further prior to the World Conference on Lung Cancer Meeting.

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      OA01.08 - Discussant - OA 01.05, OA 01.06, OA 01.07

      11:45 - 12:00  |  Presenting Author(s): Corey J Langer

      • Abstract

      Abstract not provided

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    OA02 - Novel Therapies in ROS1, HER2 and EGFR

    • Type: Oral Abstract Session
    • Track: Targeted Therapy
    • Moderators:
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      OA02.01 - Efficacy and Safety of Entrectinib in Locally Advanced or Metastatic ROS1 Fusion-Positive Non-Small Cell Lung Cancer (NSCLC)

      10:30 - 10:40  |  Presenting Author(s): Robert C. Doebele  |  Author(s): Myung-Ju Ahn, Salvatore Siena, Alexander Drilon, Matthew G Krebs, Chia-Chi Lin, Filippo G. De Braud, Thomas John, Daniel S.W. Tan, Takashi Seto, Rafal Dziadziuszko, Hendrick-Tobias Arkenau, Fabrice Barlesi, Christian Rolfo, Jürgen Wolf, Edna Chow-Maneval, Pratik S. Multani, Na Cui, Todd Riehl, Byoung Chul Cho

      • Abstract

      Background

      Entrectinib is a central nervous system (CNS) active, potent, and selective inhibitor of ROS1, TRKA/B/C and ALK. Entrectinib is more potent against ROS1 than crizotinib, the only agent currently approved for the treatment of ROS1-positive NSCLC. Interim data demonstrated that entrectinib was tolerable and achieved high objective response rates (ORR) in patients with ROS1-positive, ROS1 inhibitor-naive NSCLC, including patients with baseline CNS disease (Ahn MJ WCLC 2017).

      Method

      Phase 1/2 studies of entrectinib (ALKA, STARTRK-1, STARTRK-2; EudraCT 2012-000148-88; NCT02097810; NCT02568267) enrolled patients with locally advanced or metastatic solid tumors. The safety-evaluable population included patients who received ≥1 dose of entrectinib. The integrated efficacy analysis included ROS1-positive NSCLC patients enrolled based on identification of ROS1 fusions via nucleic acid-based diagnostic platforms. Safety was assessed by monitoring adverse events (AEs), laboratory tests, and physical examination. Tumor assessments were performed at the end of cycle 1 and every 8 weeks thereafter. All scans were submitted for blinded independent central review (BICR) using RECISTv1.1. Primary endpoints were ORR and duration of response (DOR) by BICR. Key secondary objectives were progression-free survival (PFS), overall survival (OS), and safety. Additional endpoints evaluated in patients with baseline CNS disease were intracranial ORR (defined as complete or partial responses in patients with baseline CNS lesions per BICR using RECISTv1.1), intracranial DOR, and PFS. For intracranial assessments, the CNS subgroup was derived per BICR; for systemic analyses, the CNS subgroup was derived per investigator.

      Result

      There were 53 efficacy-evaluable patients with treatment-naïve, ROS1-positive NSCLC. BICR ORR was 77.4% (95% CI 63.8–87.7) with complete responses in three patients (5.7%); median BICR DOR was 24.6 months (95% CI 11.4–34.8). Per baseline CNS status (as determined by investigator), median BICR PFS was 26.3 months (95% CI 15.7–36.6) and 13.6 months (95% CI 4.5–NR) for patients without (n=30) and with CNS disease (n=23), respectively. Intracranial ORR was 55.0% (95% CI 31.5–76.9) and median intracranial DOR was 12.9 months (95% CI 5.6–not reached [NR]) in patients with baseline CNS disease per BICR (n=20). In the overall safety-evaluable population (n=355), most treatment-related AEs were grade 1–2. Few patients required dose reduction (27.3%) or discontinued treatment (3.9%) due to treatment-related AEs.

      Conclusion

      Entrectinib was tolerable with a manageable safety profile, and showed clinically meaningful, deep and durable systemic responses in ROS1-positive NSCLC. Clinically meaningful intracranial activity was also demonstrated in patients with baseline CNS disease.

      Study Sponsor: Ignyta, Inc., a wholly owned subsidiary of F. Hoffmann-La Roche Ltd.

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      OA02.02 - Safety and Preliminary Clinical Activity of Ropotrectinib (TPX-0005), a ROS1/TRK/ALK Inhibitor, in Advanced ROS1 Fusion-Positive NSCLC

      10:40 - 10:50  |  Presenting Author(s): Jessica Jiyeong Lin  |  Author(s): Dong-Wan Kim, Alexander Drilon, Robert C. Doebele, Jeeyun Lee, Viola Zhu, Myung-Ju Ahn, John Lim, Shanna Stopatschinskaja, J. Jean Cui, David M Hyman, Ross Camidge, Sai-Hong Ignatius Ou, Alice T. Shaw, Byoung Chul Cho

      • Abstract

      Background

      Ropotrectinib is a potent ROS1/TRK/ALK inhibitor with a >90-fold greater ROS1 potency than crizotinib. Preclinical studies demonstrate robust activity against all known ROS1 resistance mutations, including solvent-front mutation G2032R.

      Method

      In this Phase 1 study (NCT03093116), TKI-naïve and TKI-refractory (≥1 TKI) pts with advanced ALK/ROS1/TRK+ solid tumors received ropotrectinib. Asymptomatic brain metastases were allowed. Primary objectives were to determine MTD and RP2D, with safety, pharmacokinetics, and preliminary antitumor efficacy as the secondary objectives. This is a safety analysis of all pts and subgroup efficacy analysis of the ROS1+ NSCLC pts on the study.

      Result

      As of 16-April-2018, 72 pts have been treated at 6 dose levels from 40mg QD to 200mg BID. Most AEs were grade 1-2. Common (>10%) treatment-related AEs included dizziness (49%), dysgeusia (46%), paresthesias (29%), constipation (19%), fatigue (18%), nausea (11%), and anemia (11%). 4 DLTs were observed at ≥240mg/day: 1 grade 3 (Gr3) dyspnea/hypoxia, 2 Gr3 & 1 Gr2 dizziness. 31 of 72 pts had ROS1+ NSCLC by local testing (FISH, n=20; NGS, n=11) with 1 pt determined as ROS1-negative by central NGS. Antitumor activity in ROS1+ NSCLC has been observed at ROS1 dose levels 40mg QD-160mg BID per investigator assessment, with the best ORR 70% for TKI-naïve and 11% for TKI-refractory pts (17% for 1 prior TKI crizotinib, n=12) (Table). Two crizotinib-resistant pts with G2032R achieved durable cPR and cSD, respectively. Ongoing blinded independent review identified 7 evaluable pts with target CNS lesions at baseline; the intracranial best ORR was 43% (3 cPR, 1 PR*). Updated efficacy data and ctDNA biomarker analyses will be presented.

      Dose Level

      TKI Naïve (n = 10)

      TKI Refractory (n = 20)

      n

      Best Overall Response

      n

      Best Overall Response

      40 mg QD (n = 6)

      2

      2 cPR (ORR 100%)

      4

      2 cSD, 1 SD, 1 PD

      80 mg QD (n = 5)

      2

      2 cPR (ORR 100%)

      3

      1 cSD, 2 SD

      160 mg QD (n = 10)

      4

      2 cPR, 2 cSD (ORR 50%)

      6

      2 cPR, 2 cSD, 1 SD, 1 PD (ORR 33%)

      240 mg QD (n = 2)

      1

      1 cPR (ORR 100%)

      1

      1 SD

      160 mg BID (n = 7)

      1

      1 PR*

      6

      1 PR*, 1 SD*, 1 cSD, 2 SD, 1 NE

      Total (n = 30)

      10

      7 cPR, 1 PR*, 2 cSD

      20

      2 cPR, 1 PR*, 6 cSD, 1 SD*, 7 SD, 2 PD, 1 NE

      Best ORR

      70%

      11%

      Median follow-up

      8 months with 90% still on treatment

      4 months with 50% still on treatment

      cPR: confirmed partial response; SD: stable disease for 2 cycles; cSD: SD for at least 4 cycles; PR* or SD*: waiting for subsequent time point scan; PD: progressive disease; NE: inevaluable; ORR: objective response rate

      Conclusion

      Ropotrectinib is well tolerated and demonstrates promising activity in pts with advanced ROS1+ NSCLC, including TKI-naïve and TKI-refractory pts. RP2D has not yet been achieved. These Phase 1 data warrant further clinical testing of ropotrectinib in ROS1+ NSCLC.

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      OA02.03 - Clinical Activity of Lorlatinib in Patients with ROS1+ Advanced Non-Small Cell Lung Cancer: Phase 2 Study Cohort EXP-6

      10:50 - 11:00  |  Presenting Author(s): Sai-Hong Ignatius Ou  |  Author(s): Alice T. Shaw, Gregory J Riely, Rita Chiari, Jessica R. Bauman, Jill S. Clancy, Holger Thurm, Gerson Peltz, Antonello Abbattista, Ben J Solomon

      • Abstract

      Background

      Among patients with ROS1-positive non-small cell lung cancer (NSCLC), most achieve initial benefit from crizotinib treatment but often develop resistance, and further treatment options are limited. Lorlatinib is a potent, brain-penetrant third-generation ALK/ROS1 TKI with broad mutational coverage. It has shown compelling clinical activity in patients with ALK-positive and ROS1-positive advanced NSCLC, most of whom had CNS metastases and had received prior crizotinib.

      Method

      This ongoing Phase 2 study (NCT01970865) enrolled patients with ROS1-positive advanced NSCLC ± asymptomatic CNS metastases without restriction on the type or number of prior lines of therapy (cohort EXP-6). Patients received lorlatinib 100 mg QD. Primary endpoints were overall and intracranial response by independent central review. Secondary endpoints included duration of response and progression-free survival. Safety was assessed in all treated patients (cohorts EXP-1–6); molecular profiling is ongoing.

      Result

      As of the data cut-off (02 Feb 2018), 47 patients with ROS1+ NSCLC were treated; 25 had baseline CNS metastases; 34 had received prior crizotinib and 13 were crizotinib-naïve. Treatment with lorlatinib led to rapid and durable responses in both crizotinib-naïve and crizotinib-pre-exposed patients (Table).

      ICR-assessed endpoint Crizotinib-naïve Crizotinib-pre-exposed Total EXP-6
      Overall, N 13 34 47
      ORR, % (95% CI) 61.5 (31.6, 86.1) 26.5 (12.9, 44.4) 36.2 (22.7, 51.5)
      Confirmed response, n 8 9 17

      Response lasting at least 12 months, n

      5 5 10
      Median time to tumor response, months (range) 1.4 (1.3–8.3) 2.5 (1.4–4.2) 1.4 (1.3–8.3)
      Intracranial (IC), N 6 19 25
      IC ORR, % (95% CI) 66.7 (22.3, 95.7) 52.6 (28.9, 75.6) 56.0 (34.9, 75.6)
      Confirmed IC response, n 4 10 14

      IC response lasting at least 12 months, n

      1 4 5
      Median PFS, months (95% CI)a 21.0 (4.2, 26.7) 8.5 (4.4, 18.0) 9.9 (5.5, 21.0)

      ICR, independent central review; PFS, progression-free survival.

      aPer Kaplan-Meier method.

      The most common treatment-related adverse events (TRAEs) in EXP-6, were hypercholesterolemia (83%) and hypertriglyceridemia (60%). In EXP-6, 36% and 23% of patients had TRAEs leading to dose interruptions and dose reductions, respectively. No permanent treatment discontinuations due to TRAEs or treatment-related deaths occurred.

      Conclusion

      Lorlatinib showed clinically meaningful benefit in patients with ROS1-positive NSCLC, including those who had received prior crizotinib or were crizotinib-naive, as demonstrated by rapid and durable responses. These findings further suggest that the activity of lorlatinib differs depending on prior exposure to crizotinib. The safety profile of lorlatinib in ROS1 patients was comparable to that previously reported in the overall ALK/ROS1 population.

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      OA02.04 - Discussant - OA 02.01, OA 02.02, OA 02.03

      11:00 - 11:15  |  Presenting Author(s): Shengxiang Ren

      • Abstract

      Abstract not provided

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      OA02.05 - CK-101 (RX518), a Third Generation Mutant-Selective Inhibitor of EGFR in NSCLC: Results of an Ongoing Phase I/II Trial

      11:15 - 11:25  |  Presenting Author(s): Melissa L. Johnson  |  Author(s): Janet Karlix, Howard A Burris, Suzanne F Jones, Dean Harris, Kenneth O’byrne, Virote Sriuranpong, Chaiyut Charoentum, Naiyarat Prasongsook, Wittawat Jitpewngam, Kosin Wirasorn, Judy Sing-Zan Wang, Saiama N. Waqar, James Oliviero, Leonid Gorelik, Xiangping Qian

      • Abstract

      Background

      CK-101 (also known as RX518) is a novel, oral, third-generation, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that selectively inhibits both EGFR-TKI-sensitizing and resistance mutations, with minimal activity on wild-type EGFR. CK-101 is being studied in an ongoing first-in-human, multicenter, Phase I/II trial in advanced non-small cell lung cancer (NSCLC) patients (pts) with EGFR mutations and other advanced malignancies in the US, Australia, New Zealand and Thailand (NCT02926768). Following dose escalation in which 18 pts received CK-101 in dose groups ranging from 100 mg to 1200 mg/day, a first dose-expansion cohort was enrolled at 400 mg bid.

      Method

      Eligible pts in dose escalation had a confirmed diagnosis of NSCLC or any advanced solid tumor where targeting EGFR was reasonable. Eligible pts in dose-expansion had a confirmed diagnosis of either (1) EGFR mutation-positive advanced or metastatic NSCLC without prior exposure to EGFR-TKI therapy, or (2) T790M-positive advanced or metastatic NSCLC with disease progression on previous EGFR-TKI therapy, with no limit on number of prior lines of systemic therapy.

      Result

      As of 25 June 2018, 37 pts were treated in dose escalation and expansion and evaluable for safety; median age 59 years, 51% male, 51% Asian, 84% ECOG PS 1. No DLTs or treatment-related SAEs were reported. Most common treatment-emergent adverse events: nausea (16%), diarrhea (14%), lacrimation increased (14%) and vomiting (11%), all grade 1/2 except one grade 3 diarrhea; no grade 4. In dose-expansion, 19 pts were treated with CK-101 at a dose of 400 mg bid and evaluable for response; 8/19 (42%) pts were treatment-naïve, 6/19 (32%) pts had brain metastases; 16/19 (84%) pts remained on treatment. Disease control rate was 100% (19/19), with 16/19 pts (84%) experiencing target lesion reduction versus baseline and 8 pts achieving a partial response (7 confirmed, 1 pending confirmation). In treatment-naïve pts, 6/8 (75%) pts achieved a partial response. In pts with brain metastases, 3/6 (50%) pts achieved a partial response. Higher drug exposures were associated with higher response rate with a confirmed ORR of 55% (6/11) in pts achieving Cmax >400 ng/mL. Median duration of response and progression-free survival were not reached as of the data cutoff.

      Conclusion

      CK-101 was well tolerated with a manageable safety profile. Durable anti-tumor activity was observed, particularly in treatment-naïve pts. Further study is ongoing to establish the optimal dose to maximize therapeutic effect in a planned Phase 3 study in treatment-naïve EGFR-mutant NSCLC pts.

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      • Abstract

      Background

      Insertions/mutations in exon 20 of EGFR or HER2 occur in ~3% of all lung adenocarcinomas. These alterations are characterized by primary resistance to tyrosine kinase inhibitors (TKIs) with response rates of <12%. We previously showed that exon 20 insertions restrict the size of drug-binding pocket, limiting binding of most available TKIs. However, poziotinib can potentially circumvent these steric changes due to its smaller, flexible structure and is a potent inhibitor of EGFR and HER2 exon 20 mutants (Robichaux et al. Nat Med, 2018). Herein, we report the results of an investigator-initiated study of poziotinib in EGFR and HER2 exon 20 mutant NSCLC (NCT03066206).

      Method

      Patients ≥18yrs with metastatic NSCLC bearing mutations/insertions in EGFR or HER2 exon 20 (except EGFR T790M) were eligible. Unlimited prior systemic and targeted therapies were permitted. Poziotinib 16mg PO daily was administered until progression, death, or withdrawal. The primary endpoint was objective response rate (ORR) based on RECIST v1.1. Response was evaluated every eight weeks. A Bayesian design was used with a plan to enroll patients in cohorts of 10 and to terminate the study if ORR was ≤20%. Secondary endpoints included DCR, PFS, OS and safety

      Result

      As of May 3, 2018, the planned EGFR cohort of 50 patients was fully enrolled, and 40 patients were evaluated for response. 65.1% of patients had received at least two prior lines of therapy for metastatic disease. 60% of patients had ≥grade 3 adverse events; most common were skin-rash (27.5%) and diarrhea (12.5%). 45.0% of patients required dose reduction to 12mg, while 17.5% required dose reduction to 8mg. One patient stopped treatment due to grade 3 skin rash. ORR at eight weeks was 58% (95%-CI 40.9-73.0) and the DCR was 90% (95%-CI 76.3-97.2). Among 23 patients who achieved partial response, 15 responses were confirmed with subsequent scans, five responses were unconfirmed, and three patients are pending confirmation. Responses were observed in 8/13 (62%) patients that were previously treated with TKI. Median PFS was 5.6mo (95%-CI 5.06-NA). Furthermore, 13 patients were enrolled in HER2 cohort. Toxicities were similar to EGFR cohort except one case of grade 5 pneumonitis, assessed to be possibly drug related. Twelve patients were evaluated for response with ORR of 50% (95% CI 21.1-78.9) at eight weeks and DCR of 83%.

      Conclusion

      In heavily pre-treated population with EGFR and HER2 exon 20 mutant NSCLC, poziotinib demonstrated encouraging antitumor activity in both TKI-naive and -refractory patients, and manageable toxicity profile.

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      OA02.07 - Updated Results of Phase 1 Study of DS-8201a in HER2-Expressing or –Mutated Advanced Non-Small-Cell Lung Cancer

      11:35 - 11:45  |  Presenting Author(s): Junji Tsurutani  |  Author(s): Haeseong Park, Toshihiko Doi, Shanu Modi, Shunji Takahashi, Kazuhiko Nakagawa, Ian E. Krop, Saiama N. Waqar, Kiyotaka Yoh, Bob T. Li, Shinichiro Taira, Takahiro Jikoh, Jasmeet Singh, Masahiro Sugihara, Pasi A Jänne

      • Abstract

      Background

      DS-8201a is a HER2-targeting antibody-drug conjugate with a novel peptide-based cleavable linker, a topoisomerase I inhibitor payload, and a high drug-to-antibody ratio (7 to 8). In preclinical studies, DS-8201a showed broad antitumor activity, in a wide range of tumors. The ongoing phase 1 trial has a dose-escalation (part 1) and -expansion (part 2) and includes subjects with advanced breast cancer, gastric cancer, and other HER2-expressing/-mutated solid tumors. Here, we present updated results for subjects with HER2-expressing or -mutated non-small cell lung cancer (NSCLC).

      Method

      Subjects with HER2-expressing (defined as IHC ≥1+ or amplified) or –mutated (detected by NGS or other platforms) NSCLC were eligible to enroll. HER2 expression and mutation were assessed using archival tissue. Adverse events (AEs), objective response rate (ORR), disease control rate (DCR: CR + PR + SD), and duration of response (DOR) were assessed.

      Result

      [Results will be updated for presentation at meeting] As of Apr 18, 2018, 12 subjects with HER2-expressing and/or -mutated NSCLC received ≥1 dose of DS-8201a at 6.4 mg/kg. Median age was 58.5 y with median of 3 prior regimens. At data cutoff, 8 of 12 (66.7%) subjects remain on treatment. HER2 IHC status was available for 7 subjects. Median duration of treatment was 3.66 months (range 0.69, 14.19). Eight of 10 (80.0%) subjects with ≥1 post-baseline scan (ps) experienced tumor shrinkage (100.0% of them at 1st ps at 6 weeks). Overall, confirmed ORR and DCR in the evaluable subjects was 5 of 8 (62.5%) and 6 of 8 (75.0%), respectively. Among subjects with HER2 IHC 2+ or IHC 3+ expression, 2 of 5 (40.0%) had a PR. Overall, median DOR was 11.5 months (range 0.03+, 11.53). Three of 12 (25.0%) subjects experienced a grade ≥3 AE. Common AEs included decreased appetite 66.7% (0.0% grade ≥3), nausea 58.3% (0.0% grade ≥3), alopecia 41.7% (0.0% grade ≥3), and fatigue 41.7% (0.0% grade ≥3). One fatal case of interstitial lung disease was reported in this subgroup.

      Conclusion

      DS-8201a demonstrated promising antitumor activity in heavily pretreated NSCLC subjects.

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      OA02.08 - Discussant - OA 02.05, OA 02.06, OA 02.07

      11:45 - 12:00  |  Presenting Author(s): Daniel B Costa

      • Abstract

      Abstract not provided

  • +

    OA03 - Advances in Lung Cancer Pathology

    • Type: Oral Abstract Session
    • Track: Pathology
    • Moderators:
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      OA03.01 - The Immunophenotyping and Genomic Characteristics of Pulmonary Sarcomatoid Carcinoma: Pleomorphic, Spindle Cell and Giant Cell Carcinoma

      10:30 - 10:40  |  Presenting Author(s): Chunyan Wu  |  Author(s): Likun Hou

      • Abstract

      Background

      Pulmonary sarcomatoid carcinoma (PSC) is a poorly differentiated non-small cell lung cancer (NSCLC) and comprises a diagnostically and therapeutically challenging group of tumors. We explored the immunohistochemical characteristics and genetic profiles of PSC (except carcinosarcoma and pulmonary blastoma)

      Method

      A total of 432 cases with surgically resected undifferentiated NSCLC (121 solid adenocarcinomas (ADC), 98 non-keratinizing squamous cell carcinomas (SQC), 118 large cell carcinomas (LCC) and 95 sarcomatoid carcinomas) were reviewed. Expression of epithelial-mesenchymal transition (EMT) markers (Cytokeratin (CK), Vimentin (Vim) and zinc-finger E-box binding homeobox 1 (ZEB1)) were studied by immunohistochemistry. 8 therapeutically-relevant genetic alterations(EGFR/BRAF/KRAS/HER2/MET exon 14 mutations and ALK/ROS1/RET fusion)of sarcomatoid carcinomas were detected by Capture-based targeted sequencing

      Result

      The expression of CK was almost positive in ADC, SQC and LCC, which of sarcomatoid component (SC) of PSC was observed positively only in 80/95(84.2%). Although vim expression was higher (88/95, 92.6%) in SC, it was also positive in ADC (37/121, 30.6%), SQC (14/98, 14.3%), LCC (12/118, 10.2%), respectively. In the contrast, SC was detected with 100% ZEB1 expression in PSC (95/95). ZEB1 expression was focal positive only in 1 cases of SQC (1/98, 1.0%). In ADC and LCC, no ZEB1 expression was found. The expression of ZEB1 had higher specificity (99%) and sensitivity (100%) than Vim expression in SC of PSC. The most frequent mutation genes were KRAS (18/58, 31.0%), EGFR (6/58, 10.3%), MET exon 14 (7/58, 12.0%) and no BRAF/HER2/ALK/ROS1/RET alteration were detected.

      Conclusion

      ZEB1 was a useful differential diagnostic marker for PSC. Targeted mutations testing may be useful for classifying and managing PSC patients.

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      OA03.02 - Nationwide Comparative Study Of PD-L1 IHC Assays on Lung Cancer: Initial Report Of LC-SCRUM-IBIS Project

      10:40 - 10:50  |  Presenting Author(s): Noriko Motoi  |  Author(s): Genichirou Ishii, Yuichiro Hayashi, Koji Tsuta, Kiyotaka Yoh, Shingo Matsumoto, Koichi Goto

      • Abstract

      Background

      Precision medicine requires accurate biomarkers for appropriate therapeutic decision. PD-L1 IHC is a predictive biomarker for immune checkpoint inhibitor (ICI), however, the complexity of PD-L1 IHC system could make interpretations confusion in practice. In this study, we compared four PD-L1 IHC systems using real-world clinical samples to reveal their properties and capability of harmonization as a part of nationwide immuno-oncology biomarker study of lung cancer (LC-SCRUM-IBIS).

      Method

      Out of 1635 lung cancer patients enrolled in LC-SCRUM-Japan, four PD-L1 IHC assays (22C3, 28-8, SP263 and SP142) and whole-exome sequencing (WES) were analyzed in addition to NGS mutation screening by the Oncomine™ Comprehensive Assay (OCA). Planned accrual is 1000. IHC was evaluated by three certified lung pathologists independently. Three-tier scoring system (cutoff value of 1, 50%) applied for tumor cell (TC) in all assays, and TC+IC scoring algorism in SP142, according to the manufactural instruction. We calculated Spearman’s correlation coefficient and kappa value among TC proportion and the original protocol’s criteria of each assays. Discordant rate among assays was examined.

      Result

      486 patients (438 nonsmall, 48 small cell carcinoma) completed IHC study analysis from February to December 2017.

      Compared to 22C3, TC-score of 28-8 (kappa value 0.896) were and SP263 (0.729) showed good, and SP142 resulted slight (0.159) correlations. SP142-tc+ic score showed fair correlation with 22C3/28-8/SP263 TC-scores (kappa= 0.213/ 0.241/ 0.291, respectively).

      Our results showed substantial reproducibility of TC score among observers across different IHC assays (range of kappa: 0.675 – 0.837). Inter-observer concordance of the SP142-IC score was also acceptable (kappa 0.591-0.779). Of note, within 22C3 positive group (>1%), 4.5/15.6/67.7/55.0 % of 28-8/SP263/SP142-tc/SP142-(tc+ic) resulted in negative, respectively, indicating a risk of lower category switching for SP263 and SP142 compared to 22C3 and 28-8. A subset (8.3%) of 22C3-negative group resulted in SP142-positive and all such discrepancy was due to IC-positivity.

      There was no significant association between each PD-L1 expression and TMB by WES and OCA. Out of 77 patients treated with ICI, most responders (11/17, 65%) had PD-L1 high expression.

      Conclusion

      Our results revealed an excellent/moderate/slight correlation between 22C3 and 28-8/SP263/SP142. SP142-positive-cases were fewer and more rigorous than the other three assays. A subset of lung cancer showed IC-only PD-L1-positivity. Inter-observer reproducibility was substantial for TC and moderate for IC. The scoring algorism affected concordance trend in a modest way. For harmonization, we should aware of each assays properties. PD-L1 IHC is not a perfect but a feasible biomarker for patients’ selection of ICI therapy.

      • Abstract

      Background
      PD-L1 immunohistochemistry (IHC) has been established as companion or complementary diagnostic assays, each developed as predictive biomarker for specific anti PD1/PD-L1 immunotherapies. The Blueprint (BP) phase 1 comparability study demonstrated that three PD-L1 assays (28-8, 22C3, SP263) showed comparable analytical performance for assessment of PD-L1 expression on tumor cells (TPS), while the SP-142 PD-L1 assay appeared to stain a lower percentage of tumor cells when compared to the other assays. The first part of BP phase 2 (BP2A) re-affirmed these findings in a larger cohort of ‘real life’ specimens scored by 24 experienced pulmonary pathologists, and also showed that the 73-10 assay developed for avelumab showed greater sensitivity than all other assays to detect PD-L1 on tumour cells. BP2A also demonstrated generally excellent inter-observer agreement for tumor cell PD-L1 scoring using both glass slides and digital images, with slightly lesser agreement for the cytology samples included in the study cohort. Inter-observer agreement for immune cell scoring on glass or digital slides was poor. Phase 2B of Blueprint (BP2B) aimed to compare PD-L1 scoring on triplet samples representing large tumor resection blocks, small biopsy samples and fine needle aspirate cell blocks prepared from the same tumor. Method
      Triplet samples of large resected tumor block, small biopsy sample and fine needle aspirate cell block (the latter two taken from the resected tumour specimen) were gathered from 31 resected primary lung cancers (17 adenocarcinomas, 12 squamous cell carcinomas, and 2 large cell carcinomas). Sections from all 93 blocks were stained with the pharmDx 28-8 and 22C3, the FDA-approved SP142 and SP263, or clinical trial associated 73-10 PD-L1 assays, in a CLIA-approved immunohistochemistry laboratory. All H&E and PD-L1 IHC slides were scanned and digital images were used to score all cases by the same 24 pathologists involved in BP2A. As before, tumor cells PD-L1 staining were scored as continuous variable and into 7 cut-off-defined categories, as used in various immune checkpoint inhibitor trials. Immune cells were not scored. Result
      The data reaffirm the relative comparability of 28-8, 22C3 and SP263 assays across the range of scores; SP142 assay scores were lower, those for 73-10 higher. Inter-observer agreement between readers ranged from moderate to near perfect (Kappa-Fleiss (K-F) scores generally >0.7); best overall agreement was on aspirates. Overall, the agreement between scores on the different sample types from the same tumor was good (most K-F scores >0.7); aspirates showed no significant difference from biopsy samples or whole surgical blocks. In contrast to biopsies and surgical blocks, scores could, however, not be rendered in about 14% of aspirate sections. Conclusion
      The results of BP2B confirms earlier results and also demonstrate comparable performance for fine needle aspirates in those cases where TPS scores were possible.

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      OA03.04 - Discussant - OA 03.01, OA 03.02, OA 03.03

      11:00 - 11:15  |  Presenting Author(s): Julien Adam

      • Abstract

      Abstract not provided

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      OA03.05 - Characterization of the Immunologic Intra-Tumor Heterogeneity in Early Stages of Non-Small Cell Lung Cancer by Multiplex Immunofluorescence

      11:15 - 11:25  |  Presenting Author(s): Alejandro Francisco Cruz  |  Author(s): Edwin Roger Parra, Mei Jiang, Junya Fujimoto, Santhoshi N. Krishnan, Souptik Barua, Arvind Rao, Chi-Wan Chow, Carmen Behrens, Neda Kalhor, Annikka Weissferdt, John V Heymach, Stephen Swisher, Boris Sepesi, Jack Lee, Cesar Moran, P. Andrew Futreal, Jianjun Zhang, Ignacio I. Wistuba

      • Abstract

      Background

      Recurrence of non-small cell lung carcinoma (NSCLC) is associated with genetic and epigenetic intra-tumor heterogeneity (ITH). The interaction between malignant cells, stromal cells, and tumor-associated immune-cells (TAICs), such as T-cell lymphocytes (TCLs) and tumor-associated macrophages (TAMs), is important for progression of NSCLC and the characterization of the immunologic ITH might be relevant to predict recurrence in surgically treated patients at early stages of NSCLC. The aim of this study was to characterize the immunologic ITH of primary NSCLC tumors at early stages using image analysis and multiplex immunofluorescence (mIF) approaches.

      Method

      Eight cases of stage IA and 8 cases of stage IB surgically resected NSCLC (11 adenocarcinomas, ADCs; and 5 squamous-cell carcinomas, SCCs) with a history of early recurrence were selected for this preliminary analysis. FFPE blocks were obtained and consecutive sections were stained with two panels of mIF for immune profiling, panel 1: pan-cytokeratin (AE1/AE3), PD-L1, PD-1, CD3, CD8, and CD68; panel 2: AE1/AE3, CD3, CD8, granzyme-B (GB), CD45RO, and FOXP3. Three not adjacent, intra-tumor regions (3mm2 each) per case were randomly selected after gridding the whole tumor section. A total of 41 intra-tumor regions were scanned by Vectra multispectral-microscope and analyzed using InForm-software. TAICs were quantified in epithelial and stromal compartments from each intra-tumor region. G-Cross AUC (area under the curve) was computed for specific intervals of distances between TAICs and malignant cells. Median distance between TAICs and malignant cells within each region was calculated.

      Result

      The median density of TCLs and TAMs were 1527 cells/mm2 and 635 cells/mm2, respectively, without significant differences between histologic subtypes. TCLs were predominantly concentered in stromal compartment (median, 2222 cells/mm2) compared with epithelial compartment (median, 332 cells/mm2). Percentage and density of TCLs and TAMs varied 4 and 8 times, respectively, between cases and regions. Non-cytotoxic T-cells and inactive cytotoxic T-cells were the most prevalent phenotypes. Higher density of TAMs and antigen-experienced TCLs were observed in stage IB than stage IA.

      Conclusion

      Characterization of immunologic ITH of NSCLC is able by mIF and image analysis with FFPE tumor tissue. There is variability of TAICs densities between regions from the same tumor and different subpopulations were observed. TAMs and exhausted T-cells were more prominent in stage IB (tumor >3cm) suggesting these cells may play an important role in recurrence. Ongoing studies with a larger cohort and comparison with non-recurrent surgically treated patients are warranted. Supported by CPRITRP160668 and UTLungSPORE grants

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      OA03.06 - Extraction of Radiomic Values from Lung Adenocarcinoma with Near-Pure Histological Subtypes

      11:25 - 11:35  |  Presenting Author(s): Mong-Wei Lin  |  Author(s): Shun-Mao Yang, Li-Wei Chen, Hao-Jen Wang, Leng-Rong Chen, Kuo-Lung Lor, Yi-Chang Chen, Min-Shu Hsieh, Jin-Shing Chen, Yeun-Chung Chang, Chung-Ming Chen

      • Abstract

      Background

      Histological subtypes of lung adenocarcinomas classified by the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS) system have been investigated using radiomic approaches. However, the results have had limitations since of invasive lung adenocarcinomas may be heterogeneous, with two or more subtypes. To reduce the influence of heterogeneity during radiomic analysis, computed tomography (CT) images of lung adenocarcinomas with near-pure adenocarcinoma subtypes were analyzed to extract representative radiomic features of different subtypes.

      Method

      We enrolled 95 patients who underwent complete resection for lung adenocarcinoma and a pathological diagnosis of a “near-pure” (≥70%) IASLC/ATS/ERS histological subtype. Conventional histogram/morphological features and complex radiomic features (grey-level-based statistical features and component variance-based features) of thin-cut CT data of tumor regions were analyzed. A prediction model based on leave-one-out cross-validation (LOOCV) and logistic regression (LR) was used to classify all five subtypes and three pathologic grades (lepidic, acinar/papillary, micropapillary/solid) of adenocarcinomas. The validation was performed using 36 near-pure adenocarcinomas in a later cohort.

      Result

      A total of 31 lepidic, 14 papillary, 32 acinar, 10 micropapillary, and 8 solid adenocarcinomas were analyzed. With 21 conventional and complex radiomic features, for 5 subtypes and 3 pathological grades, the prediction models achieved accuracy rates of 84.2% (80/95) and 91.6% (87/95), respectively, while accuracy was 71.6% and 85.3%, respectively, if only conventional features were used. The accuracy rate for the validation set (n=36) was 83.3% (30/36) and 94.4% (34/36) in 5 subtypes and 3 pathological grades, respectively, using conventional and complex features, while it was 66.7% and 77.8% only using conventional features, respectively.

      Conclusion

      Lung adenocarcinoma with high purity histological subtypes demonstrates strong stratification of radiomic values, which provide basic information for accurate pathological subtyping and image parcellation of tumor sub-regions.

      figure for wclc 2018.png

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      OA03.07 - Three-Dimensional Immunofluorescence Analysis of Dynamic Vessel Co-Option of Spread Through Air Spaces (STAS) in Lung Cancer

      11:35 - 11:45  |  Presenting Author(s): Yukako Yagi  |  Author(s): Rania G Aly, Kazuhiro Tabata, Natasha Rekhtman, Takashi Eguchi, Joseph Montecalvo, Katia Manova, Prasad S. Adusumilli, Meera Hameed, William D Travis

      • Abstract

      Background

      STAS was identified, by the 2015 WHO classification, as a new method of invasion in lung adenocarcinoma, with poor prognosis. Blood vessel co-option is a mechanism by which spreading intraalveolar tumor cells connect to the surrounding vasculature to survive. The aim of this study was to visualize the dynamic mechanism of blood vessel co-option using a high resolution and high-quality 3D reconstruction, and multiplex immunofluorescence (IF).

      Method

      A 3D reconstruction image of a case of invasive lung adenocarcinoma with extensive STAS was performed on the formalin fixed paraffin-embedded (FFPE) block. 150 serial sections were obtained by the automated sectioning system AS410 (DNS. Ltd, Japan), and stained with H&E (100 slides), and multiplex IF (30 slides) for CD31, type IV collagen, TTF-1 and E-Cadherin to assess the relation between STAS and the surrounding lung parenchyma and vasculature. The IF stained sections were scanned with 0.33um/pixel by Panoramic P250 Flash (3D Histech Ltd, Hungary) Whole Slide Imaging Scanner (WSI). The WSIs were reconstructed into 3D exported to Imaris 8.0 (Bitplane, MA, US) for signal assessment.

      Result

      Serial 3D image analysis identifies the presence of STAS mainly in the form of micropapillary clusters. The multiplex IF staining highlighted the co-option which was determined by the spread and then attachment of STAS (TTF-1 and E-Cadherin positive) to distant alveolar wall capillaries (CD31 positive) with preservation of the alveolar wall (figure). This relation between STAS and the surrounding lung parenchyma was visualized in all serial sections of the whole FFPE block thickness. 01s1632681_ cd31a488_ecada594_col4a647_ttfa546_65.5x2.jpg

      Conclusion

      The survival of STAS, beyond the tumor edge, in lung adenocarcinoma is a viable mechanism for tumor recurrence. The combination of the high resolution and high-quality 3D reconstruction and multiplex immunofluorescence in our study, supports the concept that dynamic blood vessel co-option is a mechanism for STAS survival.

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      OA03.08 - Discussant - OA 03.05, OA 03.06, OA 03.07

      11:45 - 12:00  |  Presenting Author(s): David L. Rimm

      • Abstract

      Abstract not provided

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    OA04 - Improving Access and Outcomes in Lung Cancer Management

    • Type: Oral Abstract Session
    • Track: Nursing and Allied Professionals
    • Moderators:
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      OA04.01 - What is the Cost of a Strong Evidence for the Treatment of Advanced Non-Small Cell Lung Cancer?

      10:30 - 10:40  |  Presenting Author(s): Pedro Aguiar Jr  |  Author(s): Barbara Gutierres, Barbara Dourado, Alanda Alves, Carmelia Maria Noia Barreto, Gilberto de Lima Lopes, Auro Del Giglio

      • Abstract

      Background

      Evidence-based medicine was developed to guide medical decisions based upon the strongest scientific evidence available in the literature. However, large randomized clinical trials are expensive. In addition, new antineoplastic drugs development is also extremely expensive. Therefore, we hypothesized that the strongest evidence available nowadays comes from studies developed by the pharmaceutical industry.

      Method

      We carried out a search on network databases for studies published between 2014 and 2017. We included only experimental studies that assessed the treatment for advanced or metastatic non-small cell lung cancer. All included studies were divided into two groups: studies funded by pharmaceutical industry and studies funded by other sources. The primary end point was to compare the evidence strength of each group. Secondary end points were to compare other aspects, such as the number of patients included by each group of studies and the number of innovative drugs studied by each group of studies.

      Result

      We found 1,502 studies and included 299 studies (154 sponsored by pharmaceutical industry and 145 funded by other sources). 52,988 patients were included in all studies (36,455 in studies sponsored by industry and 16,533 in studies with other funding sources; p < 0.001). The studies funded by pharmaceutical industry had the stronger evidence compared with studies with other sources of funding (p = 0.005). Moreover, studies sponsored by pharmaceutical industry studied more innovative therapies (72.4% versus 48.9%; p < 0.001) and had a higher proportion of open access manuscript (60.8% versus 43.9%; p = 0.004). Results are summarized in the table.

      Parameter Industry Sponsored P value

      Yes

      154 (100%)

      No

      145 (100%)
      Number of patients 36,455 16,533 <0.001
      Mean N of patients 236.7 115.6
      Line First 110 (71.4%) 94 (64.8%) 0.220
      Second or more 44 (28.6%) 51 (35.2%)
      Biomarker Yes 55 (35.9%) 55 (37.9%) 0.723
      No 98 (64.1%) 90 (62.1%)
      Innovative Tx Yes 110 (72.4%) 69 (48.9%) <0.001
      No 42 (27.6%) 71 (51.1%)
      Phase I 20 (13%) 25 (17.2%) 0.409
      II 101 (65.6%) 97 (66.9%)
      III 32 (20.8%) 21 (14.5%)
      IV 1 (0.6%) 2 (1.4%)
      Evidence Level 1 0 (0%) 1 (0.7%) 0.005
      2 76 (49.4%) 52 (35.9%)
      3 78 (50.6%) 87 (60%)
      4 0 (0%) 5 (3.4%)
      Experimental Yes 35 (47.3%) 26 (50%) 0.765
      Superiority No 39 (52.7%) 26 (50%)
      Open Access Yes 93 (60.8%) 61 (43.9%) 0.004
      Article No 60 (39.2%) 78 (56.1%)

      Conclusion

      Studies funded by pharmaceutical industry had stronger evidence, tested more innovative therapies, and were more accessible to the readers compared with studies developed with other sources of funding. These findings may alert oncology cooperative groups to the need of more studies with more evidence strength.

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      OA04.02 - Demographic, Psychosocial, and Behavioral Associations with Cancer Screening Among a Homeless Population

      10:40 - 10:50  |  Presenting Author(s): Lovoria B Williams  |  Author(s): Stephen W Looney, Thomas Joshua, Amber McCall, Martha S Tingen

      • Abstract

      Background

      Although cancer incidence and mortality is declining, cancer remains among the leading causes of death worldwide. Research shows that cancer morbidity and mortality can be reduced by early detection. Yet, both cancer risks and screening behavior remain understudied in the United States homeless population. Lung cancer is the deadliest of cancers. Given the recent lung cancer screening guideline, it is especially important to assess population-based awareness of the screening recommendation among the homeless population, a population known to have higher cancer risk behaviors and lower cancer screening rates.

      Method

      Researchers conducted a cross-sectional survey of homeless individuals (n =201) who attended a 1-day community event. Eligible study participants were English-speaking adults, aged 21 and above. Willing participants completed a 1-page 33 item paper survey. The analysis describes the demographic, psychosocial, and behavioral associations with cancer screenings and knowledge of the lung cancer screening recommendation.

      Result

      Participants’ mean age was 51.7 years (SD 13.6); the group was largely African American (77.3%) and male (67.9%). Despite higher cancer risk behaviors, knowledge of lung cancer screening and general participation rates for cancer screenings were below national benchmarks. Among women, the breast and cervical cancer screening rates were 46.5% and 85.1%. Among men, the prostate cancer screening rate was 34.2%. Among all participants, the colon cancer-screening rate was 44%. Cancer risk behaviors were higher than national rates and lung cancer screening knowledge was low (23.0%). Some cancer screening behaviors were associated with age, income, health status, obesity, tobacco use, and physical activity level.

      Conclusion

      The associations of screening with modifiable risk factors such as smoking, physical activity and obesity suggests that relevant behavior change interventions are necessary among this high-risk population. Given the barriers to screening of poverty-stricken individuals, such as lack of transportation and access, nurses must not only educate patients on lung cancer screening, they must assist with identifying payment resources and care navigation. Moreover, nurses must be educated on the ambiguity and inconsistency among evidenced-based screening guidelines and be prepared to engage patients in shared decision-making that weighs the recommendations with the patient’s individual cancer risks. To improve cancer survival among disparate populations, sustained community outreach is necessary to increase awareness of screening recommendations, identify high-risk individuals, and navigate them to resources. It is imperative that resources are provided to support relevant behavior change interventions, such as tobacco cessation in this high-risk population.

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      OA04.03 - The Role of Comprehensive Genomic Profiling in the Community Setting 

      10:50 - 11:00  |  Presenting Author(s): Kimberly Ann Rohan

      • Abstract

      Background

      Comprehensive Genomic Profiling (CGP) is biomarker information to helo match patients to approved targeted therapies, immunotherapies, and clinical trials. This information can assist practitioners in caring for patients with solid tumors in decision making. Nurses play a key role in educating paitnets on how the testing is done, what information it will provide and how that information will be used in clinical practice.

      Method

      A retrospective analysis was done on the results of Comprehensive Genomic Profiling (Foundation One) on paitents that were tested in our practice from 2014-2017. The Edward Cancer Center is a community hospital based cancer center in the western suburbs of Chicago. The practice has 7 oncologists and 4 Advanced Practice Nurses. The practice saw approximately 650 new cases of cancer last year. It is rare that a patient presents with Comprehensive Genomic Profining (CGP). Our center ordered CGP on 46 patients with a cancer diagnosis after discussion with their primary oncologist. Each case was reviewed for number of genomic alterations identified, treatment associated with potential for clinical trial benefit, therapies associated with lack of response and the clinical decisions that were made based on the findings.

      Result

      Of the 46 charts reviewed: 263 genomic alterations were identified, 172 therapies were associated with potential clinical benefit and 11 therapies associated with lack of response. Of these patients, 6 (13%) were referred to clinical trial and 12 (26%) resulted in change in therapy. Of the lung cancer patients, 2 (6%) were referred to clinical trial and 11 (34%) resulted in change in therapy.

      Conclusion

      Comprehesive Genomic Profiling is a useful tool in identifying patients in the community setting for clinical trial enrollement. 6-13% exceeds the national clinical trial enrollment. The results also assist in directing patient care and in directing change of therapy to more targeted therapies or continuation of current therapy. There were 4 (8.5%) patients that opted to stop care and enroll in hospice care based on the CGP lresults.

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      OA04.04 - Discussant - OA 04.01, OA 04.02, OA 04.03

      11:00 - 11:15  |  Presenting Author(s): Jhanelle Elaine Gray

      • Abstract

      Abstract not provided

    • +

      OA04.05 - An Early Rehabilitation Intervention for Enhancing Oxygenation From Lung Cancer Surgery

      11:15 - 11:25  |  Presenting Author(s): Wei Ling Hsiao

      • Abstract

      Background

      The purpose of this study is to test the effects of an early rehabilitation intervention on oxygenation, postoperative complications, and recovery from lung cancer surgery.

      Method

      The study uses an experimental design. Ninety patients scheduled for lung cancer surgeries was recruited from thoracic surgery units of a medical center in Taiwan. Patients were randomly assigned to the intervention or the control group. The intervention includes a 5-day postoperative in-hospital rehabilitation from post op day 1. The main components of the rehabilitation were aerobic and strength exercises as well as breathing training by using an incentive spirometry. Peripheral capillary oxygen saturation (SpO2) was measured in the morning of the preoperative day and of the 4 consecutive days from postoperative day one to four by using the Nellcor™ OxiMax N-65 Portable Pulse Oximeter. The SpO2/FiO2 (S/F) ratio was then calculated to assess patients’ oxygenation. Data on postoperative pulmonary compilations and durations of chest tube drainage were collected from the patients’ charts.

      Result

      The patients’ demographics and baseline measures were equivalent between groups. Results of GEE showed a significant group by time interaction effect on S/F ratio. As for the parameter estimates, from postoperative day 1 to day 4, the S/F ratio improvement in the intervention group was 74.49 (Wald X2 = 46.42, p<0.001) more than in the control group. Result of Chi-square test showed that the number of postoperative lung complications in the intervention group (n =1) was significantly less (X2 = 8.39, p = 0.004) than it in the control group (n =10). Result of t- test showed that the duration of chest tube drainage in the intervention group (2.00±1.00 days) was significantly shorter (t =-2.32, p = 0.022) than it in the control group (2.56±1.25 days).

      Conclusion

      The study results support the effects of the early rehabilitation intervention on enhancing oxygenation, preventing complications, and promoting recovery from lung cancer surgery as indicated by shortened the duration of chest tube drainage. Surgery to remove the cancer is one of the primary treatment options for non-small cell lung cancer. However, lung cancer surgery may result in decreasing lung capacity and expansion; therefore, increase risks for postoperative pulmonary complications. Pulmonary rehabilitation designed to enhance lung expansion and ventilation may help to reduce postoperative lung complications and promote patients’ recovery from lung cancer surgery.

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      OA04.06 - Perceptions of Non-Participation in a Rehabilitation Intervention After Surgery for Non-Small Cell Lung Cancer

      11:25 - 11:35  |  Presenting Author(s): Mai Nanna Schoenau  |  Author(s): Malene Missel

      • Abstract

      Background

      Patients with non-small lung cancer (NSCLC) are difficult to engage in clinical trials. Few studies have examined in-depth why these patients refuse to participate. In a Danish randomized clinical trial; ’Postoperative rehabilitation in operable lung cancer patients (PROLUCA)’ only 32% of eligible participants consented to participate in the trial. The purpose of this qualitative study was therefore to explore perceptions, considerations and barriers of non-participation in PROLUCA.

      Method

      This study was inspired by Reflective Life Research as developed by Dahlberg et al. as a descriptive and interpretive phenomenological research approach. Participants are patients who declined to participate in PROLUCA (non-participants). They were purposefully sampled and recruited from the group of patients who were found to be eligible for the exercise intervention but who declined to participate. Data were collected though telephone interviews. Openness, curiosity and sensitivity played an important role in carrying out the interviews. Analysis was performed according to Reflective Life Research.

      Result

      Fifteen non-participants consented to participate in qualitative interviews. Nine men and six women with a mean age of 68 years (range 48-84) were included. Mean time since surgery was 21 month (range 12-28). Five patients were working and ten were retired, eleven patients lived with a partner.

      The analysis revealed three essential themes referred to the patients’ experiences of being ‘Between healthy life and good life’, ‘Under the influence of society’ and their experiences of ‘Health and rehabilitation as a personal responsibility’. Perceptions of non-participation in rehabilitation after surgery for lung cancer are moderated between freedom and necessity. Patients experience ambivalence between a wish to participate in rehabilitation and not having the energy to participate. Patients refused to participate due to daily life priorities and lack of motivation which furthermore is related to social and interpersonal relationships. The patients exercise history is also essential in declining participation. Additionally the patients are under influence of norms and health perceptions from the society.

      Conclusion

      Patients’ perception of "the good life" was fundamental for accepting or declining participation in a rehabilitation intervention study. Consideration and barriers of non-participation was influenced by norms from the society, motivation, priorities, exercise history, social and interpersonal relations.

      This study has contributed with a sensitive awareness of why patients following lung cancer surgery might refuse participating in rehabilitation. This knowledge can be taken into consideration in the planning of future clinical trials with lung cancer patients.

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      OA04.07 - Early Initiated Postoperative Rehabilitation Reduces Fatigue in Patients with Operable Lung Cancer: A Randomized Trial

      11:35 - 11:45  |  Presenting Author(s): Morten Quist  |  Author(s): Maja Schick Sommer, Jette Vibe-Petersen, Maja Stærkind Bohlbro, Seppo W Langer, Klaus Richter Larsen, Karen Trier, Merete Christensen, Paul Frost Clementsen, Malene Missel, Carsten Henriksen, Kristina Poulsen, Henning Langberg, Jesper Holst Pedersen

      • Abstract

      Background

      Surgical tolerability and perioperative risk of complications are correlated with high age, smoking history, comorbidities, low cardiorespiratory fitness (VO2peak) and low functional capacity, which paradoxically are characteristics describing the average patient with lung cancer. Little is known about the optimal amount and timing of exercise strain in concern of the operation wound and with regard improvement of physical function and quality of life (QOL). On this background, we decided to investigate the effect of early vs. late initiated postoperative rehabilitation in patients with operable lung cancer on exercise capacity, functional capacity, muscle strength, and QOL.

      Method

      The study was designed as a two-armed randomized controlled trial with randomization to either early initiated postoperative rehabilitation (14 days after surgery (ERG)) or a control arm with late initiated postoperative rehabilitation (14 weeks after surgery (LRG)). The primary endpoint was a change in maximum oxygen consumption (VO2peak) from baseline to post intervention 26 weeks following lung resection. Fatigue was measured with EORTC QLQ C30 LC13.

      Result

      From April 2013 to June 2016, 582 patients with operable NSCLC were screened for eligibility. With 119 patients randomized in the early rehabilitation group (ERG) (68 females, 51 males; median age 65), and 116 randomized to late rehabilitation group (LRG) (62 females, 54 males; median age 65) the recruitment rate was 52.6%. There was a non-significant decrease in VO2peak in both ERG and LRG from baseline to 26 weeks and no significant difference between ERG and LRG (p=0.9269). There was a significant decrease from baseline to 14 weeks in both ERG (p=0.027) and LRG (p<0.001) and a significant difference between groups (p=0.0018). There was a non-significant increase from 14 weeks to 26 weeks in ERG (p=0.464) and a significant increase from 14 weeks to 26 weeks in LRG (p<0.001) and a significant difference between the two groups (p=0.0003). We found no significant differences in QOL but we found a significant difference between ERG and LRG from baseline to 14 weeks in fatigue level in favour of ERG.

      Conclusion

      This is the first randomized controlled trial to investigate the effects of early vs. late initiated postoperative rehabilitation in patients with lung cancer. There is no difference in the commencement (early vs. late) of a postoperative exercise program for patients with lung cancer on exercise capacity. But to reduce fatigue patients should be recommended to initiate early exercise programs.

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      OA04.08 - Discussant - OA 04.05, OA 04.06, OA 04.07

      11:45 - 12:00  |  Presenting Author(s): Pippa Labuc

      • Abstract

      Abstract not provided

  • +

    PC01 - Controversies in Mesothelioma

    • Type: Pro-Con Session
    • Track: Mesothelioma
    • Moderators:
    • +

      PC01.01 - PRO Intrapleural Chemotherapy Is It the Future?

      10:30 - 10:45  |  Presenting Author(s): Isabelle Opitz, Alessandra Curioni Fontecedro

      • Abstract

      Abstract

      Considerable progress was achieved in the field of mesothelioma (MPM) research and treatment over the last decades. However, high local recurrence rates – even after aggressive treatment - remain an unresolved problem. Based on anatomic constraints, it is impossible to leave adequate safety margins - usually required for oncological surgery - when resecting mesothelioma, therefore leading to only macroscopic – but not microscopic - complete resection (MCR). The remaining microscopically small tumor residuals are most probably the origin of later recurrence.

      Intracavitary local treatment modalities target this hypothesis. Substances can be applied locally in desired high doses, while side effects can be reduced by decreased systemic absorption. Several intracavitary approaches have been evaluated to try to reduce local recurrence and were mostly applied after MCR, either lung sparing (extended) pleurectomy / decortication ((e)P/D) or extrapleural pneumonectomy (EPP). Intracavitary chemotherapy has been successfully applied in peritoneal carcinomatosis1-4 and the knowledge gained transferred to MPM because of certain similarities of both tumors. Adding hyperthermia to the concept is based on the principle that hypothermia leads to increased penetration depth of the chemotherapeutic agent into the tissue and therefore a maximized cytotoxic effect on tumor cells.

      Looking at current guidelines, intracavitary treatments have not yet entered routine treatment regimens for mesothelioma patients. The recommendation of the American Society of Clinical Oncology Clinical Practice Guideline (ASCO)5 summarizes: Intracavitary therapies (chemotherapy or photodynamic therapy) may be administered safely in experienced centers of excellence, preferably in the context of a clinical trial. Their role in improving outcome is indeterminate (Type of recommendation: evidence based; Evidence quality: low; Strength of recommendation: weak).

      Hyperthermic intraoperative chemotherapy (HIOC) with cisplatin has demonstrated safety and some efficacy in two phase I or II prospective clinical trials in patients undergoing EPP and P/D immediately after surgery6, 7. A safe maximally tolerated dose and the methodology to reduce associated complications have been established (table 1).

      Another technique to reduce systemic side effects and simultaneously increase the local concentration of the drug is to combine cisplatin with a fibrin glue. Cisplatin-fibrin can be sprayed on the resection surface of the chest wall and the lung after surgery (figure 1)8.The pharmacokinetic advantages and efficacy to reduce tumor recurrence have been demonstrated in several preclinical studies9-11. In a phase I dose escalation trial (INFLuenCe-Meso) safety was confirmed, and currently further tested in a phase II clinical trial (NCT01644994).

      Addionally to intracavitary applied chemotherapeutics which are mainly platinum based other substances were tested. Tada et al recently published the results of a phase I clinical trial using zoledronic acid12. This intrapleuraly applied drug is a third generation bisphosphonate and was used in patients with inoperable MPM. Prior to this, the efficacy was equally demonstrated in preclinical studies12, 13.

      figure 1.png

      Figure 1: Application of cisplatin-fibrin after MCR

      Table 1: intracavitary chemotherapy

      n

      Histology

      N2 or Nx

      IMIG stage

      intraoperative regimen

      HIPEC

      Surgery type

      Peri-op Mortality

      Morbidity / Toxicity

      Adjuvant systemic CTX

      Adjuvant RT

      Median OS (months)

      Median PFS (months)

      Opitz 2016

      12

      8 epithelioid

      4 biphasic

      3

      I-II: 3

      III-IV: 9

      Cisplatin + fibrin

      no

      P/D

      0%

      33%

      None

      None

      21

      8

      Sugarbaker 2013

      72

      63 epithelioid

      9 biphasic

      46

      I-II: 14

      III-IV: 60

      cisplatin

      yes

      P/D or EPP

      4.2%

      NR

      57%

      57%

      35.3

      27.1

      Tilleman 2009

      92

      53 epithelioid

      39 non-epithelioid

      NR

      I-II: 14

      III-IV: 78

      cisplatin

      Yes

      EPP

      4.3%

      49%

      NR

      NR

      13.1

      15.3

      Zellos 2009

      29

      24 epithelioid

      5 non-epithelioid

      9

      I-II: 18

      III: 11

      cisplatin

      Yes

      NR

      7%

      NR

      NR

      NR

      20

      16

      Richards 2006

      44

      24 epithelioid

      17 biphasic

      3 sarcomatoid

      33

      I-II: 27

      II-III: 17

      cisplatin

      Yes

      P/D

      11%

      25%

      None

      None

      13

      7.2

      Lu 2005

      33

      23 epithelioid

      2 biphasic

      3 sarcomatoid

      5 unspecified

      NR

      I-II: 11

      III-IV: 17

      Liposomal entrapped cisplatin analogue

      No

      NA

      9%

      NR

      None

      None

      13.2

      5

      Chang 2004

      50

      NR

      31

      I-II: 19

      III: 31

      cisplatin

      Yes

      EPP

      2%

      60%

      Unknown

      Unknown

      NR

      NR

      Monneuse 2003

      17

      NR

      NR

      I-II: 10

      III-IV: 7

      mitomycin C and/or cisplatin

      Yes

      P/D or pleurectomy

      6%

      29%

      NR

      NR

      18

      NR

      Van Ruth 2003

      20

      16 epithelioid

      4 biphasic

      0

      NR

      cisplatin + doxorubicin

      Yes

      12 P/D

      8 EPP

      0%

      65%

      None

      Thoracotomy scar and drainage ducts

      11

      8

      Ratto 1999

      10

      4 epithelioid

      6 biphasic

      0

      I-II: 10

      cisplatin

      Yes

      P/D or EPP

      0%

      20%

      None

      55 Gy to chest wall incision

      NR

      NR

      Colleoni 1996

      20

      10 epithelioid

      7 biphasic

      3 sarcomatoid

      2

      NR

      cisplatin + cytarabine

      No

      P/D

      0%

      NR

      Epirubicin, mitomycin

      None

      11.5

      7.4

      Colleoni 1996

      14

      NR

      NR

      NR

      Cisplatin + interferon α

      No

      pleurectomy

      0%

      7%

      29% carboplatin + interferon α

      None

      NR

      NR

      Sauter 1995

      13

      NR

      NR

      NR

      cisplatin + cytosine arabinoside

      No

      Subtotal pleurectomy

      8%

      23%

      Cisplatin + mitomycin C

      9

      6

      Lee 1995

      15

      7 epithelioid

      4 biphasic

      4 sarcomatoid

      0

      NR

      cisplatin + cytosine arabinoside

      No

      P/D

      0%

      13%

      46%

      73%

      11.5

      NR

      Rusch 1994

      27

      19 epithelioid

      6 biphasic

      2 sarcomatoid

      16

      I-II: 9

      III-IV: 18

      cisplatin + mitomycin

      No

      P/D

      3.7%

      None

      Cisplatin, mitomycin

      None

      18.3

      13.6

      Rice 1994

      19

      10 epithelioid

      7 biphasic

      2 sarcomatoid

      5

      I: 13

      III: 6

      cisplatin + mitomycin C

      No

      P/D or EPP

      5%

      32%

      Cisplatin

      None

      13

      11

      Literature:

      1. Spratt JS, Adcock RA, Muskovin M, et al. Clinical delivery system for intraperitoneal hyperthermic chemotherapy. Cancer Res 1980;40:256-260.

      2. Spratt JS, Adcock RA, Sherrill W, et al. Hyperthermic peritoneal perfusion system in canines. Cancer Res 1980;40:253-255.

      3. Sugarbaker PH. Surgical management of peritoneal carcinosis: diagnosis, prevention and treatment. Langenbecks Arch Chir 1988;373:189-196.

      4. Sugarbaker PH, Gianola FJ, Speyer JL, et al. Prospective randomized trial of intravenous v intraperitoneal 5-FU in patients with advanced primary colon or rectal cancer. Semin Oncol 1985;12:101-111.

      5. Kindler HL, Ismaila N, Armato SG, 3rd, et al. Treatment of Malignant Pleural Mesothelioma: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 2018;36:1343-1373.

      6. Zellos L, Richards WG, Capalbo L, et al. A phase I study of extrapleural pneumonectomy and intracavitary intraoperative hyperthermic cisplatin with amifostine cytoprotection for malignant pleural mesothelioma. J Thorac Cardiovasc Surg 2009;137:453-458.

      7. Richards WG, Zellos L, Bueno R, et al. Phase I to II Study of Pleurectomy/Decortication and Intraoperative Intracavitary Hyperthermic Cisplatin Lavage for Mesothelioma. J Clin Oncol 2006;24:1561-1567.

      8. Opitz I, Kostron A, Lauk O, et al. Intracavitary Cisplatin-Fibrin After Resection of Malignant Pleural Mesothelioma. ORAL 14.05. JTO; 2015;10(9), Supplement 2.

      9. Lardinois D, Jung FJ, Opitz I, et al. Intrapleural topical application of cisplatin with the surgical carrier Vivostat increases the local drug concentration in an immune-competent rat model with malignant pleuromesothelioma. J Thorac Cardiovasc Surg 2006;131:697-703.

      10. Opitz I, Lardinois D, Arni S, et al. Local recurrence model of malignant pleural mesothelioma for investigation of intrapleural treatment. Eur J Cardiothorac Surg 2007;31:773-778.

      11. Opitz I, Erne BV, Demirbas S, et al. Optimized intrapleural cisplatin chemotherapy with a fibrin carrier after extrapleural pneumonectomy: a preclinical study. J Thorac Cardiovasc Surg 2011;141:65-71.

      12. Tada Y, Hiroshima K, Shimada H, et al. An intrapleural administration of zoledronic acid for inoperable malignant mesothelioma patients: a phase I clinical study protocol. Springerplus 2016;5:195.

      13. Scheller EL, Hankenson KD, Reuben JS, et al. Zoledronic acid inhibits macrophage SOCS3 expression and enhances cytokine production. J Cell Biochem 2011;112:3364-3372.

    • +

      PC01.02 - CON Intrapleural Chemotherapy Is It the Future?

      10:45 - 11:00  |  Presenting Author(s): David Rice

      • Abstract

      Abstract not provided

    • +

      PC01.03 - PRO IO in Mesothelioma Should Only Be Given on Clinical Trials

      11:00 - 11:15  |  Presenting Author(s): Penelope Bradbury

      • Abstract

      Abstract

      It is 15 years since the pivotal study of pemetrexed and cisplatin versus cisplatin in inoperable pleural mesothelioma was reported, demonstrating a median overall survival (OS) improvement for the combination (pemetrexed/cisplatin 12.1 months vs. cisplatin 9.3 months) [1]. Since that time the only trial to demonstrate a further improvement in OS has been with the addition of bevacizumab to standard chemotherapy (median OS 18.8 months vs. 16.1 (hazard ratio [HR] 0·77 [0·62–0·95]; p=0·0167) [2]. IO is showing promise in mesothelioma. The PD-1 inhibitors, pembrolizumab and nivolumab as single agents have response rates ranging from 18-29% (Table), with prolonged duration of responses reported. In combination, nivolumab and ipilimumab has a disease control rate (DCR) at 12 weeks of 50%, and the combination of durvalumab and tremelimumab had response rate of 28%. In combination with chemotherapy durvalumab, pemetrexed and cisplatin had a 65% 6 month progression free survival and 55% response rate (Table). While these results are encouraging, the majority of reported trials are small, single arm, with response or disease control rates as the primary endpoints. The only randomized control trial to have been completed so far, evaluated tremelimumab as a single agent in patients with previously treated mesothelioma following encouraging results from two single arm single institution studies of tremelimumab (9). Unfortunately, the primary endpoint of OS was not met (tremelimumab vs. placebo median OS 7.7 months vs. 7.3 months (0·92 [95% CI 0·76−1·12], p=0·41). It is notable that the DCR on the placebo arm (defined as CR, PR or SD of at least 12 weeks) was 21·7% (16·0–28·3) highlighting some patients have indolent disease and the need for randomized trials comparing with standard of care. There are a number of randomized trials currently accruing, which will address the role of checkpoint inhibitors for the treatment of mesothelioma and may establish a new standard of care in the future.

      1. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. Vogelzang NJ, Rusthoven JJ, Symanowski J et al. J Clin Oncol. 2003 Jul 15;21(14):2636-44.

      2.Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a randomised, controlled, open-label, phase 3 trial. Zalcman G, Mazieres J, Margery J et al. French Cooperative Thoracic Intergroup (IFCT). Lancet. 2016 Apr 2;387(10026):1405-1414.

      3. Clinical safety and activity of pembrolizumab in patients with malignant pleural mesothelioma (KEYNOTE-028): preliminary results from a non-randomised, open-label, phase 1b trial. Alley EW, Lopez J, Santoro A et al. Lancet Oncol. 2017 May;18(5):623-630

      4. A Phase II Study of Nivolumab: A Multicenter, Open-Label, Single Arm Study in Malignant Pleural Mesothelioma (MERIT). Goto Y, Okada M, Kijima T et al. WCLC 2017 MA 19.01

      5.Avelumab (MSB0010718C; anti-PD-L1) in patients with advanced unresectable mesothelioma from the JAVELIN solid tumor phase Ib trial: Safety, clinical activity, and PD-L1 expression. Hassan R, Thomas A, Patel MR. et al. J Clin Oncol 34, 2016 (suppl; abstr 8503)

      6. Tremelimumab combined with durvalumab in patients with mesothelioma (NIBIT-MESO-1): an open-label, non-randomised, phase 2 study. Calabrò L, Morra A, Giannarelli D et al. Lancet Respir Med. 2018 Jun;6(6):451-460. doi: 10.1016/S2213-2600(18)30151-6. Epub 2018 May 15.

      7. Second- or third-line nivolumab (Nivo) versus nivo plus ipilimumab (Ipi) in malignant pleural mesothelioma (MPM) patients: Results of the IFCT-1501 MAPS2 randomized phase II trial. Scherpereel A, Mazieres J, Greillier L et al. French Cooperative Thoracic Intergroup (IFCT). J Clin Oncol 35, 2017 (suppl; abstr LBA8507)

      8. DREAM: A phase II study of durvalumab with first line chemotherapy in mesothelioma—First results. Nowak AK, Lesterhuis WJ, Maxwell Hughes BG et al. J Clin Oncol 36, 2018 (suppl; abstr 8503)

      9. Efficacy and safety of an intensified schedule of tremelimumab for chemotherapy-resistant malignant mesothelioma: an open-label, single-arm, phase 2 study. Calabrò L, Morra A, Fonsatti E et al. Lancet Respir Med 2015;3: 301–09

      10. Tremelimumab as second-line or third-line treatment in relapsed malignant mesothelioma (DETERMINE): a multicentre, international, randomised, double-blind, placebo-controlled phase 2b trial. Maio M, Scherpereel A, Calabrò L et al. Lancet Oncol 2017; 18: 1261–73

      Trial

      Drug

      Trial design

      Patient population (patient number)

      Endpoint

      Efficacy

      KeyNote 0-28

      Alley et al. [3]

      Pembrolizumab

      1B, single arm

      Post chemotherapy or unable to receive (N=25)

      Safety/tolerability

      ORR

      PR=20%; SD 52% Clinical Benefit 40% (95% CI 21·1–61·3) Median PFS 5.4 months (3.4-7.5)

      MERIT

      Goto et al. [4]

      Nivolumab

      Single arm

      2nd or 3rd line (N=34)

      ORR

      ORR 29% (16.8-46.2) DCR 67.6% (50.8-80.9%)

      PFS 6.1 (95%CI: 2.9, NR)

      JAVELIN

      Hassan et al. [5]

      Avelumab

      Single Arm

      2nd Line

      (N=53)

      ORR

      ORR 9.4% (42.3-3.1-20.7)

      DCR 56.6% (42.3-70.2)

      NIBIT-MESO1

      Luana Calabrò et al. [6]

      Tremelimumab/ Durvalumab

      Single arm

      2nd line or first line N=40

      Immune OR

      28% [95% CI 15–44])

      Median duration of immune response 16.1 months (IQR 11·5–20·5).

      MAPS-2

      A Scherpereel et al. [7]

      Nivolumab

      Nivolumab/

      Ipilimumab

      Non-comparative randomized

      2nd or 3rd Line

      (N=129)

      DCR at 12 weeks

      44.4% (31.2-57.7)

      50% (36.7-67.3)

      DREAM

      Nowak et al. [8]

      Pemetrexed/ cisplatin/ durvalumab

      Single arm

      First line, inoperable (N=31)

      PFS at 6 months

      65% PFS at 6 months

      Confirmed ORR 55%

      Tremelimumab Intensified schedule. Luana Calabrò et al. [9]

      Tremelimumab

      Single arm

      2nd Line

      (N=29)

      iORR

      4 PR (13·8%; 3·9–31·7)

      DCR 52%. median duration 10·9 months (95% CI 8·2–13·6).

      DETERMINE

      Michele Maio et al. [10]

      Tremelimumab vs. placebo

      Phase IIB randomized

      2nd or 3rd line

      (N=571)

      OS

      median OS 7.7 vs. 7.3 months (0·92 [95% CI 0·76−1·12], p=0·41)

      DCR (CR, PR or SD of at least 12 weeks). (27·7%, 23·3–32·5 versus 21·7%, 16·0–28·3)

    • +

      PC01.04 - CON in Mesothelioma Should Only Be Given on Clinical Trials

      11:15 - 11:30  |  Presenting Author(s): Evan Alley

      • Abstract

      Abstract

      Malignant pleural mesothelioma (MPM) is a relatively rare malignancy that is considered to be incurable despite advances in surgery, radiation, and chemotherapy. For patients with disease progression after primary platinum/pemetrexed-based therapy, there are limited options for treatment and no approved second-line agents. Recent data from several studies have demonstrated clinically meaningful, and sometimes remarkable activity of checkpoint inhibitors in patients with MPM that has failed first-line therapy. Although the data sets are relatively small, response and survival rates are consistent across studies and appear to be better than those seen in historical controls. Undoubtedly, larger trials with randomized cohorts would provide more robust data. However, access to clinical trials for rare diseases such as MPM is limited in many parts of the world. Therefore, the use of checkpoint inhibitor therapy is a reasonable and medically appropriate option for patients with MPM, especially when a clinical trial is unavailable.

    • +

      PC01.05 - PRO Radiation Options: Are We SMART Enough?

      11:30 - 11:45  |  Presenting Author(s): John Cho

      • Abstract

      Abstract

      Malignant pleural mesotheliomas (MPM) are rare but aggressive tumours involving the pleura associated with prior asbestos exposure. Although asbestos use has been significantly curtailed, the latency period between asbestos exposure and development of MPM is long, ranging up to 40 years [1]. The incidence of MPM is still increasing and expected to peak by the 2020s.

      The prognosis of MPM is grim with disappointing treatment outcomes. The median survival is 4 to 12 months without treatment [2] and the 2-year overall survival is 0 to 12% [3]. Its management is controversial without consensus as to what constitutes the best treatment. There is still debate as to the type of resection these patients should receive. Previous enthusiasm for aggressive debulking resection using extra-pleural pneumonectomy (EPP) has been tempered by lack of benefit and the considerable toxicity seen [4].

      Several features unique to MPM has conspired to hamper the discovery of its optimal management. First, MPM is rare (with annual incidence of approximately 1 in 100, 000). Rare tumours are often left orphaned by pharmaceuticals due to the difficulty justifying the cost of drug development for such a small patient population. Furthermore, it is challenging to mount large scale clinical trials due to poor accrual rates. Outside of specialized MPM clinics, most clinicians see MPMs infrequently, greatly limiting the accumulation of clinical expertise and experience in its management.

      Second, MPM involves the entire hemithorax (pleural envelope). Large volume disease is, in general, more difficult to manage, both surgically and radiotherapeutically. EPP is a major surgical procedure associated with significant perioperative morbidity and mortality. Hemithoracic radiation therapy (RT) needs to be planned carefully in order to avoid the risk of fatal radiation pneumonitis is the contralateral lung [5]. Patients must be carefully selected to ensure the disease is still resectable and patients must be sufficiently fit enough to tolerate and complete their treatment. As a result, only 20% of MPM patients are suitable for aggressive management at the time of assessment.

      Third, MPM is heterogeneous disease entity with heterogeneous management approaches, varying from best supportive care to aggressive trimodality treatment. Clinical heterogeneity introduces clinical variance and “noise” into its management which, in turn, makes identification of any therapeutic “signal” more difficult. Normally, this limitation can be mitigated by increasing the sample size and, thus, the power of the study but in rare tumours, this is not easily achieved.

      Surgery, by itself, is generally considered to be a palliative option, not a curative one. Even with an EPP, one cannot achieve complete microscopic resection (R0) due to the presence of malignant pleural effusions contaminating the pleural space and surgical bed. As a result, without additional therapy, most patients fail locally in the thoracic cavity. Adjuvant therapy is, thus, a critical component in managing MPM. EPP followed by adjuvant hemithoracic RT was the first treatment approach that was able to show local control in the hemithorax was possible [6].

      However, when their patterns of failure were analyzed more carefully, most of the recurrences were distant and usually involved the contralateral lung or abdomen. This suggested that a possible mechanism for distant failure could be from the tumour spillage into these compartments at the time of EPP during the removal of the diaphragm and pericardium.

      We hypothesized that altering the order of treatment to neoadjuvant hemithoracic RT followed by EPP would reduce the risk of distant metastases by preventing the irradiated clonogens from implanting and potentially improving survival. This provided the rationale for the Surgery for Mesothelioma After RT (SMART) study. This clinical trial is still on-going but our published interim results demonstrated a 3 year overall survival rate of 75% [7]. Other advantages to this approach are: the short accelerated treatment with an overall treatment time of 2 weeks from RT to EPP; excellent patient compliance with 100% completion rate; and acceptable treatment toxicity.

      As our understanding of the tumour microenvironment and the complex interaction between the tumour, host immune system, and therapy improves, we expect treatment outcomes will also improve. Newer targeted and immuno-oncologic agents show much promise and are an active topic of current research. In particular, we anticipate that the combination of immunotherapy agents and radiation will be an area of tremendous interest due to their synergistic effects and potentiation of the immune system [8].

      References:

      1. Bianchi C, Giarelli L, Grandi G, Brollo A, Ramani L, Zuch C. Latency periods in asbestos-related mesothelioma of the pleura. Eur J Cancer Prev. 1997;6(2):162-6.

      2. Ruffie P, Feld R, Minkin S, Cormier Y, Boutan-Laroze A, Ginsberg R, et al. Diffuse malignant mesothelioma of the pleura in Ontario and Quebec: a retrospective study of 332 patients. J Clin Oncol. 1989;7(8):1157-68.

      3. Curran D, Sahmoud T, Therasse P, van Meerbeeck J, Postmus PE, Giaccone G. Prognostic factors in patients with pleural mesothelioma: the European Organization for Research and Treatment of Cancer experience. J Clin Oncol. 1998;16(1):145-52.

      4. Treasure T, Lang-Lazdunski L, Waller D, Bliss JM, Tan C, Entwisle J, et al. Extra-pleural pneumonectomy versus no extra-pleural pneumonectomy for patients with malignant pleural mesothelioma: clinical outcomes of the Mesothelioma and Radical Surgery (MARS) randomised feasibility study. Lancet Oncol. 2011;12(8):763-72

      5. Allen AM, Czerminska M, Jänne PA, Sugarbaker DJ, Bueno R, Harris JR, Court L, Baldini EH. Fatal pneumonitis associated with intensity-modulated radiation therapy for mesothelioma. Int J Radiat Oncol Biol Phys. 2006 Jul 1;65(3):640-5.

      6. Rusch VW, Rosenzweig K, Venkatraman E, Leon L, Raben A, Harrison L, Bains MS, Downey RJ, Ginsberg RJ. A phase II trial of surgical resection and adjuvant high-dose hemithoracic radiation for malignant pleural mesothelioma.J Thorac Cardiovasc Surg. 2001 Oct;122(4):788-95.

      7. de Perrot M, Feld R, Leighl NB, Hope A, Waddell TK, Keshavjee S, et al. Accelerated hemithoracic radiation followed by extrapleural pneumonectomy for malignant pleural mesothelioma. J Thorac Cardiovasc Surg. 2016;151(2):468-73

      8. Sharon E, Polley MY, Bernstein MB, Ahmed M. Immunotherapy and radiation therapy: considerations for successfully combining radiation into the paradigm of immuno-oncology drug development. Radiat Res. 2014 Aug;182(2):252-7.

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      PC01.06 - CON Radiation Options: Are We SMART Enough?

      11:45 - 12:00  |  Presenting Author(s): Charles B. Simone

      • Abstract

      Abstract not provided

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    ISS09 - Symposium Supported by Merck: Pembrolizumab: The Evolving Standard of Care in Advanced and Early-Stage Lung Cancer (Not IASLC CME Accredited)

    • Moderators:
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      Welcome and Introduction

      12:00 - 12:00  |  Presenting Author(s): Quincy Chu

      • Abstract

      Abstract not provided

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      First- and Second-Line Use of Immune Checkpoint Inhibitor Monotherapy for Metastatic NSCLC

      12:00 - 12:15  |  Presenting Author(s): Martin Reck

      • Abstract

      Abstract not provided

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      Combination Options in First-Line Metastatic NSCLC

      12:15 - 12:30  |  Presenting Author(s): Silvia Novello

      • Abstract

      Abstract not provided

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      Future Utilization of Immunotherapy

      12:30 - 12:45  |  Presenting Author(s): Quincy Chu

      • Abstract

      Abstract not provided

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      Patient Selection – Cases on the Use of Monotherapy, Chemotherapy/IO Combinations, and IO/IO Combinations

      12:45 - 13:00  |  Presenting Author(s): Joachim G.J.V. Aerts

      • Abstract

      Abstract not provided

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      Panel Discussion

      13:00 - 13:25  |  Presenting Author(s): Quincy Chu, Martin Reck, Silvia Novello, Joachim G.J.V. Aerts

      • Abstract

      Abstract not provided

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      Closing Remarks

      13:25 - 13:30  |  Presenting Author(s): Quincy Chu

      • Abstract

      Abstract not provided

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    JTO - Meet the JTO Editor

    • Type: Meet the JTO Editor
    • Track:
    • Moderators:
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      JTO.01 - Meet the JTO Editor

      12:00 - 13:30  |  Presenting Author(s): Alex Adjei

      • Abstract

      Abstract not provided

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    ES01 - Advances in Lung Cancer Screening Through Imaging

    • Type: Educational Session
    • Track: Screening and Early Detection
    • Moderators:
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      ES01.01 - Image Quality Characteristics and Nodule Growth Measurement, Medical Physics and Machine Parameters

      13:30 - 13:50  |  Presenting Author(s): Ricardo S Avila

      • Abstract

      Abstract

      Modern CT scanners are routinely being used to determine the malignancy potential of small sub-centimeter pulmonary nodules. Increasingly, this involves CT scanning and quantitative volume measurement of lung nodules over short time intervals (e.g. 3 or 6 months) to determine whether a change in nodule size consistent with malignant growth has occurred. Although it may appear that current CT scanners are more than capable of reliably performing these quantitative measurements with high quality due to their ability to obtain sub-millimeter resolution lung images, many clinical sites are not taking the steps needed to achieve consistent high quality small lung nodule measurement results. A study of volume measurement performance in a phase II clinical trial observed multiple clinical sites using CT scanners which resulted in errors in volume change measurements as high as 43% [1]. In addition, a 2016 crowd-sourcing study of CT scanner image quality performance using the site’s low dose CT lung cancer screening acquisition protocol revealed that 37% of sites used insufficient slice thickness (<= 1.25mm slice thickness is needed) and only 19% of sites used the needed slice thickness and a reconstruction kernel that avoided excessive smoothing and avoided high levels of edge enhancement [2]. Poor CT image acquisition performance has the potential to result in poor lung nodule volume measurement performance which can negatively impact patient care by contributing to unnecessary biopsies and delays in early lung cancer diagnosis.

      To address these issues the RSNA’s Quantitative Imaging Biomarkers Alliance (QIBA®) has developed the QIBA CT Small Lung Nodule Profile that provides a comprehensive set of specifications to ensure that a clinical site attains a minimum level of quantitative imaging performance necessary to achieve a specified lung nodule volume measurement accuracy. The Small Lung Nodule Profile outlines six fundamental image quality characteristics that are needed throughout the full scanner field of view to support precise volumetric measurement of small lung nodules. These characteristics are (1) Edge Enhancement, (2) Three-Dimensional Resolution, (3) Resolution Aspect Ratio, (4) CT linearity, (5) Spatial Warping, and (6) Noise. In general, CT scanners achieve highest fundamental image quality performance at scanner iso-center with some scanners and image acquisition protocols exhibiting large losses in image quality performance as a function of distance from scanner iso-center [3]. These fundamental image quality properties can now be quickly and easily measured by a technologist at any clinical site using a new image quality measurement phantom and fully automated and cloud-based phantom analysis software.

      To determine the clinical impact of achieved CT image quality performance, a new set of modeling and simulation tools has been developed that can create simulated CT images given the image quality characteristics for a CT scanner and image acquisition protocol [4]. Quantitative measurement software can then be applied to these images resulting in expected measurement performance for a clinical task, such as the bias and precision of solid lung nodule volume change measurement for virtual lung nodules of different sizes. Having these estimates of a CT scanners performance can further be used to one day quantitatively determine the minimum time interval needed in order to be able to distinguish malignant nodule volume growth from a stable lung nodule. Regularly performing these measurements also has the potential to offer numerous advantages to lung cancer screening sites including the ability to determine if scans from two different CT scanner models will produce sufficiently similar image quality and measurement performance.

      In summary, a new set of phantoms and cloud-based software tools is available that enables more careful control and optimization of CT lung cancer imaging performance based on fundamental image quality properties. These new tools provide several new opportunities for clinical sites to more precisely perform CT lung cancer imaging studies and measurements.

      References

      [1] Henschke CI, Yankelevitz DF, Yip R, Archer A, Zahlmann G, Krishnan K, Helba B, Avila R, “Tumor volume measurement error using computed tomography imaging in a phase II clinical trial in lung cancer.” Journal of Medical Imaging 3(3), 035505 (Jul–Sep 2016).

      [2] Avila R, Yankelevitz D, Yip R, Henschke C, “P1.03-021 Initial Results from A Novel and Low Cost Method For Measuring CT Image Quality,” January 2017. Journal of Thoracic Oncology 12(1):S554-S555.

      [3] Avila R, Subramaniam R, Henschke C, Yankelevitz D, “Hot Topic: Clinical Implications of CT Image Quality Variation in Low Dose Lung Cancer Screening Scans,” 4th World Congress of Thoracic Imaging Proceedings, Journal of Thoracic Imaging, accepted for oral presentation, 2017.

      [4] Avila R, Jirapatnakul A, Subramaniam R, Yankelevitz D, “A new method for predicting CT lung nodule volume measurement performance,” SPIE Medical Imaging Proceedings, 2017.

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      ES01.02 - Image Interpretation and Advances from the Perspective of the Radiologist

      13:50 - 14:10  |  Presenting Author(s): David F Yankelevitz

      • Abstract

      Abstract

      To a large extent the success of the screening process depends on the algorithm used to manage the findings. Therefore, even though the image production might be identical for two different screening programs, if they differ in the way they manage findings, especially nodules, the comparative results between them would be quite different. It is with this in mind that screening programs develop and choose their workup algorithm. In regard to how these algorithms are chosen, several features must be balanced including the rate of false positives and also potential delays in diagnosing lung cancer. Each of these is associated with a potential cost, the fewer the false positives might be associated with an increase in the number of cases where lung cancer diagnosis is delayed. As we have moved from 5 mm size thresholds to 8 mm size thresholds on the baseline scan we can clearly see how these factors are balanced against each other. The number of false positives dramatically declines as the number of cancers where diagnosis will be delayed by nine months will increase. While it is generally assumed that there is a substantial downside to delaying diagnosis, the challenge is understanding how much the delay actually costs in terms of decrease in the curability of the cancer and this is then considered in terms of how often this might occur.

      Another major feature of management protocols is their dependence on change in size over time to guide the management protocol. Different protocols apply different criteria for measuring change. One of the main differences is that some recommend the use of 3D volumetric analysis while others still rely on 2D measurements. As a general rule, the 3D approach has inherent advantages in that boundaries for the nodule are automatically chosen by the computer, asymmetric growth can be more easily recognized, and the proportional change for a given amount of change is far greater for volume then for diameter measurements. Nevertheless, there may still be circumstances where volume measures can still be misleading and the radiologist still has a very important role in visually inspecting the nodule to confirm whether change has occurred. Along with the measurement of size change, the time interval between measurements is also important in determining whether growth is meaningful. It is not simply enough to say that a nodule is growing, but rather the intent is to understand its growth rate, and this depends on time, with shorter time intervals between scans introducing greater uncertainty.

      There are currently many algorithms that have been developed. Some focus solely on screening such as Lung-RADS, while others are designed primarily for the incidentally detected nodules. Differences between the algorithms focus primarily on the size thresholds used to define a positive result, the time intervals between repeat scans, the choice of management for a positive finding, differences in the management of nodule subtypes (solid, part-solid, nonsolid), and differences between baseline rounds and repeat rounds. These different algorithms will be compared and data will be presented in terms of the influence on the rate of positive results. An additional consideration here is also how we define a positive result. Some algorithms define the positivity based on a size threshold, whereas others consider this based on a growth threshold or a combination of size and growth. When these growth thresholds are used, the rate of positive results dramatically decreases.

      In addition to the finding of lung nodules there are many other findings that commonly occur on the scans such as micro-nodules, areas of atelectasis, perifissural nodules, waxing and waning nodules, endobronchial nodules, presumed pneumonias, that might be found by the radiologist but there are no specific guidance rules for management. Here again the radiologist is confronted with the challenge of attempting to balance excess workup against obtaining a firm clinical diagnosis. While many of these examples have no authoritative guidelines as to how they should be managed, some practical guidance is presented.

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      ES01.03 - Deep Machine Learning for Screening LDCT

      14:10 - 14:30  |  Presenting Author(s): Bram Van Ginneken

      • Abstract

      Abstract

      The first computer algorithms to automatically detect pulmonary nodules in CT scans, based on classical machine learning approaches, were developed almost two decades ago. These systems appeared in commercially available computer-aided detection packages. However, a recent study concluded that such older software systems fail to flag a substantial number of cancerous lesions and have a fairly high false positive rate.

      Recently, algorithms based on deep learning, in particular, convolutional neural networks, have been developed that report high sensitivity with low false positive rates. Similar deep learning algorithms have been successful in classifying nodules as solid, subsolid or part-solid with accuracy comparable to radiologists, and in estimating the probability of malignancy of nodules.

      The 2017 Kaggle Data Science Bowl combined these tasks into a single challenge where 2000 teams developed methods to predict, on the basis of a single screening CT scan, whether a patient would be diagnosed with lung cancer within one year of the date of the scan. The 10 best performing solutions are now available under an open source license and form the basis of commercial solutions that show, in recent validation studies, a performance comparable to radiologists.

      Thorough validation studies are now needed to investigate if the good performance of these deep learning systems can be replicated, independent of CT parameters, and how such systems can be implemented in a lung cancer screening setting. Possibilities include the use of AI software as a second reader, as a concurrent reader, or even a stand-alone reader for a fraction of the cases, when widespread implementation of screening will put a too large burden on scarce radiological resources.

      In this lecture, I will review the currently available computer solutions and discuss their validation and integration into CT lung screening worksflows.

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      ES01.04 - Multi-Phasic Screening - Can We Address Competing Causes of Morbidity * Mortality Such as Coronary Artery Disease and COPD

      14:30 - 14:50  |  Presenting Author(s): Rozemarijn Vliegenthart

      • Abstract

      Abstract

      Lung cancer, chronic obstructive pulmonary disease (COPD) and cardiovascular disease (CVD) are highly prevalent in the Western population (annual incidences in the Netherlands: lung cancer n=12,200, COPD n=53,300, and CVD n=101,700). This results in a high burden on the health care system and associated costs, with annual costs of 10 billion euros in the Netherlands alone. Furthermore, lung cancer, COPD and CAD are responsible for a high burden of morbidity, with disability adjusted live year reduction of 2.9, 3.4 and 5.0, respectively. For these so-called Big-3 diseases, treatment is most often initiated at late stages due to late diagnosis after development of symptoms. Early detection and treatment will cure many patients in time, and delay or stop disease progression. Therefore, prevention and early detection are crucial.

      Currently, no screening is performed for the Big-3. The impact of low-dose computed tomography (CT) lung cancer screening on lung cancer stage shift and reduction of lung cancer mortality has been demonstrated.(1,2) These results have led to recommendations to implement CT screening in high-risk individuals in the USA. Population-based studies have shown the strong relationship between CT-derived extent of CAD and COPD, and mortality, also in lung cancer screening setting.(3-8) However, there is as yet no evidence from randomized controlled trials regarding benefit of CT screening for COPD or CAD. As the high-risk population for the Big-3 is comparable (namely long-term [ex-]smokers), combining imaging biomarkers will likely improve CT screening efficiency.

      Technological developments in CT allow the determination of early imaging biomarkers for the Big-3, namely lung nodule volume, coronary artery calcium score and lung density/ bronchial wall thickness with low-dose CT (see Figure). Combined evaluation of early signs of the Big-3 diseases has not been extensively explored yet. Major advantages of integrated Big-3 screening can be anticipated due to shared risk factors (in particular long-term smoking) and thus overlapping at-risk population, simultaneous presence of B3 diseases, and the health economic yield compared to a single disease. However, at this moment there is no single CT acquisition that allows for accurate assessment of all Big-3 biomarkers. In particular, calcium scoring based on low-dose chest CT, while providing a good correlation on a population basis, is inaccurate for determining the score on an individual basis.(9)

      biomarkers.jpg

      Furthermore, there are several challenges that need to be addressed in the preparation and establishment of a B3 screening program. These include the need for evidence of morbidity/mortality reduction for screening of COPD and CAD. Also, B3 imaging biomarkers, particularly for COPD, need validation and standardization. Another hurdle is the labour-intensive work required to obtain B3 imaging biomarkers. Also, education and training for evaluation of B3 CT screening examinations is lacking. Finally, the cost-efficiency of integral B3 screening has not been established.

      The presentation includes discussion of the background of interest in Big-3 screening, estimated health economic consequences of Big-3 screening, status of imaging biomarker development for the Big-3 diseases, screening population and CT scan protocol, and impediments to Big-3 screening implementation.

      References:

      1. Aberle DR, Adams AM, Berg CD, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 2011;365:395–409.

      2. van Klaveren RJ, Oudkerk M, Prokop M, et al. Management of lung nodules detected by volume CT scanning. N Engl J Med 2009;361:2221-9.

      3. Oudkerk M, Stillman AE, Halliburton SS, et al; European Society of Cardiac Radiology; North American Society for Cardiovascular Imaging. 2008. Coronary artery calcium screening: current status and recommendations from the European Society of Cardiac Radiology and North American Society for Cardiovascular Imaging. Eur Radiol. 18:2785-807.

      4. Hecht HS, Cronin P, Blaha MJ, et al. 2016 SCCT/STR guidelines for coronary artery calcium scoring of noncontrast noncardiac chest CT scans: A report of the Society of Cardiovascular Computed Tomography and Society of Thoracic Radiology. J Cardiovasc Comput Tomogr. 2017;11:74-84.

      5. Mets OM, Vliegenthart R, Gondrie MJ, et al. Lung cancer screening CT-based prediction of cardiovascular events. JACC Cardiovasc Imaging. 2013;6:899-907.

      6. Oelsner EC, Smith BM, Hoffman EA, et al. Prognostic Significance of Large Airway Dimensions on Computed Tomography in the General Population. The Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study. Ann Am Thorac Soc. 2018;15:718-27.

      7. Mets OM, Buckens CF, Zanen P, et al. Identification of chronic obstructive pulmonary disease in lung cancer screening computed tomographic scans. JAMA. 2011;306:1775-81.

      8. Oelsner EC, Carr JJ, Enright PL, et al. Per cent emphysema is associated with respiratory and lung cancer mortality in the general population: a cohort study. Thorax. 2016;71:624-32.

      9. Xie X, Zhao Y, de Bock GH, et al. Validation and prognosis of coronary artery calcium scoring in nontriggered thoracic computed tomography: systematic review and meta-analysis. Circ Cardiovasc Imaging. 2013 Jul;6(4):514-21.

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      ES01.05 - Q&A

      14:50 - 15:00

      • Abstract

      Abstract not provided

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    MA04 - Novel Approaches with IO

    • Type: Mini Oral Abstract Session
    • Track: Immunooncology
    • Moderators:
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      MA04.01 - Cemiplimab, a Human Monoclonal Anti-PD-1, Alone or in Combination with Radiotherapy: Phase 1 NSCLC Expansion Cohorts

      13:30 - 13:35  |  Presenting Author(s): Victor Moreno  |  Author(s): Marta Gil-Martin, Melissa L. Johnson, Raid Aljumaily, Maria Pilar Lopez-Criado, Donald W Northfelt, Marka Crittenden, Salma Jabbour, Lee Rosen, Emiliano Calvo, Kyriakos P Papadopoulos, Pilar Garrido, Asuncion Hervás Morón, Petra Rietschel, Kosalai Mohan, Jingjin Li, Elizabeth Stankevich, Minjie Feng, Israel Lowy, Matthew Fury

      • Abstract

      Background

      Cemiplimab (REGN2810), a human monoclonal anti-PD-1, has exhibited substantial antitumor activities in patients with advanced malignancies in a first-in-human study. We report interim results of the Phase 1 expansion cohorts (ECs 1 and 2) of cemiplimab, alone or plus radiotherapy, in advanced NSCLC (NCT02383212).

      Method

      Patients with advanced NSCLC who had relapsed after, or were refractory to, at least, first-line therapy received cemiplimab 200 mg Q2W in EC 1, or cemiplimab 3 mg/kg Q2W plus radiotherapy (9 Gy × 3 times/week 1 week after first dose of cemiplimab) to a single lesion in EC 2. For EC 2, patients were required to have NSCLC for which palliative radiation therapy was indicated. Planned treatment duration was up to 48 weeks in both ECs. The co-primary objectives were to evaluate the safety, tolerability, and efficacy of cemiplimab, alone or plus radiotherapy. Tumor measurements (of non-irradiated lesions) were performed by RECIST 1.1 Q8W.

      Result

      As of Sept 1, 2017, 20 patients (13 M/ 7 F; median age 64.0 years [range, 50–82]) and 33 patients (22 M/ 11 F; median age 67.0 years [range, 47–82]) were enrolled in EC 1 and EC 2, respectively. ECOG performance status 1 versus 0 was 80.0% versus 20.0% and 66.7% versus 30.3%, respectively, for ECs 1 and 2, and missing in one in EC 2; 75.0% (EC 1) and 48.5% (EC 2) had received prior radiotherapy. Investigator-assessed overall response rate (ORR; complete response [CR] + partial response [PR]) was 40.0% (1 CR and 7 PRs) and 18.2% (6 PRs) in EC 1 and EC 2, respectively. Disease control rate (ORR + stable disease [SD]) was 60.0% (1 CR + 7 PRs + 4 SDs) and 72.7% (6 PRs + 18 SDs) in EC 1 and EC 2, respectively. The most common treatment-emergent adverse events (TEAEs) of any grade were arthralgia, asthenia, cough, and dyspnea (each 20.0%) in EC 1, and decreased appetite (30.3%), fatigue (27.3%), cough (24.2%), asthenia and back pain (each 21.2%) in EC 2. Grade ≥3 TEAEs occurring in ≥2 patients were pneumonia (10.0%) in EC 1; and anemia (12.1%), hypophosphatemia and urinary tract infection (each 6.1%) in EC 2. One patient in EC 2 experienced TEAE of pneumonitis with an outcome of death, considered related to study drug.

      Conclusion

      Cemiplimab monotherapy demonstrated substantial antitumor activity in pretreated NSCLC patients. The safety profiles were comparable with other anti-PD-1 agents and radiotherapy.

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      • Abstract

      Background

      Responses in NSCLC to agents targeting the PD-1/PD-L1 axis are correlated with PD-L1 expression by immunohistochemistry (IHC), tumor mutational burden (TMB), interferon-associated mRNA expression profile (GEP), and the absence of liver metastases. Anti-PD-1 impedes the inhibition of T cells while pegilodecakin (AM0010) stimulates the survival and expansion of intratumoral, antigen-activated CD8+ T cells (Mumm et al, 2010). This provides a rationale for combining anti-PD-1 agents with pegilodecakin.

      Method

      Pretreated NSCLC subjects (N = 34) received pegilodecakin (10-20 µg/kg QD, SC) with pembrolizumab (2 mg/kg, Q3W, IV; n = 5) or nivolumab (3 mg/kg, Q2W, IV; n = 29). Median follow-up is 31.2 months (range, 28.3-33+ months) and 17.5 months (range, 8.3- 25.9+ months), respectively. Responses were assessed by irRC. Twenty subjects had sufficient tissue for PD-L1 testing with the 22C3 IHC assay (CLIA) and 10 subjects had sufficient tissue for TMB evaluation by whole exome sequencing (WES) and pretreatment GEP by NanoString.

      Result

      In 26 subjects evaluable for response, the ORR was 41% (11 PRs). Another 12 subjects (46%) had SD as best response. As investigators were asked to preferentially enroll PD-L1–negative patients, PD-L1 expression was <1% in 12 of 20 PD-L1–evaluable subjects with 4 achieving a PR. Ten subjects had sufficient tissue for TMB and GEP, including 6 PRs. Five of the 8 who tested low to intermediate for TMB (<243 mut) had a PR as did 2 of 6 GEP-negative subjects. In addition, 5 of 8 subjects with liver metastasis had a PR. The mPFS and mOS of the 5 NSCLC subjects (4/4 tested PD-L1 <1%) treated with pegilodecakin + pembrolizumab was 10.9 and 32.2 months, respectively. The mPFS and mOS for the pegilodecakin + nivolumab cohort (8/16 tested PD-L1 <1%) has not been reached.

      Conclusion

      Pegilodecakin, when added to anti-PD-1 therapy in advanced NSCLC patients, was associated with response rates and durability of benefit greater than has been seen with anti-PD-1 alone. Responses were seen in settings in which anti-PD-1 therapy has demonstrated limited benefit, such as absent PD-L1 expression, low TMB, and/or the presence of liver metastasis. These preliminary findings support further studies of pegilodecakin with anti-PD-1 therapies.

      • Abstract

      Background

      Prospective data on immunotherapy for NSCLC with oncogenic driver mutations are limited. We recently reported first results from the global IMMUNOTARGET registry (Mazières, ASCO 2018). Here, we present new data for PD-L1 and mutation subgroups.

      Method

      In 2017, we started an international retrospective registry study ("IMMUNOTARGET") for patients with advanced NSCLC, known driver mutations (KRAS, EGFR, ALK, ROS1, BRAF, HER2, MET and RET) and PD-L1 immune checkpoint inhibitor therapy. The registry is approved by University of Toulouse and Swissethics, and funded by University of Toulouse and Cantonal Hospital of Lucerne. Anonymized real-world data submitted to the coordinating center include: patient and tumor characteristics, mutation test methods and results, systemic therapy lines, immune related adverse events, best response by RECIST, survival, and tumor PD-L1 expression (optional). Statistical calculations including best response, median PFS and OS are done at University of Toulouse.

      Result

      In April 2018, the registry included 551 pts from Europe, USA, Israel and Australia. Patients were 50% male/female, 28% current smokers, median age 60 years (range 28-83), 85% had PS0/1. Most (73%) tumors were stage IV at diagnosis, almost all (96%) were adenocarcinomas. Molecular classification by dominant driver mutation: KRAS=271 (49%), EGFR=125 (23%), BRAF=43 (8%), MET=36 (7%), HER2=29 (5%), ALK=23 (4%), RET=16 (3%), ROS1=7 (1%), 1 (0.2%) not classified (ALK+RET+MET). Most pts received nivolumab (466) or pembrolizumab (48) and were treated with immunotherapy in second or third line (67%). The median number of cycles was 5 (range 1-68). Fifty (11%) pts had grade 3-5 toxicity. Median OS from start of immunotherapy was 13.3 months, median PFS was 2.8 months. Best response was PR/CR in: KRAS=26%, BRAF=24%, ROS1=17%, MET=16%, EGFR=12%, HER2=7%, RET=6%, ALK=0%. Percentage of PD-L1 positive cells was available for 177 pts: 0%=71 (40%), 1-49%=46 (26%), 50-100%=60 (34%). Median % of positive cells was highest for ROS1 (90%), BRAF (50%), MET (30%) and RET (26%) mutant tumors. PD-L1 positivity was predictive for improved PFS in KRAS and EGFR mutant tumors. PD-L1 status was known in 18 tumors with ALK, ROS1 or RET rearrangements: 5 had 0%, 4 had 1-49% and 9 had 50%-100%. No tumor remissions were observed in this subgroup. The registry remains open, updated results will be presented at the conference.

      Conclusion

      Although response rates were lower than in KRAS mutant NSCLC, individual tumors with other driver mutations responded to immunotherapy. PD-L1 expression may not accurately predict clinical benefit from immunotherapy in some molecular subgroups, better markers are needed.

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      MA04.04 - Discussant - MA 04.01, MA 04.02, MA 04.03

      13:45 - 14:00  |  Presenting Author(s): Jose Pacheco

      • Abstract

      Abstract not provided

    • +

      MA04.05 - Outcomes in NSCLC Patients Treated with First-Line Pembrolizumab and a PD-L1 TPS of 50-74% vs 75-100% or 50-89% vs 90-100%

      14:00 - 14:05  |  Presenting Author(s): Mark M. Awad  |  Author(s): Elizabeth Jimenez Alguilar, Justin F Gainor, Sasha Kravets, Sara Khosrowjerdi, Christine A Lydon, Anika Adeni, Safiya Subegdjo, Hira Rizvi, Matthew D. Hellmann

      • Abstract

      Background

      Among patients with NSCLC and a PD-L1 tumor proportion score (TPS) ≥50%, the response rate to the PD-1 inhibitor pembrolizumab is ~45%. Whether certain subsets of patients with a PD-L1 TPS ≥50% are more likely to benefit from treatment with a PD-1 inhibitor is currently unknown. We compared outcomes among NSCLC patients treated with first-line pembrolizumab and different PD-L1 TPS groupings: 50-74% vs 75-100% or 50-89% vs 90-100%.

      Method

      We retrospectively analyzed patients who received commercial pembrolizumab as first-line treatment for NSCLC with a PD-L1 TPS of ≥50% from the Dana-Farber Cancer Institute, Memorial Sloan Kettering Cancer Center, and Massachusetts General Hospital. Clinicopathologic characteristics and clinical outcomes were compared among patients with a PD-L1 TPS of 50-74% vs 75-100% or 50-89% vs 90-100%. Event-time distributions were estimated using Kaplan-Meier and compared with the log-rank test.

      Result

      172 patients were identified for inclusion in this study. In the entire cohort, the overall response rate (ORR) to pembrolizumab was 33.9%, median progression-free survival (mPFS) was 4.8 months, and median overall survival (mOS) was 20.6 months. Compared to patients with TPS 50-74% (N=68, 39.5%), patients with TPS 75-100% (N=104, 60.5%) had a significantly higher ORR (45.2% vs 20.6%, P=0.001), a significantly longer mPFS (5.3 vs 2.5 mo, HR=0.61 [95% CI: 0.41-0.90], P=0.008), and a trend towards improved mOS (33.6 vs 20.6 mo, HR=0.60 [95% CI: 0.34-1.04], P=0.056). Compared to patients with TPS 50-89% (N=99, 57.6%), patients with TPS 90-100% (N=73, 42.4%) had a significantly higher ORR (50.7% vs 24.2%, P<0.001), a significantly longer mPFS (6.4 vs 2.8 mo, HR=0.52 [95% CI: 0.36-0.76], P<0.001), and a significantly longer mOS (33.6 vs 18.0 mo, HR=0.46 [95% CI: 0.27-0.79], P=0.008). There were no significant differences in smoking history, histology, sex, and age between patients in each TPS cutoff group.

      Conclusion

      Among NSCLCs with a PD-L1 TPS ≥50% treated with first-line pembrolizumab, higher PD-L1 TPS levels above 75% and 90% are associated with improved clinical outcomes compared to NSCLCs with lower PD-L1 levels.

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      MA04.06 - PD-1 Blockade Promotes Hyperprogressive Disease in NSCLC Through Macrophages Activation via Antibody-Fc/FcR Interaction

      14:05 - 14:10  |  Presenting Author(s): Gabriella Sozzi  |  Author(s): Michele Sommariva, Massimo Moro, Claudia Proto, Diego Signorelli, Monica Ganzinelli, Sabina Sangaletti, Mattia Boeri, Giuseppe Lo Russo, Simona Ferro, Elena Tassi, Veronica Huber, Lucia Sfondrini, Massimo Milione, Claudio Tripodo, Mario Colombo, Andrea Anichini, Andrea Balsari, Licia Rivoltini, Marina Chiara Garassino

      • Abstract

      Background

      In a subset of patients, named hyperprogressors (HPs), immunotherapy seems to paradoxically boost tumor growth. However, neither pathological and clinical features nor the underlying biological mechanism have been identified. We dissected the role of tumor-myeloid cells crosstalk as possible players.

      Method

      HPs were defined on the basis of clinical and radiological features. Baseline histological samples from patients treated with immune checkpoints inhibitors (ICI) were evaluated by immunohistochemistry for myeloid and lymphoid markers. We tested the effect on tumor growth of murine and human ICI in T-cell deficient mice injected with human lung cancer cell lines and PDXs bearing different genotypes (EGFR+, KRAS+, STK11+ and wt). Innate immune microenvironment was evaluated by FACS analysis and immunohistochemistry. In vitro studies of ICI binding functional modulation were performed in human myeloid cells from patients and healthy donors.

      Result

      In a clinical series of 187 patients treated with ICI, hyperprogression was observed in 40 (26.3%) cases. All available HP pre-treatment tissue samples (11 cases) showed CD163+CD33+PD-L1+Arginase-A1+ clustered epithelioid macrophages infiltrating the tumor foci also expressing FcRs including CD32b. No differences in T cell compartment were observed. Murine and human PD1 blocking mAbs induced a boost of tumor growth in H460 xenografs in imunocompromised mice. A similar effect was observed in EGFR+ but not in KRAS+ and wt PDXs treated with human anti-PD1. Notably, no hyperprogression was observed after treatment with murine and human anti PD-1 F(ab)2. Hyperprogressive tumors were enriched in arginase+ myeloid-macrophage cells and fibrotic features. ICI bind in vitro to human macrophages and monocytes via Fc/FcR interactions, likely involving CD32b (FcgRIIb) and triggering functional polarization.

      Conclusion

      Our results provide evidence that FcR triggering on macrophages by ICI delivers a signaling cascade promoting a functional reprogramming of these cells toward a more aggressive pro-tumorigenic behavior eventually inducing hyperprogression in a subset of patients with distinctive immune and genetic profile. A validation prospective study in ongoing.

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      MA04.07 - MicroRNA-Based Liquid Biopsy Combines with PD-L1 Tumor Expression to Predict Response to Immunotherapy in Advance NSCLC Patients

      14:10 - 14:15  |  Presenting Author(s): Mattia Boeri  |  Author(s): Massimo Milione, Diego Signorelli, Claudia Proto, Giuseppe Lo Russo, Carlotta Galeone, Giovanni Centonze, Ugo Pastorino, Marina Chiara Garassino, Gabriella Sozzi

      • Abstract

      Background

      The advent of the new immune checkpoint inhibitors (ICIs) targeting the PD-1/L1 axis drastically improves survival of advance non-small-cell lung cancer (NSCLC) patients. However, only a limited subset of patients actually benefits of ICIs treatment and PD-L1 as predictive biomarker has a limited efficacy. We have previously identified a plasma microRNA-signature classifier (MSC) reflecting a circulating tumor-host interaction with diagnostic and prognostic value in low-dose computed tomography (LDCT) lung cancer screening trials.

      Method

      The tumor immune contexture of 40 LDCT-screening detected lung tumors was characterized by the “cell-type identification by estimating relative subsets of RNA transcripts” (CIBERSORT) software. In a consecutive series of 84 advanced lung cancer patients treated with ICIs, both plasma and tissue samples were collected and prospectively analyzed. Both 2-years progression free (PFS) and overall survival (OS) in strata of plasma MSC risk level alone or combined with tumor PD-L1 expression were evaluated in univariate and multivariate analysis by log-rank test and Cox proportional hazards models.

      Result

      A pro-tumorigenic immune contexture was identified in tumors of MSC high risk patients. Lower levels of cytotoxic CD8+ and CD4+ T cells and increased levels of Tregs, γδ T Cells, M2 macrophages characterized these tumors. In addition, genes differentially expressed according to MSC risk level (high vs. intermediate and low) were associated with 5-years OS in the screening series (p-values=0.02), as well as in additional 1000 cases from The Cancer Genome Atlas database (p-values<0.01). In the 84 advanced NSCLC patients treated with ICIs, the PFS hazard ratio ranged from 0.44 (95%CI: 0.25-0.75) of PD-L1 (adjusted p-value=0.005) and 0.38 (95%CI:0.2-0.73) of MSC (adjusted p-value=0.004) alone, to 0.25 (95%CI: 0.14-0.45) if combined (adjusted p-value<0.0001). In the subgroup of 45 patients with both plasma and tumor tissue available, the combination of MSC and PD-L1 stratified patients in three groups with 2-years PFS ranging from 25%to 10% and 0% (p-value=0.01) according to the presence of 2, 1 or 0 favorable markers, respectively. Similar results were obtained when considering OS, where the median survival time for patients with no favorable markers was 5.6 months (p-value<0.0001).

      Conclusion

      Overall, these findings suggest that a circulating microRNA-based risk level, reflecting an altered tumor immune contexture, could implement PD-L1 tumor tissue expression as predictive biomarkers of response to immunotherapy.

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      MA04.08 - Discussant - MA 04.05, MA 04.06, MA 04.07

      14:15 - 14:30  |  Presenting Author(s): Patrick M Forde

      • Abstract

      Abstract not provided

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      MA04.09 - Neoadjuvant Atezolizumab in Resectable Non-Small Cell Lung Cancer (NSCLC): Updated Results from a Multicenter Study (LCMC3)

      14:30 - 14:35  |  Presenting Author(s): Valerie W Rusch  |  Author(s): Jamie E Chaft, Bruce E Johnson, Ignacio I. Wistuba, Mark G Kris, Jay M Lee, Paul A. Bunn, Jr., David J Kwiatkowski, Karen L. Reckamp, David J. Finley, Eric B. Haura, Saiama N. Waqar, Robert C. Doebele, Edward B Garon, Justin Blasberg, Alan Nicholas, Katja Schulze, See Phan, Mayank Gandhi, David P Carbone

      • Abstract

      Background

      Cisplatin-based chemotherapy, before or after surgery, provides only a 5% benefit in 5yr. OS in resectable NSCLC. A 20 patient study (NEJM April 2018) showed that preoperative immune checkpoint inhibitor therapy yielded a clinically meaningful major pathologic response rate (MPR ≤10% residual viable tumor cells) and did not delay or complicate surgery. This large multicenter trial measures MPR and biomarkers of benefit using neoadjuvant atezolizumab (atezo) [NCT02927301].

      Method

      We planned 2 cycles of atezo (1200mg, days 1, 22) in patients with stages IB -selected IIIB resectable NSCLC prior to surgical resection (day 40 +/- 10). Chest CT, PET were planned pre-atezo and presurgery to assess response. Primary tumor +/- node biopsies and blood samples were obtained before atezo and presurgery for biomarker studies. The primary endpoint was MPR. Secondary endpoints included safety, response by PD-L1, OS, and DFS.

      Result

      For this updated efficacy and safety analysis (Feb’18 datacut), we report first 54 of 180 planned pts: 29 males, median age 65 yr, all ECOG 0-1; 17 current, 33 former smokers; 35 non-squamous NSCLC; clinical stages Ib/IIa/IIb/IIIa/IIIb = 5/11/13/20/5. Two pts received one dose of atezo due to treatment related AE (Gr 1 pyrexia, Gr 2 dyspnea) but underwent uncomplicated resection with MPR assessment. There was 1 unrelated Gr 5 AE (sudden cardiac death post surgical resection), 16 Gr 3-4 AEs (3 treatment related). Surgery was delayed in 1 pt due to Gr3 pneumonitis. By RECIST, 3 pts had PR, and 49 had SD. 50 pts underwent surgery and 47 pts had MPR assessment: 2 pts discontinued study preop due to radiographic PD and 2 discontinued due to other reasons; 3 pts had unresectable disease. MPR rate was 10/50 (20%, 95% CI 10-34%) including 3 pts who had pCR (no viable tumor cells) in the primary tumor. Excluding 5 pts who had known driver mutations (4 EGFR+, 1 ALK+), MPR rate was 10/45 (22%, 95% CI 11-37%). PD-L1 status was evaluable in 44/54 pts; 8/10 pts with MPR had PD-L1+ status and 2 had unknown PD-L1 status; 8/28 PDL-1 (+) patients had MPR (29%).

      Conclusion

      In a multicenter study, neoadjuvant atezo was well tolerated. MPR rate is encouraging. Clinical and pathological responses are often discordant. Correlative analyses on pre- and post atezo tissues are ongoing. Preliminary correlative analyses in blood samples are included in a separate abstract.

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      MA04.10 - Comprehensive Peripheral Blood Immunophenotyping and T-Cell Clonal Analysis During Neoadjuvant Immunotherapy with Atezolizumab in NSCLC

      14:35 - 14:40  |  Presenting Author(s): Filiz Oezkan  |  Author(s): Kai He, Dwight Hall Owen, Maciej Pietrzak, Rhonda Kitzler, Rebecca Pearson, Alan Nicholas, Paul A. Bunn, Jr., Mark G Kris, David J. Kwiatkowski, Bruce E Johnson, Fred R. Hirsch, Ignacio I. Wistuba, Valerie W Rusch, Jay M. Lee, Mayank Gandhi, Katja Schulze, David S. Shames, Gerard Lozanski, David P Carbone

      • Abstract

      Background

      Immune-checkpoint blockade targeting PD-L1/PD-1 to activate anti-tumor immunity is associated with improved response rates and survival compared to chemotherapy in selected metastatic NSCLC patients. Evaluation of the pre-therapeutic immune profile and its treatment-related evolution associated with clinical benefit will guide future immunotherapy development and support clinical decision-making. Here, we present an analysis of peripheral blood (PB) immunophenotyping and T-cell-receptor (TCR) clonality before and after immunotherapy from an ongoing 180-patient phase II study of atezolizumab as neoadjuvant therapy with stage IB-IIIB resectable NSCLC (NCT02927301; LCMC3).

      Method

      As of February 5th datacut, the first 54 enrolled and dosed patients are presented. The biomarker evaluable population (BEP) further subset to patients with paired PB samples analyzed within 72 hours after collection and a major pathological response (MPR) assessment. Comprehensive immune cell phenotyping (10-color flow cytometry, IMMUNOME) and TCR-Vß-analysis by flow cytometry were performed. Immunoprofile analyses were correlated with atezolizumab treatment, pathological response and PD-L1 expression.

      Result

      In this ongoing analysis, BEP included 31 patients. 5 patients (16%, 95% CI (5%, 34%)) had a MPR; all of which stained positive for PD-L1 by IHC using 22C3 (TPS≥1%) and SP142 (PD-L1 expression on ≥1% tumor cells (TC) and/or tumor infiltrating immune cells (IC)) at baseline. We observed significant increases in natural killer (NK) cells (p=0.005) and CD8+ T-cells (p=0.031) and a Th1-response related dendritic cell (DC) subpopulation (p=0.031) and significant decreases in B-cells (p=0.015) after treatment.

      Patients who achieved MPR show lower baseline levels of degranulated CD8+ T-cells (p=0.015), late-activated NK-cells (p=0.043), memory CD4+ (p=0.048) and memory CD8+ T-cells (p=0.032); changes in PB NK-cells (p=0.041), a decrease in M-MDSCs and a Th-2 and Th-17-response related DC subpopulation (p=0.043) in response to treatment were noted in patients with MPR versus non-MPR.

      Among the 16 patients with TC/IC 1/2/3 (> 1% PD-L1 expression) the following significant differences were observed compared to TC0/IC0 (7 patients): higher levels of late-activated CD4+ T-cells (p=0.025) and mid-activated CD8+ T-cells (p=0.044) at baseline, decrease of senescent T-cells (p=0.041), monocytic myeloid-suppressor cell subpopulations (M-MDSCs) and an increase in a Th1-response related DC subpopulation (p=0.026) after treatment.

      TCR clonality analysis showed expansions in Vß-subtypes after atezolizumab treatment.

      Conclusion

      Immunophenotyping and TCR-Vß-repertoire analysis in peripheral blood samples from NSCLC patients treated with neoadjuvant atezolizumab show differences in immune cell subsets in baseline samples and changes after treatment.

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      MA04.11 - Neoantigen Targeting and T Cell Reshaping in Resectable NSCLC Patients Treated with Neoadjuvant PD-1 Blockade

      14:40 - 14:45  |  Presenting Author(s): Kellie Nicole Smith  |  Author(s): Margueritta El Asmar, Jiajia Zhang, Justina X Caushi, Zhicheng Ji, Valsamo Anagnostou, Tricia R Cottrell, Hok Yee Chan, Prerna Suri, Haidan Guo, Kristen A. Marrone, Jarushka Naidoo, Taha Merghoub, Jamie E Chaft, Matthew D. Hellmann, Janis M Taube, Julie R. Brahmer, Patrick M Forde, Victor Velculescu, Drew M Pardoll, Hongkai Ji

      • Abstract

      Background

      PD-1 blockade is now standard treatment for advanced non-small cell lung cancer (NSCLC) and has recently shown impressive efficacy in promoting major pathologic response (MPR) and delaying relapse in the neoadjuvant setting. The role of tumor mutational burden, and specifically T cells targeting neoantigens derived from these mutations, in facilitating tumor clearance has been demonstrated in advanced NSCLC. However, it is unknown how neoadjuvant PD-1 blockade impacts the frequency and function of tumor specific T cells and their ability to promote major pathologic response, or how these factors may synergize to prevent or delay relapse after surgical resection.

      Method

      Whole exome sequencing and neoantigen prediction was performed on pre-treatment tumor biopsies and matched normal tissue from 11 patients with resectable NSCLC treated with neoadjuvant nivolumab as part of a clinical trial (NCT02259621). T cell recognition of peptides representing candidate neoantigens was evaluated using the MANAFEST assay, which identifies T cell receptor clonotypes corresponding to antigen specificities. T cell receptor sequencing was additionally performed on serial peripheral blood T cells, pre-treatment tumor biopsies, and resected post-treatment tissues. A bioinformatic platform was developed to evaluate the dynamics of intratumoral T cell clonotypes, and more specifically neoantigen-specific clonotypes detected before, during, and after treatment and during long-term follow-up.

      Result

      High-magnitude, polyclonal neoantigen-specific T cell responses were detected in the peripheral blood and persisted for many months after surgical resection and cessation of treatment. Binding to and stability with cognate HLA I molecules was validated for reactive neoantigens. Significant treatment-induced systemic perturbations in the tumor-specific T cell repertoire and an influx of peripheral T cell clonotypes into tumor tissue and lymph nodes was observed in patients regardless of pathologic response, whereas peripheral clonotypic reshaping of the anti-tumor repertoire and intratumoral T cell clonality were associated with MPR status.

      Conclusion

      We show significant and systemic alterations in the peripheral anti-tumor T cell repertoire in NSCLC patients treated with neoadjuvant anti-PD-1 regardless of MPR status. Notwithstanding, the impaired restructuring of the anti-tumor T cell repertoire in patients without MPR highlights a potential immunological deficiency to overcome in future therapeutic approaches aiming to increase the MPR rate in NSCLC patients treated with neoadjuvant PD-1 blockade.

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      MA04.12 - Discussant - MA 04.09, MA 04.10, MA 04.11

      14:45 - 15:00  |  Presenting Author(s): Alex Adjei

      • Abstract

      Abstract not provided

  • +

    MA05 - Improving Outcomes in Locoregional NSCLC II

    • Type: Mini Oral Abstract Session
    • Track: Treatment of Locoregional Disease - NSCLC
    • Moderators:
    • +

      MA05.01 - E6508: Phase II Study of Immunotherapy with Tecemotide and Bevacizumab after Chemoradiation in Unresectable Stage III NS-NSCLC

      13:30 - 13:35  |  Presenting Author(s): Jyoti Patel  |  Author(s): Ju-Whei Lee, Henry Wagner Jr, David P Carbone, Anil Shanker, Leora Horn, Melissa L. Johnson, David E Gerber, Jane Jijun Liu, Millie S Das, Mohammad Ali Al-Nsour, Christopher S R Dakhil, Suresh S. Ramalingam, Joan Schiller

      • Abstract

      Background

      Chemoradiation (CRT) is standard of care for unresectable stage III NSCLC. Tecemotide is a MUC1 antigen-specific cancer immunotherapy. Bevacizumab is considered to have a significant role in immune modulation. Immunotherapy in combination with VEGF blockade was tested in this phase II trial combining tecemotide and bevacizumab in patients with stage III NS- NSCLC.

      Method

      Subjects with stage III NS- NSCLC suitable for definitive CRT received carboplatin(C) AUC 2 + paclitaxel(P) 45 mg/m2 weekly + 66 Gy/33fx/6.5wk and consolidation C AUC 6 + P 225 mg/m2 q21 days x 2. Patients with CR/PR/SD were then registered onto Step 2 (S2). S2 was 6 weekly tecemotide injections followed by q6 weekly injections and bevacizumab 15 mg/kg q3 weeks for up to 34 doses. The primary endpoint was safety of tecemotide and bevacizumab after CRT and consolidation. The proportion of circulating dendritic cells and their expression of CD40, HLA-DR and CD123 (IL-3R) were analyzed by flow cytometry at various time points.

      Result

      70 patients were enrolled from Dec 2010 to Oct 2014; 68 started therapy, and 39 completed CRT and consolidation therapy. Reasons for discontinuation included progression (11) and toxicity (10). 33 patients were registered to S2. The median number of S2 cycles was 12 (range 2-34). S2 toxicity: gr 3 N=9 (6 hypertension), gr 4 N=1, gr 5 N=1. Among the treated and eligible patients (n=31), from study entry, the median PFS was 14.3 (95% CI 11.0-22.2), OS was 40.1 (95% CI 21.7-NA) months. A correlative trend of increased expression of CD40 and HLA-DR on CD11c+ cells was observed at cycle 7 (week 21) of S2.

      e6508.patel.png

      Conclusion

      This cooperative group trial met its endpoint, demonstrating tolerability of tecemotide and bevacizumab after CRT and consolidation in NS-NSCLC pts. In this select group of patients, therapy with tecemotide and bevacizumab was associated with encouraging PFS and OS.

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      MA05.02 - PACIFIC Subgroup Analysis: Pneumonitis in Stage III, Unresectable NSCLC Patients Treated with Durvalumab vs. Placebo After CRT

      13:35 - 13:40  |  Presenting Author(s): Johan F. Vansteenkiste  |  Author(s): Jarushka Naidoo, Corinne Faivre-Finn, Mustafa Özgüroğlu, Augusto Villegas, Davey Daniel, Shuji Murakami, Rina Hui, Ki Hyeong Lee, Byoung Chul Cho, Kaoru Kubota, Lynne Poole, Catherine Wadsworth, Phillip A. Dennis, Scott J Antonia

      • Abstract

      Background

      In the Phase 3 PACIFIC study of durvalumab versus placebo in patients with stage III, unresectable non-small cell lung cancer (NSCLC) after concurrent chemoradiotherapy (cCRT), on-treatment pneumonitis or radiation pneumonitis (‘pneumonitis’) occurred in both arms with similar rates of grade 3/4 pneumonitis (durvalumab, 3.4%; placebo, 2.6%). We performed exploratory analyses to further characterize time to onset and duration of pneumonitis and examine its relationship with underlying risk factors, including patient characteristics and prior CRT.

      Method

      PACIFIC (NCT02125461) was a randomized, double-blind study of patients with WHO PS 0/1 without progression after ≥2 cycles of platinum-based cCRT. Patients were stratified by age, sex, and smoking history and randomized (2:1) 1–42 days after completing cCRT to durvalumab 10 mg/kg IV Q2W or placebo up to 12 months. Potential associations between the presence of the AE pneumonitis (investigator assessed with review/adjudication by study sponsor) and baseline characteristics or patient disposition were investigated.

      Result

      As of Feb 13, 2017, 709 patients had received treatment; 33.6% on durvalumab and 24.9% on placebo had any-grade pneumonitis. Treatment exposure was similar in patients with or without pneumonitis across both arms. Median time to onset of pneumonitis from treatment start was the same for both durvalumab and placebo, 55.0 days (73.0 and 76.5 days from RT completion). Pneumonitis was self-limited, with median durations of 64.0 and 57.0 days, respectively. Patients with pneumonitis were more likely to be Asian (47.9% vs 17.6%) or have EGFR mutations (11.0% vs 3.8%); however, the proportions of patients with pneumonitis and these risk factors were numerically lower with durvalumab than with placebo (Asian: 44.4% [71/160] vs 57.6% [34/59]; EGFRm: 10.6% [17/160] vs 11.9% [7/59]), suggesting no apparent interaction with treatment. There were no apparent associations of pneumonitis with baseline respiratory disorders, prior RT dose, or prior cisplatin or carboplatin use. Previous induction CT was more commonly associated with the absence of pneumonitis in both treatment arms (durvalumab: 30.1% vs 17.5%; placebo: 31.5% vs 20.3%). The presence of pneumonitis was associated with greater discontinuation due to AEs (durvalumab: 25.6% vs 10.2%; placebo: 18.6% vs 6.8%) regardless of treatment.

      Conclusion

      Rates of pneumonitis were higher in Asian patients and those with EGFRm, as previously reported. Durvalumab did not increase pneumonitis in patients with these risk factors. There were no differences in treatment exposure in patients based on the presence/absence of pneumonitis. Multivariate analyses may further assist in the discernment of etiologic risks.

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      MA05.03 - Immune Microenvironment and its Association with Adjuvant Chemotherapy Benefit in Locoregionally Advanced Lung Adenocarcinoma

      13:40 - 13:45  |  Presenting Author(s): Raj Ghanshyam Vaghjiani  |  Author(s): Takashi Eguchi, Navin Chintala, Xiaoyu Li, Rania G Aly, Katsura Emoto, Kay See Tan, David R. Jones, Prasad S. Adusumilli

      • Abstract

      Background

      The impact of the tumor immune microenvironment on the effectiveness of platinum-based adjuvant chemotherapy (ACT) in locoregionally advanced (stage II-III) lung adenocarcinoma (ADC) is unknown. We performed an analysis of the cellular components of the tumoral and tumor-associated stromal immune environment in stage II-III lung ADC and examined their association with ACT benefit.

      Method

      Tissue microarrays (6 tumor and 3 stromal cores from each tumor) were constructed using resected tissue from patients with pT2-T4N1 lung ADC (n=500, 2000-2012) who did (n=225) and did not (n=214) receive ACT. Multiplex immunofluorescence was used to determine the quantity, localization, and colocalization of 21 types of immune cells and markers (including PD-1, PD-L1, CD3, CD20, CD68, CD163, MPO, and PanCK). The association between immune cell infiltration and recurrence free probability (RFP) was compared using Kaplan-Meier methods, and benefit from ACT by unsupervised hierarchical cluster modeling.

      Result

      Overall, increased tumoral infiltration of CD20+ B-cells and CD3+ and CD4+ T-cells was associated with an improvement in 5-yr RFP (CD20+ low vs high: 37% vs 49%, p=.03; CD3+: 39% vs 48%, p=.003; and CD4+: 39% vs 47%, p=.02, respectively) whereas increased stromal MPO+ neutrophil infiltration was associated with a worse 5-yr RFP (low vs high: 50% vs 38%, p=.003). Among patients who received ACT, cluster modeling revealed 5 risk groups (Groups A-E; Figure) with immune signatures including tumoral B-cells and CD163+PD-1+ macrophages as well as stromal CD57+ NK-cells and CD163+PD-L1+ macrophages that provided a progressive stratification of RFP following adjuvant treatment.

      vaghjiani.jpg

      Conclusion

      Immune infiltration analysis can predict benefit from ACT and thereby provide a rationale to select patients for either chemotherapy, immunotherapy, or combination therapy following surgical resection.

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      MA05.04 - Discussant - MA 05.01, MA 05.02, MA 05.03

      13:45 - 14:00  |  Presenting Author(s): Scott N. Gettinger

      • Abstract

      Abstract not provided

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      MA05.05 - Photon-Based Cardiac Sparing Via Volumetric Modulated Arc Therapy in Thoracic Radiation Therapy for Locally Advanced Non-Small Cell Lung Cancer

      14:00 - 14:05  |  Presenting Author(s): Matthew J Ferris  |  Author(s): Katherine Sykes, Oluwatosin A Kayode, Jonathan Wolf, Robert H Press, Jeffrey M Switchenko, Walter John Curran, Jr., Kristin A Higgins

      • Abstract

      Background

      Increasing radiation dose to the heart is associated with worse survival in stage III non-small cell lung cancer. Techniques to reduce the dose to the heart, including proton beam therapy (PBT), are being evaluated in ongoing clinical trials. However, advanced technologies such as PBT are not readily accessible for most patients. We therefore sought to evaluate the efficacy of volumetric modulated arc therapy (VMAT), a readily available technology in the United States, to spare cardiac substructures and determine how a cardiac optimization treatment planning algorithm influences dose distribution to other thoracic organs at risk (OARs).

      Method

      We selected stage III non-small cell lung cancer patients who were treated at our institution with VMAT to 60 Gy in 2 Gy fractions. Cardiac substructures were retrospectively contoured, and included: valves, atrioventricular node (AVN), coronary arteries (CA), chambers, and great vessels. New radiation treatment plans were created to spare these structures while preserving planning target volume (PTV) coverage and maintaining standard dose constraints to OARs. Dosimetry variables—maximum dose (Dmax), mean dose (Dmean), and common clinically relevant dose-volume relationships—for the new cardiac-sparing radiation treatment plans were compared via paired t-test to the original radiation treatment plans.

      Result

      Twenty-six patients, treated from July 2013 to September 2017, were included. Statistically significant improvements were demonstrated for all cardiac structures for the new cardiac-sparing plans compared to the original plans, while maintaining appropriate lung, esophagus, and spinal cord constraints, and PTV coverage goals, as demonstrated in Table 1 (significant P-values in bold).

      Table 1

      Dosimetry variable

      Cardiac-sparing plan (mean)

      Original plan (mean)

      P-value*

      Cardiac parameters

      Heart Dmax

      64.9 Gy

      63.6 Gy

      0.928

      Heart Dmean

      12.3

      16.1

      < 0.001

      Heart V5Gy

      55.4

      64.1

      0.003

      Heart V30Gy

      12.5

      18.7

      < 0.001

      Heart V40Gy

      7.9

      11.5

      < 0.001

      Heart V45Gy

      6.5

      11.5

      < 0.001

      Heart V60Gy

      2.7

      3.4

      0.001

      Aortic valve Dmax

      22.9

      31.7

      < 0.001

      Aortic valve Dmean

      11.4

      31.7

      < 0.001

      Mitral valve Dmax

      24.6

      29.4

      0.002

      Mitral valve Dmean

      11.2

      16.7

      < 0.001

      Pulmonic valve Dmax

      26.8

      35.4

      < 0.001

      Pulmonic valve Dmean

      14.1

      25.1

      < 0.001

      Tricuspid valve Dmax

      9.7

      16.6

      < 0.001

      Tricuspid valve Dmean

      5.6

      10.3

      < 0.001

      AVN Dmax

      13.4

      20.4

      < 0.001

      AVN Dmean

      8.1

      14.0

      < 0.001

      Left main CA Dmax

      26.4

      38.8

      < 0.001

      Left main CA Dmean

      16.4

      30.2

      < 0.001

      Left anterior descending CA Dmax

      27.4

      34.8

      < 0.001

      Left anterior descending CA Dmean

      14.4

      22.6

      < 0.001

      Left circumflex CA Dmean

      32.6

      36.8

      0.001

      Left circumflex CA Dmean

      19.3

      26.9

      < 0.001

      Right CA Dmax

      18.1

      26.1

      < 0.001

      Right CA Dmean

      9.4

      15.7

      < 0.001

      Left atrium Dmax

      51.8

      54.8

      0.091

      Left atrium Dmean

      17.5

      21.0

      < 0.001

      Left ventricle Dmax

      35.7

      40.1

      < 0.001

      Left ventricle Dmean

      8.3

      11.3

      < 0.001

      Right atrium Dmax

      31.4

      36.1

      0.004

      Right atrium Dmean

      11.1

      13.9

      < 0.001

      Right ventricle Dmax

      23.7

      33.2

      < 0.001

      Right ventricle Dmean

      6.9

      12.2

      < 0.001

      Aorta Dmax

      50.8

      55.3

      0.001

      Aorta Dmean

      20.4

      27.9

      < 0.001

      Pulmonary artery Dmax

      65.2

      65.1

      0.895

      Pulmonary artery Dmean

      32.3

      37.9

      < 0.001

      Superior vena cava Dmax

      47.4

      51.7

      0.002

      Superior vena cava Dmean

      29.4

      33.1

      0.006

      Other OAR parameters

      Lungs V5Gy

      56.5

      58.2

      0.121

      Lungs V20

      22.4

      23.3

      0.083

      Lungs Dmean

      13.6

      14.8

      0.012

      Spinal cord Dmax

      28.0

      31.1

      0.013

      Esophagus Dmean

      21.2

      22.1

      0.023

      PTV coverage parameters

      PTV Dmax

      65.5

      67.2

      0.189

      PTV minimum dose

      51.2

      52.7

      0.019

      PTV V100%

      95.2%

      95.4%

      0.195

      Conclusion

      Dose to the heart and cardiac substructures can be substantially lowered using a cardiac-sparing optimization algorithm with VMAT, without increasing radiation dose other thoracic OARs or compromising PTV coverage. Though time-consuming, delineation of the full complement of cardiac substructures provides an effective means of improving the quality of radiation treatment plans with readily available technologies.

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      MA05.06 - Locally Advanced Lung Cancer Radiotherapy in Deep Inspiration Breath Hold: Dosimetric Benefits from a Prospective Trial

      14:05 - 14:10  |  Presenting Author(s): Mirjana Josipovic  |  Author(s): Marianne C Aznar, Jonas Scherman Rydhög, Jakob Borup Thomsen, Sidsel Marie Skov Damkjaer, Lotte Nygård, Mette Pøhl, Seppo W Langer, Lena Specht, Gitte Fredberg Persson

      • Abstract

      Background

      Radiotherapy for locally advanced non-small cell lung (NSCLC) cancer is often complicated by treatment-related toxicity. A toxicity-reducing technique is deep inspiration breath hold (DIBH), where the lungs inflate and the heart is pushed downwards. DIBH is widely applied in breast radiotherapy, but only sporadically in NSCLC. We initiated the INHALE trial, investigating compliance and benefits of DIBH for NSCLC at a single academic institution.

      Method

      Patients referred for definitive radiotherapy of locally advanced NSCLC (66Gy/33 fractions) were included from May 2015-Dec 2017. All patients underwent respiratory coaching for voluntary visually guided DIBH and were imaged with PET/CT, 4D-CT and DIBH-CT. Target volumes were defined according to national guidelines. PTV margins were patient- and modality-specific. For all patients, FB and DIBH plans were made with volumetric modulated arc therapy, with equal PTV coverage. The plan with the lowest lung and/or heart dose was chosen for treatment. Normal tissue complication probability for pneumonitis was calculated retrospectively based on a logistic dose response model.

      Result

      The treatment intent was maintained in 69 of included 88 patients (2 were downstaged, 12 upstaged, 2 withdrew consent, other causes in 3). 62/69 were DIBH compliant and in 61 patients a FB and a DIBH plan were made (in one patient, 4DCT image quality was not sufficient). In 54/61 patients, the DIBH plan was chosen for treatment. 3/54 patients lost DIBH compliance within the first few fractions.

      All data is presented as median (range), with p<0.001 (Wilcoxon signed rank). Lung volume increased in DIBH by 55% (20-168%). Compared to FB, DIBH reduced mean lung dose from 14.4Gy (1.2-25.3Gy) to 11.8Gy (1.0-20.4Gy), and lung V20 from 23.7% (1.5-47.8%) to 20.8% (1.2-39.7%). Reduced lung dose translated to reduced pneumonitis risk: from 8.6% (2.3-23.3%) to 6.5% (2.2-14.4%). Lung dose constraints were violated in 5/62 patients in FB and 1/62 patients in DIBH.

      Mean heart dose was reduced from 3.6Gy (0.1-25.8Gy) in FB to 2.4Gy (0.1-25.3Gy) in DIBH. DIBH reduced mean heart dose in 44/61 patients. The differences between FB and DIBH varied between – 6.6Gy and 8.9Gy, stressing the influence of tumour location on the potential of reducing heart dose with DIBH.

      Conclusion

      Benefits of changed anatomy with DIBH were reduced dose to lungs and, for most patients, to the heart. Curative treatment intent could be maintained in more patients. Risk of developing radiation pneumonitis was reduced. Continuous follow up of INHALE patients will reveal how the reduced risk is manifested clinically.

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      MA05.07 - Dose Escalated Chemo-RT to 84 Gy in Stage III NSCLC Appears Excessively Toxic: Results from a Randomized Phase II Trial

      14:10 - 14:15  |  Presenting Author(s): Jan Nyman  |  Author(s): Stefan Bergström, Hedvig Björkestrand, Anna-Maja Svärd, Simon Ekman, Erik Lundin, Erik Holmberg, Mikael Johansson, Signe Friesland, Andreas Hallqvist

      • Abstract

      Background

      Concurrent chemoradiotherapy is the mainstay treatment for NSCLC stage III disease, however, with a rather high probability of locoregional and metastatic recurrence further treatment optimization is warranted. Based on previous one-armed trials with dose escalated radiotherapy, showing feasibility, the Swedish Lung Cancer Study Group aimed to investigate whether dose escalation based on individual normal tissue constraints could improve outcome in this randomized phase II trial.

      Method

      NSCLC patients with stage III disease, good performance status (0-1), adequate lung function (FEV1 > 1.0 L and CO diff. > 40%) received three cycles of cisplatin (75 mg/m2 day 1) and vinorelbine (25 mg/m2 day 1 and 8) every third week. The radiotherapy started concurrently with the second cycle, with either 2 Gy daily, 5 days a week, to a total dose of 68 Gy (standard arm A) or escalated therapy (B) based on constraints to the spinal cord, esophagus and lungs up to 84 Gy by adding an extra fraction of 2 Gy per week while keeping the total treatment time constant at seven weeks with the same dose to involved nodes and primary tumor.

      Result

      A pre-planned safety analysis revealed excessive toxicity and decreased survival in the escalated arm, and the study was stopped. Thirty-six patients were included during 2011-2013 (56% male, 78% with adenocarcinoma, 64% with PS 0 and 53% with stage IIIB). The median progression-free survival (PFS) and overall survival (OS) were 11 and 17 months in the dose escalated group compared to 28 and 45 months in the standard group. The 1-, 3- and 5-year survival rates were 56%, 33% and 17% in the escalated arm and 72%, 61% and 34% in the standard arm. There were four toxicity-related deaths due to esophageal perforations (one in arm A and three in arm B) and three deaths due to pneumonitis (one in arm A and two in arm B).

      Conclusion

      Dose-escalated concurrent chemoradiotherapy to 84 Gy to primary tumor and nodal disease is hazardous, with a high risk of excessive toxicity, whereas modern standard dose chemoradiotherapy with proper staging given in the control arm shows a promising outcome with a median survival of 45 months and a 5-year survival of 34%. A possible step forward will be to improve systemic therapy, but future approaches with escalated radiotherapy may include boost techniques to remaining PET positive areas or different escalation schedules to the primary tumor and mediastinal nodes.

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      MA05.08 - Discussant - MA 05.05, MA 05.06, MA 05.07

      14:15 - 14:30  |  Presenting Author(s): Benjamin H Lok

      • Abstract

      Abstract not provided

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      MA05.09 - PFS and Cardiac-Toxicity-Adjusted-PFS As Predictors of OS in Locally Advanced NSCLC Treated with Concurrent Chemoradiation

      14:30 - 14:35  |  Presenting Author(s): Chen Hu  |  Author(s): Mitchell Machtay, James Dignam, Rebecca Paulus, Jeffrey Bradley

      • Abstract

      Background

      Overall survival (OS) is the gold standard for LA-NSCLC with chemoradiation (CCRT), while the complex relationships among RT dosimetry, systemic therapies, cardiopulmonary toxicity, progression (PD) and OS are also of increasing scientific and clinical interest.

      Method

      NRG Oncology RTOG 0617 (NCT00533949) was a randomized phase 3 trial comparing standard (SD, 60 Gy) versus high-dose (HD, 74 Gy) CCRT +/- cetuximab from 11/07-06/11. This secondary analysis includes 469 patients (pts) given ≥50 Gy. A PFS event was defined as the first occurrence of local, regional, distant PD or death w/o documented PD. A CTA-PFS event was the first occurrence of grade 2+ treatment-related cardiac toxicity event or a PFS event. Landmark analyses at 6mo and 12mo were used to minimize the immortal time bias. Cox model with PD or CT/PD as a time-dependent covariate was used to evaluate their predictive roles. Median f/u time for surviving pts was 5.1 years.

      Result

      As previously reported, pts treated with HD had significantly lower OS rates (HR=1.28, 95%CI: 1.04-1.58, p=0.018) and CTA-PFS rates (HR=1.24, 95%CI: 1.02-1.51, p=0.035), and marginally lower PFS rates (HR=1.21, 95%CI: 0.99-1.47, p=0.06) than pts treated with SD. Median survival time (MST) among pts having PD within 6mo versus not were 13.4mo (95%CI: 10.0-19.0mo) and 30.7mo (95%CI: 28.0-37.0mo) (p<0.001). MST for pts having PD within 12mo versus not were 20.6mo (95%CI: 18.8-25.0mo) and 60mo (95%CI: 47.6-74.5mo)(p<0.001). Results are similar when using CTA-PFS with 6mo or 12mo cutoff (p<0.001). RT dose was no longer significantly associated with OS (p=0.08 or p=0.15) when PD or CT/PD was included in multivariable analysis (p<0.001), suggesting OS differences in HD/SD may be partially captured by PFS or CTA-PFS.

      Conclusion

      Long-term survival results from RTOG 0617 suggest that PFS (or CTA-PFS) status at 6mo or 12mo predicts long-term OS, and may potentially be considered as a surrogate endpoint of OS in clinical trials. Pts who were progression-free at 12mo had a MST of 5 years. Further validation on external datasets and in the modern era of immunotherapy are needed.

      Funding: This project was supported by grants NCORP (UG1CA189867), NRG Operations (U10CA180868), NRG SDMC (U10CA180822), IROC (U24CA180803), and CTEP from the National Cancer Institute (NCI).

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      MA05.10 - The Pathologic Response of Locally Advanced NSCLC Treated with Concomitant Chemoradiation to 60 Gy in Image Guided Radiation Therapy (IGRT)

      14:35 - 14:40  |  Presenting Author(s): Sarit Appel  |  Author(s): Jair Bar, Damien Urban, Amir Onn, Marina Perelman, Yaacov Richard Lawrence, Alon Ben-Nun, Ory Haisraely, Zvi Symon, Tatiana Rabin El Ezra, Edith Marom, Sivan Liberman, Efrat Ofek

      • Abstract

      Background

      Neoadjuvant concomitant chemoradiation (NACCRT) was historically limited to 45 Gy. We recently published data on the safety of a higher radiation dose in this setting. Here we evaluate the pathologic response of locally advanced non small cell lung cancer (LANSCLC) treated with 60Gy NACCRT combined with modern IGRT.

      Method

      Our cohort comprised patients that underwent NACCRT followed by surgery during August 2012-December 2017 at our institution. We retrospectively collected the demographic, stage, histology, and treatment details. Radiation was planned using eclipse system to deliver 2 Gy per fraction to a total of 60 Gy

      Treatment effect was determined from the pathologic specimen in accordance with College of American Pathologists recommendations, based on the modified tumor regression grading: Favorable pathologic responses included major tumor regression (MTR); we also evaluated the average percent of the residual tumor cells seen in the specimen. Statistical analysis was performed to analyze treatment effect on the pathologic response using spearman correlation and Kruskal-Wallis test with SPSS software v.24.

      Result

      Our cohort included 70 patients. Mean age was 63 years (range 45–79.7), men n=49 (70%), smoking status: never smokers n=11 (16.2%), past smokers n=10 (14.7%), current smokers n=47 (69.1%). Histology consisted adenocarcinoma n=42 (60%), squamous n=21 (30%) and other n=7 (10). Stage 2 were n=65 (78.3%) and stage 3 n=15 (21.4%). Chemotherapy consisted of platinum-doublet administered to 69 patients (98.5%). A mean radiation dose of 59 Gy (range 46-72 Gy) was delivered with IGRT prior to each fraction. Five patients received lower radiation doses due to toxicity or dose constraints. Surgery comprised of lobectomy n=50 (71.4%), chest wall resection n=9 (12.9%) or pneumonectomy n=11 (15.7%). Negative surgical margins were achieved in n=63 (90%) and positive margins in n=7 (10%). 30-day mortality was n=2 (2.8%) both cases after Right-sided pneumonectomy.

      MTR was observed in 45 cases (64.3%) including a pathological complete response in 25 (35.7%) and < 10% residual tumor in 20 cases (28.5%). The mean percent of residual tumor cells was 16% and the median 6.5%. Percent of residual tumor cells did not correlate to radiation dose (Rs=0.092), and not to the histology (p= 0.165), and not to type of chemotherapy (p=0.35).

      Conclusion

      NACCRT delivered to 60 Gy with modern image-guided radiation therapy is safe. Two thirds of such patients achieve major tumor regression.

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      MA05.11 - Radiomics Analysis Using SVM Predicts Mediastinal Lymph Nodes Status of Squamous Cell Lung Cancer by Pre-Treatment Chest CT Scan

      14:40 - 14:45  |  Presenting Author(s): Xing Wang, Wu Nan  |  Author(s): Shi Yan, Quanzheng Li, Ning Guo, Zhe Guo

      • Abstract

      Background

      Assessment of mediastinal lymph nodes (N2 station) is essential in staging patients with Non-small-cell lung cancer (NSCLC), for patients with preoperative confirmed N2 status should follow neoadjuvant therapy before surgery, and occult N2 status should be avoided. There are several invasive and non-invasive exams available for preoperative N staging, like EBUS-TBNA and PET-CT scan. Chest CT scan was the basic examination of every patient, while only the length of minor axis could be used to predict lymph node involvement, and the potential value of CT might be underestimated. In this study we aimed to explore the value of radiomics analysis with machine learning in differentiating N2 from N1/N0 subjects using pre-treatment chest CT.

      Method

      Ninety-three patients with squamous cell lung cancer, who underwent pre-treatment CT scans were included in this study. By use of Laplacian of Gaussian (LoG) filter and matrix based radiomics models (e.g. gray-level co-occurrence matrix), comprehensive radiomics features were extracted from the regions of interest which were manually delineated on primary tumors. We performed radiomics analysis using support vector machine (SVM) to test texture and heterogeneity features derived from pre-treatment CT images as indicators for the staging of lymph node metastasis, especially N2. The gold standard of N staging is confirmed pathologically after systematic mediastinal lymphadenectomy (N2 subjects=31).

      Result

      For the performance evaluation of single image feature, there are 16 features able to differentiate N2 subjects from others (N0 and N1) with p value <0.05. Furthermore, SVM training and classification were performed using 5-feature combinations as inputs. With feature selection, the best performance of N2 prediction is 83% accuracy with 87% sensitivity and 81% specificity.

      figure.jpg

      Conclusion

      Radiomics analysis using SVM training can successfully predict N staging by pre-treatment chest CT scan for NSCLC patients, which could diminish the odds of occult N2 status and provide unique information preoperatively for treatment planning.

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      MA05.12 - Discussant - MA 05.09, MA 05.10, MA 05.11

      14:45 - 15:00  |  Presenting Author(s): Matthew Hatton

      • Abstract

      Abstract not provided