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Fabrice Barlesi

Moderator of

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    OA07 - Precision Medicine Involves Biology and Patients (ID 132)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Advanced NSCLC
    • Presentations: 9
    • Now Available
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      OA07.01 - Osimertinib Plus Platinum/Pemetrexed in Newly-Diagnosed Advanced EGFRm-Positive NSCLC; The Phase 3 FLAURA2 Study (Now Available) (ID 2383)

      11:00 - 12:30  |  Presenting Author(s): Pasi A Jänne  |  Author(s): David Planchard, Paul Howarth, Alexander Todd, Kunihiko Kobayashi

      • Abstract
      • Presentation
      • Slides

      Background

      Osimertinib is a third-generation, CNS-active EGFR-TKI that potently and selectively inhibits both sensitizing EGFR and T790M mutations. Osimertinib is considered the standard of care for patients with newly-diagnosed advanced/metastatic NSCLC harbouring EGFR-activating mutations, based on results of the phase 3 FLAURA trial, which demonstrated a statistically and clinically significant progression-free survival (PFS) benefit for osimertinib over erlotinib or gefitinib. Evidence indicates that adding chemotherapy to gefitinib improves efficacy outcomes versus EGFR TKI monotherapy in newly-diagnosed patients with EGFRm NSCLC (Nakamura et al JCO 2018;36:9005). Adding platinum/pemetrexed to osimertinib could further improve outcomes for newly-diagnosed patients with EGFRm-positive NSCLC.

      Method

      The phase 3, open-label, FLAURA2 study aims to assess the efficacy and safety of osimertinib plus cisplatin/carboplatin plus pemetrexed in adults with locally-advanced/metastatic EGFRm-positive (Ex19del and/or L858R) NSCLC who have not received prior therapy for advanced disease. Patients are required to have a WHO performance status (PS) 0-1, life expectancy >12 weeks and not be amenable to curative surgery or radiotherapy. An initial non-randomised run-in phase (n=30) will assess the safety and tolerability of osimertinib 80 mg once daily (QD) with either cisplatin or carboplatin, and pemetrexed, both administered every 3 weeks (Q3W) for 4 cycles, followed by osimertinib 80 mg QD plus pemetrexed maintenance Q3W until progression or discontinuation. Based on evaluation of safety data from the run-in after ≥12 patients from each group have received ≥3 cycles of study treatment or discontinued therapy, the second phase will randomise approximately 556 patients 1:1 to receive osimertinib 80 mg QD with pemetrexed and cisplatin/carboplatin for 4 cycles followed by osimertinib plus pemetrexed maintenance Q3W or osimertinib alone (80 mg QD), to be continued until progression or discontinuation. Randomisation will be stratified by race (Chinese/Asian vs. non-Chinese/Asian vs. non-Asian), WHO PS (0 vs. 1), and tissue EGFR mutation test at enrolment (cobas® EGFR Mutation Test vs local assessment). A futility analysis of the randomized phase is planned for when approximately 83 PFS events have occurred. The primary endpoint is PFS based on investigator assessment of response using RECIST 1.1 criteria (blinded central assessment is included as a sensitivity analysis). Secondary endpoints include overall survival, objective response rate, duration of response, PFS2, health-related quality of life and safety. Effects on CNS metastases in patients with lesions at baseline will be included as an exploratory endpoint. Enrolment is planned for Q3 2019 for the safety run-in and Q1 2020 for the randomized phase.

      Result

      Section not applicable

      Conclusion

      Section not applicable

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      OA07.02 - LKB1 Mutations in Metastatic Non-Small Cell Lung Cancer (mNSCLC): Prognostic Value in the Real World (Now Available) (ID 902)

      11:00 - 12:30  |  Presenting Author(s): Norah Shire  |  Author(s): Asieh Golozar, Jenna Collins, Kathy Fraeman, Beth Nordstrom, Robert McEwen, Brandon Higgs

      • Abstract
      • Presentation
      • Slides

      Background

      Despite recent advances in treating mNSCLC, many patients fail to respond. Identifying genetic markers may help maximize clinical benefit and avoid unnecessary toxicity. LKB1/STK11 alterations (LKB1m) and co-occurring KRAS mutations/LKB1 loss (KRAS/LKB1) have been associated with poor outcomes in patients treated with immunotherapy (IO). Among chemotherapy-treated patients, however, the prognostic value is less understood. This retrospective study examined LKB1m, KRAS/LKB1 and outcomes in patients with mNSCLC receiving IO (as monotherapy or in combination) or chemotherapy in the real-world setting.

      Method

      Adult patients with mNSCLC who initiated first line (1L) treatment between Jan 2013 and Jun 2017 and had been profiled with the FoundationOne assay in routine care were enrolled from the Flatiron Health Oncology electronic medical record database. Associations between LKB1m, LKB1/KRAS and overall survival (OS) or progression-free survival (PFS) were evaluated by line of therapy (1L and second line [2L]) according to histology (non-squamous/squamous and non-squamous only) using multivariate Cox proportional hazards models. All analyses were stratified by IO or chemotherapy.

      Result

      2407 patients (1847 non-squamous) were included; average age was 66.1 years at 1L initiation. 328 (13.6%) patients harbored LKB1m and 157 (6.5%) harbored KRAS/LKB1. Among IO-treated patients in the 2L setting, LKB1m was associated with shorter OS and PFS versus wild type. A similar association was observed in the 1L setting and in the non-squamous only subgroup. In patients receiving chemotherapy, LKB1m was associated with worse outcomes only in the 1L setting. All associations were generally more pronounced among KRAS/LKB1 compared with LKB1m patients.

      Table. Association between LKB1m and OS or PFS in mNSCLC stratified by IO or chemotherapy and lines of therapy
      Mutation group
      LKB1m
      All mNSCLC Non-Squamous
      Outcome IO Chemotherapy IO Chemotherapy
      1L (n = 270) 2L (n = 670) 1L (n =2,137) 2L (n = 863) 1L (n = 187) 2L (n = 498) 1L (n = 1,687) 2L (n = 683)
      LKB1m, N (%) 40 (14.8) 111 (16.6) 288 (13.5) 83 (9.6) 38 (20.3) 97 (19.5) 257 (15.2) 75 (11.0)
      OS
      Median 341 192 340 350 431 201 356 400
      (IQR) (221 – NA) (72 – 523) (284 – 405) (307 – 451) (221 – NA) (73 – 613) (287 – 415) (307 – 453)
      HR 1.43 1.59 1.40 1.07 1.40 1.67 1.43 1.05
      (95% CI) (0.90 – 2.27) (1.25 – 2.03) (1.21 – 1.63) (0.81 – 1.41) (0.84 – 2.32) (1.27 – 2.19) (1.22 – 1.68) (0.78 – 1.42)
      PFS
      Median 122 67 136 122 125 68 136 128
      (IQR) (83 – 295) (46 – 118) (119 – 146) (97 – 147) (81 – 299) (46 – 114) (122 – 149) (98 – 153)
      HR 1.43 1.59 1.40 1.07 1.36 1.55 1.38 1.07
      (95% CI) (0.90 – 2.27) (1.25 – 2.03) (1.21 – 1.63) (0.81 – 1.41) (0.92 – 2.03) (1.22 1.97) (1.20 – 1.59) (0.82 – 1.39)
      KRAS/LKB1
      All mNSCLC Non-squamous
      IO Chemotherapy IO Chemotherapy
      1L (n = 270) 2L (n = 670) 1L (n =2,137) 2L (n = 863) 1L (n = 187) 2L (n = 498) 1L (n = 1,687) 2L (n = 683)
      KRAS/LKB1, N (%) 17 (6.3) 56 (8.4) 140 (6.6) 42 (4.9) 16 (8.6) 52 (10.4) 133 (7.9) 40 (5.9)
      OS
      Median 303 209 356 343 341 230 363 350
      (IQR) (222 – NA) (72 – 666) (272 – 450) (254 – 554) (130 – NA) (72 – 666) (284 – 462) (254 – 554)
      HR 1.46 1.63 1.55 1.27 1.44 1.78 1.61 1.28
      (95% CI) (0.74 – 2.86) (1.16 2.29) (1.26 – 1.90) (0.87 – 1.84) (0.68 – 3.05) (1.22 – 2.59) (1.29 – 2.00) (0.86 – 1.90)
      PFS
      Median 126 67 136 133 174 68 136 133
      (IQR) (77 – 291) (46 – 91) (112 – 160) (91 – 190) (72 – 295) (47 – 91) (112 – 160) (91 – 190)
      HR 1.34 1.81 1.40 1.08 1.34 1.86 1.44 1.05
      (95% CI) (0.80 – 2.24) (1.35 2.44) (1.16 – 1.68) (0.77 – 1.51) (0.76 – 2.36) (1.35 2.57) (1.19 1.75) (0.74 – 1.50)
      Note: Bold text indicates significant results; reference group for LKB1m is LKB1wt; reference group for KRAS/LKB1 is KRASwt/LKB1wt
      Median OS and PFS and IQRs are expressed in days
      Abbreviations: KRAS mutation/LKB1 loss (KRAS/LKB1), Hazard ratio (HR), Interquartile range (IQR), Confidence interval (CI), Immunotherapy (IO), Overall Survival (OS), Progression-free survival (PFS), Wild type (wt)
      Conclusion

      LKB1m and LKB1/KRAS were associated with numerically worse OS and PFS in the 1L setting, irrespective of treatment, and in IO-treated patients in the 2L setting. Results of this real-world study support previous clinical findings and suggest unique relevance of these mutations in 1L chemotherapy and for 1L and 2L IO.

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      OA07.03 - Clinical Outcome of Non-Small Cell Lung Cancer with EGFR/HER2 Exon 20 Insertions Identified in the LC-SCRUM-Japan (Now Available) (ID 629)

      11:00 - 12:30  |  Presenting Author(s): Hibiki Udagawa  |  Author(s): Shingo Matsumoto, Yuichiro Ohe, Miyako Satouchi, Naoki Furuya, Young Hak Kim, Takashi Seto, Kenzo Soejima, Daisuke Hayakawa, Terufumi Kato, Shingo Miyamoto, Kadoaki Ohashi, Sho Saeki, Hiromitsu Ohta, Daichi Fujimoto, Akimasa Sekine, Kiyotaka Yoh, Koichi Goto

      • Abstract
      • Presentation
      • Slides

      Background

      In-frame insertions in exon 20 (Ex20ins) of EGFR/HER2 occur in 2-5 % of non-small cell lung cancer (NSCLC). There is no approved targeted therapy for patients with these mutations. Historical control data would be valuable for the development of novel targeted therapies for these rare cancers.

      Method

      A nationwide genome screening project in Japan (LC-SCRUM-Japan) has been established for the development of molecular-targeted therapies for lung cancers. In this project, 161 cancer-related genes have been analyzed by a next-generation sequencing (NGS) system, Oncomine™ Comprehensive Assay. The therapeutic efficacy and survival of the patients with non-squamous (non-sq) NSCLC harboring EGFR/HER2 Ex20ins were evaluated using a large-scale clinico-genomic database in the LC-SCRUM-Japan.

      Result

      A total of 3441 advanced non-sq NSCLC patients were successfully analyzed from 2015 to 2018. EGFR Ex20ins were detected in 73 patients (2%; M766_A767insASV/A767_S768insSVD/H773_V774insH/D770_N771insNPH/N771_P772insPH/others=22/17/5/4/4/21) and HER2 Ex20ins were detected in 128 patients (4%; A775_G776insYVMA/G776delinsVC/P780_Y781insGSP/others=95/16/10/7). The median age of the patients was 62 (range, 33-90) years. Eighty-one patients (40%) were male and 114 (57%) were never smoker. Two-hundred patients (99%) were diagnosed as adenocarcinoma and 1 as adenosquamous-cell carcinoma. Based on our database, the median overall survivals in patients with EGFR Ex20ins were 22.4 (95%CI, 15.3-36.8) months, and those with HER2 Ex20ins were 18.8 (13.6-30.3) months. In the patients with EGFR/HER2 Ex20ins, the objective response rate (ORR) and median progression-free survivals (mPFS) of 1st-line platinum-containing chemotherapies were 32% and 6.0 (5.7-7.0) months, respectively. The ORR and mPFS of docetaxel with or without ramucirumab were 26% and 5.1 (3.8-5.9) months, respectively. The ORR and mPFS of PD-1 inhibitor were 0% and 2.0 (1.6-2.6) months, respectively. No significant difference in the therapeutic efficacy of these drugs was observed between the patients with EGFR Ex20ins and HER2 Ex20ins. In 19 patients with EGFR Ex20ins treated with 1st/2nd generation EGFR-TKIs, the ORR was 5% (a M766_A767insASV-positive tumor responded to afatinib) and the mPFS was 2.1 (1.3-4.2) months.

      Conclusion

      The patients with EGFR/HER2 Ex20ins-positive NSCLC showed poor responses to PD-1 inhibitors and 1st/2nd generation EGFR-TKIs. These historical data are highly informative in evaluating the efficacy of novel targeted therapies for EGFR/HER2 Ex20ins-positive NSCLC.

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      OA07.04 - Discussant - OA07.01, OA07.02, OA07.03 (Now Available) (ID 3758)

      11:00 - 12:30  |  Presenting Author(s): Vladmir Cláudio Cordeiro De Lima

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      OA07.05 - High-Grade Chemotherapy-Induced Peripheral Neuropathy (CIPN):  An Analysis of ECOG-ACRIN Lung Cancer Clinical Trials (Now Available) (ID 1431)

      11:00 - 12:30  |  Presenting Author(s): Sawsan Rashdan  |  Author(s): Suzanne E Dahlberg, David E. Gerber, Alan Sandler, Joan H Schiller, David Johnson, Suresh S Ramalingam

      • Abstract
      • Presentation
      • Slides

      Background

      High-grade (CTCAE grade ≥3) CIPN implies severe symptoms and limitation of self-care activities of daily living (ADL). To date, studies characterizing the incidence of and factors associated with CIPN have been conducted almost exclusively in breast cancer populations. As such, they generally evaluate only women and lack assessment of platinum-based chemotherapy. We therefore examined the incidence and factors associated with high-grade CIPN among patients treated on ECOG-ACRIN advanced non-small cell lung cancer (NSCLC) clinical trials.

      Method

      We included two completed trials in the analysis: E1594 (comparison of 4 chemotherapy regimens: cisplatin-paclitaxel, cisplatin-gemcitabine, cisplatin-docetaxel, carboplatin-paclitaxel) and E4599 (carboplatin-paclitaxel ± bevacizumab). We identified patients who developed treatment-related grade ≥3 CIPN. Multivariable logistic regression modeling was performed to estimate adjusted odds ratios. For the treatment variable, the reference group ended up combining the cisplatin+paclitaxel and cisplatin+docetaxel arms since their results were not significantly different from one another. Body-mass index (BMI) was categorized by median value (25.2 kg/m2).

      Result

      Among 1,989 total patients, 167 (8.4%) developed grade ≥3 CIPN. Incidence was highest for the carboplatin-paclitaxel regimen (9.9%) and lowest for cisplatin-paclitaxel (4.5%) (P=0.006). Grade ≥3 CIPN was associated with BMI (9.9% for ≥25.2 kg/m2 vs 6.9% for <25.2 kg/m2; P=0.02) and sex (6.9% for men vs 10.4% for women; P=0.006). There was a non-significant trend toward association with age (10.4% for ≥70 years versus 7.8% for <70 years; P=0.08). In multivariate analysis, chemotherapy regimen, sex, and BMI remained independently associated with grade ≥3 CIPN.

      Conclusion

      Carboplatin-paclitaxel chemotherapy, female sex, and high BMI are associated with the development of high-grade CIPN. Given the clinical severity of this condition and the potential for long-term persistence, consideration of risk-based monitoring and treatment selection may be warranted.

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      OA07.06 - Patient Knowledge and Expectations Related to Return of Genomic Results in the Lung-MAP (SWOG 1400) Biomarker-Driven Clinical Trial (Now Available) (ID 730)

      11:00 - 12:30  |  Presenting Author(s): Joshua A Roth  |  Author(s): Meghna S Trivedi, Stacy Gray, Donald Patrick, Wylie Burke, Debbie Delaney, Kate Watabayashi, Paul Litwin, Parth Shah, Katherine D. Crew, Monica Yee, Mary Redman, Vassiliki A Papadimitrakopoulou, Karen Kelly, David R Gandara, Dawn L Hershman, Scott D Ramsey

      • Abstract
      • Presentation
      • Slides

      Background

      Biomarker-driven clinical trials (BDCTs)--where participants qualify for targeted therapy sub-studies based on tumor genomic testing results--represent a new paradigm in oncology clinical trials. However, BDCTs’ complex designs are difficult to communicate to patients considering participation, and deficits in knowledge and expectations have implications for shared decision-making and informed consent. The objective of this pilot study was to evaluate patient knowledge and expectations related to return of genomic results in the Lung-MAP (SWOG 1400) BDCT.

      Method

      From 8/2017 to 4/2019, we recruited a subset of participants with advanced non-small cell lung cancer (NSCLC) from among patients enrolled in the Lung-MAP genomic screening study (SWOG 1400). Participants completed a 38-item telephone survey conducted by trained staff within 30 days of consent. Survey questions assessed patient knowledge about the benefits and risks of study participation and expectations about return of genomic results in the study. The survey was structured as 5-level scale responses (‘strongly disagree’ [1] to ‘strongly agree’ [5]) and true/false/don’t know. Survey questions were adapted from prior studies that evaluated knowledge and expectations about return of genomic results. Descriptive statistics (means, medians, proportions) were assessed in this preliminary analysis.

      Result

      Among 123 participants, median age was 67, 61.0% were male, 95.1% were white, 22.0% had a 4-year college education or more, and 28.5% had a household income of <$25,000/year. In the overall sample, 82.9% ‘strongly/somewhat agreed’ with the statement ‘I received enough information about the testing in Lung-MAP to understand the benefits of enrolling’ and 73.2% ‘strongly/somewhat agreed’ with the statement ‘I received enough information…to understand the risks of enrolling’. Among the sub-group that ‘strongly/somewhat agreed’ with understanding trial benefits: 89.2% correctly believed that it was ‘true’ that test results would help to select their cancer treatment (8.8% responded ‘don’t know’), 8.8% correctly believed it was ‘false’ that the somatic testing in the study would provide information to find out if family members had increased risk of cancer (40.2% responded ‘don’t know’), and 11.8% correctly believed it was ‘false’ that results would tell them about their risk of developing diseases besides cancer (38.2% responded ‘don’t know’).

      Conclusion

      Among participants in a large BDCT, a majority of participants had serious deficits about the reporting of genomic results despite reporting to have enough information to understand benefits and risks. Our findings suggest that further research is needed to identify effective approaches to communicating information about BDCTs to improve patient knowledge about return of genomic results.

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      OA07.07 - Quality of Life (QoL) Analysis in Lung Cancer: A Systematic Review of Phase III Trials Published Between 2012 and 2018 (Now Available) (ID 1958)

      11:00 - 12:30  |  Presenting Author(s): Maria Lucia Reale  |  Author(s): Emmanuele De Luca, Pasquale Lombardi, Laura Marandino, Clizia Zichi, Daniele Pignataro, Eleonora Ghisoni, Rosario Francesco Di Stefano, Annapaola Mariniello, Elena Trevisi, Gianmarco Leone, Leonardo Muratori, Anna La Salvia, Cristina Sonetto, Paolo Bironzo, Massimo Aglietta, Silvia Novello, Giorgio Vittorio Scagliotti, Francesco Perrone, Massimo Di Maio

      • Abstract
      • Presentation
      • Slides

      Background

      We previously reported that QoL is not included among endpoints and QoL results are underreported in a high proportion of phase III trials in oncology. Here we describe QoL prevalence and heterogeneity in QoL reporting in lung cancer phase III trials.

      Method

      We selected all primary publications of lung cancer phase III trials evaluating anticancer drugs published between 2012 and 2018 by 11 major journals. We analyzed QoL inclusion among endpoints, presence of QoL results and methodology of QoL analysis.

      Result

      122 publications were identified. In 39 (32.0%) publications, QoL was not listed among endpoints: 10/17 (58.8%) early stage/locally advanced NSCLC, 15/54 (27.8%) first-line of advanced NSCLC; 10/41 (24.4%) second and further lines of advanced NSCLC, 4/10 (40.0%) SCLC. Proportion of trials not including QoL was similar over time: 32.9% publications in 2012-2015 vs. 30.6% in 2016-2018. QoL was not listed among endpoints in primary publication in 16/80 (20.0%) for-profit trials vs. 23/42 (54.8%) no-profit trials. Out of 83 trials including QoL among endpoints, QoL results were not reported in 36 primary publications (43.4%). Proportion of trials not reporting QoL results in primary publication significantly increased over time (30.6% 2012-2015 vs. 61.8% 2016-2018, p=0.005). Overall, QoL data were not available in 65/122 (61.5%) primary publications, due to the absence as endpoint or unpublished results. QoL data were not available in primary publication in 48/80 (60.0%) for-profit trials vs. 27/42 (64.3%) no-profit trials. QoL data were lacking in 48/78 (70.6%) publications of trials with overall survival as primary endpoint, 27/54 (50.0%) with other primary endpoints and 28/54 (51.9%) publications with a positive result. For trials including QoL among endpoints but lacking QoL results in primary publication, probability of secondary publication was 6.3%, 30.1% and 49.8% after 1, 2 and 3 years respectively, without evidence of improvement in time to publication comparing 2012-2015 vs. 2016-2018. Out of 83 trials including QoL, most common tools were EORTC QLQ-C30 (42, 50.6%); EORTC LC13 (39, 47.0%); EQ-5D (37, 44.6%); LCSS (19, 22.9%); FACT-L (15, 18.1%). Out of 58 trials with available results, common methods of analysis were mean scores or changes (45, 77.6%), time to deterioration (31, 53.4%) and proportion of responders (19, 32.8%). Availability of a secondary QoL publication allowed a higher number of methods of QoL analysis (p<0.001).

      Conclusion

      QoL is not assessed in a high proportion of phase III trials evaluating lung cancer patients, a setting where attention to QoL should be particularly high, due to symptoms and limited life expectancy. Furthermore, the timely inclusion of QoL results in primary publications is worsening in recent years. Secondary publications allow a more complete description of QoL results, but imply a delay in their availability.

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      OA07.08 - Discussant - OA07.05, OA07.06, OA07.07 (Now Available) (ID 3759)

      11:00 - 12:30  |  Presenting Author(s): Mary O'Brien

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      OA07.09 - Daniel C. Idhe Lectureship Award for Medical Oncology (Now Available) (ID 3904)

      11:00 - 12:30  |  Presenting Author(s): Shao Weng Daniel Tan

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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Author of

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    ES06 - New Approaches in Second Line Treatment In NSCLC (ID 9)

    • Event: WCLC 2019
    • Type: Educational Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      ES06.02 - What Is the Best Strategy in Progressive Disease After Consolidation with Durvalumanb, or Rapid Progressors to First Line? (Now Available) (ID 3182)

      13:30 - 15:00  |  Presenting Author(s): Fabrice Barlesi

      • Abstract
      • Presentation
      • Slides

      Abstract

      Immune Check Points Inhibitors (ICIs) have dramatically changed the management of locally advanced and advanced NSCLC patients. While the survival improvement compared to previous standard of care is undoubtable, several patients still progress on or relapse after ICIs. How should these patients be managed?

      To better understand how to manage these patients, we should probably try to better understand the underlying mechanism(s) of resistance to ICIs. Schematically, we can propose three main categories, with primary resistances, occurring early after ICIs initiation, secondary resistances, occurring after a previous response or disease stabilization on ICIs, and follow-up resistances, occurring after stopping ICIs, either per protocol or severe adverse event(s).

      Management of primary resistances to ICIs. Although no validated definition is available, primary resistances might include hyperprogressors and progressors within the first 12- (to 18) weeks of treatment with ICIs. It represents approximately 20 to 30% of stage III NSCLC patients receiving durvalumab after concomitant chemo-radiation, 30% of stage IV patients PD-L1 50% or more NSCLC patients treated with pembrolizumab and 20 to 30% of stage IV patients NSCLC patients treated with a combination of chemotherapy and ICIs.

      Few data are available on the underlying biological mechanisms to explain these primary resistances.

      Considering clinical data of the PACIFIC trial, 41% of patients in the durvalumab arm (without precise characterization of the time or progression) received a subsequent therapy. For the patients who already received durvalumab as a consolidation treatment, 20 patients received a subsequent ICI. The response rate in this case was 0%. With a longer follow, different patients’ profiles will certainly be reported in this setting, with possibly responses to ICIs alone or in combination for patients relapsing a long time after stopping Durvalumab.

      Considering clinical data for stage IV NSCLC patients treated in the first line setting in monotherapy, a recent long term analysis of the Keynote 024 trial. The management of patients with an early progression on Pembrolizumab was not specifically detailed. Globally, 56 out of 154 patients received a subsequent oncologic treatment, mainly chemotherapy.

      Considering clinical data for stage IV NSCLC patients treated in the first line setting with combination of chemotherapy and ICIs, few results are available to date on the management of early progressors.

      Finally, all trials assessing the efficacy of new IO agents or new ICI-based combinations as a rescue treatment after failure of a previous line of ICIs are globally disappointing. A summary of ongoing trials will be presented at the meeting.

      In summary, the best strategy to date for early progressors on ICIs, alone or in combination, unfortunately remains a standard chemotherapy; a participation in a clinical trials should be also discussed giving the efficacy of rescue treatments in this situation.

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    MA07 - Clinical Questions and Potential Blood Markers for Immunotherapy (ID 125)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
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      MA07.05 - Immune Checkpoint Inhibitor (ICPi) Re-Challenge: Outcomes Analysis in a French National Cohort of Non-Small-Cell Lung Cancer (NSCLC) Patients (Now Available) (ID 1903)

      13:30 - 15:00  |  Author(s): Fabrice Barlesi

      • Abstract
      • Presentation
      • Slides

      Background

      Anti-PD1/PDL1 deeply changed the NSCLC therapeutic algorithm in the past few years. Unfortunately, a majority of patients experiences disease progression. ICPis re-challenge could be an attractive option but no data supporting this strategy are available. Here we report outcomes of a large cohort of NSCLC patients treated with anti-PD1/PDL1 re-challenge.

      Method

      We retrospectively collected data about 144 advanced NSCLC patients (diagnosis between 2010 and 2018) from 26 French centers. Patients were re-challenged with ICPis after at least 12 weeks of discontinuation for toxicity, disease progression or clinical decision. Progression Free Survival (PFS) and Overall Survival (OS) were calculated from the start of first or second ICPi to disease progression (PFS1;PFSR) and death or last follow-up (OS1;OS2) respectively.

      Result

      Median age was 63 year [39 –83], most of patients were male (67%), smokers (87%), adenocarcinomas (62%) and stage IV at diagnosis (66%). Most of patients received the first ICPi round in first or second line (66%) and the second ICPi round in third line or later (79%). In both settings patients received preferentially an anti-PD1 (87%) and no differences were detected regarding brain metastasis or ECOG PS (P = 1.10-1 and P = 1.10-1 respectively). The Best Response during the re-challenge was not associated to that one achieved to the first ICPi (P = 1.10-1). The median PFS1 and PFSR were 13 months [95% CI 10-16.5] and 4.4 months [95% CI 3-6.5] respectively. PFSR was longer in patients discontinued because of clinical decision (6.5 months [95% CI 2.5-11.9]) or toxicity (5.8 months [95%CI 3.5-18]) compared to disease progression (2.9 months [95% CI 2.0-4.4]) (P = 2.10-2) and in those not receiving chemotherapy between the two ICPis (5.8 months [95%CI 4.1-10.5]) compared to those who did (3.0 months [95% CI 2.0-4.4])(P = 2.10-3). Median OS1 was 3.3 years [95% CI 2.9-3.9] without differences according to the discontinuation reason (P =2.10-1). Median OS2 was 1.5 y [95%CI 1.0-2.1] and was longer in patients discontinuing the first ICPi due to toxicity (2.1y [95%CI 1.4-NR]) compared to disease progression (1.0y [95%CI 0.4-1.5]) or clinical decision (1.5y [95%CI 0.4-NR]) (P = 3.10-2). Neither OS1 nor OS2 were affected by treatments received between the two ICPis (P = 3.10-1 and P = 1.10-1 respectively).

      Conclusion

      ICPis re-challenge might be a useful option mainly in patients discontinuing the first ICPi because of toxicity or clinical decision and in those able to keep a treatment-free period between the two ICPis.

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    MA14 - The Adequate MTarget Is Still the Issue (ID 140)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      MA14.03 - EGFR M+ Subgroup of Phase 1b Study of Telisotuzumab Vedotin (Teliso-V) Plus Erlotinib in c-Met+ Non-Small Cell Lung Cancer (Now Available) (ID 1622)

      15:45 - 17:15  |  Author(s): Fabrice Barlesi

      • Abstract
      • Presentation
      • Slides

      Background

      Telisotuzumab vedotin (ABBV-399; teliso-v) is an anti-c-Met antibody conjugated with monomethyl auristatin E, a tubulin polymerization inhibitor. Preliminary activity was reported for the teliso-v + erlotinib combination in c-Met overexpressing (c-MET+) non-small cell lung cancer (NSCLC) patients, with an activating EGFR mutation and for whom prior EGFR TKI failed. We present mature data from the EGFR M+ subgroup of the teliso-v + erlotinib cohort of a phase 1b study (NCT02099058).

      Method

      Teliso-v was administered at 2.4 mg/kg (dose-escalation phase) or 2.7 mg/kg intravenously once every 3 weeks, and erlotinib at 150 mg orally once a day/prior tolerated dose in adult patients with advanced NSCLC. For efficacy analysis, c-Met+ was defined as central lab IHC H-score ≥150 or local lab MET amplification (MET/CEN7 ≥2); EGFR M+ was defined as del19 or L858R by local lab. Pharmacokinetics were assessed. All patients who received teliso-v + erlotinib were evaluated for safety.

      Result

      As of Dec 2018, 42 NSCLC patients received teliso-v + erlotinib; 37 were c-MET+ (36 evaluable: 35 H-score≥150, 1 MET amplified). Median age was 65 years, 25 patients (69%) had ECOG PS 1, 29 (81%) were EGFR M+ (of these: 48% had T790M, 10% had MET amplification, 3% had polysomy, 97% had prior EGFR TKI, 55% 3rd-generation TKI, 69% TKI as last prior therapy, and 62% platinum doublet). All-grade (≥20%) adverse events (AEs) were dermatitis acneiform (38%), diarrhea (36%), peripheral motor/sensory neuropathy (52%; 7% Grade 3), dyspnea, fatigue, hypoalbuminemia (31% each), decreased appetite, nausea (24% each), asthenia, vomiting (21% each). Grade ≥3 (≥10%) AE: pulmonary embolism (14%). Pharmacokinetics of teliso-v for the combination were similar to single-agent teliso-v. The table presents efficacy data.

      Patients with EGFR mutation
      (n=29)

      Objective response rate*, % (95% CI)
      Complete response, n

      34.5 (17.9, 54.3)
      1

      Median duration of response, months
      (95% CI)

      NR
      (2.8, NE)

      Median PFS, months (95% CI)

      NR
      (2.8, NE)

      Median follow-up, months 4
      6-month PFS rate, % (95% CI)

      51 (30, 69)

      Median treatment duration, month (range)
      Teliso-v
      Erlotinib


      3.5 (0.71–10.4)
      5.3 (0.71–25.4)

      Objective response rate by subgroup of interest, n (%)
      Received prior 3rd generation EGFR TKI
      C-met amplified, copy number gain, or polysomy
      EGFR TKI-containing regimen as last-line therapies


      6/16 (37.5)
      5/7 (71.4)
      8/20 (40.0)

      *RECIST version 1.1.

      EGFR, epidermal growth factor receptor; NE, not estimable; NR, not reached; PFS, progression-free survival; RECIST, Response Evaluation Criteria in Solid Tumors; TKI, tyrosine kinase inhibitor;

      Conclusion

      These data suggest acceptable safety and promising activity of teliso-v + erlotinib in patients with c-Met+ NSCLC with an activating EGFR mutation and for whom EGFR TKI has failed.

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    OA04 - Immuno Combinations and the Role of TMB (ID 126)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
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      OA04.02 - CheckMate 817: First-Line Nivolumab + Ipilimumab in Patients with ECOG PS 2 and Other Special Populations with Advanced NSCLC (Now Available) (ID 1876)

      15:15 - 16:45  |  Presenting Author(s): Fabrice Barlesi

      • Abstract
      • Presentation
      • Slides

      Background

      Data are limited for immunotherapy in patients with advanced NSCLC and poor performance status or other comorbidities. CheckMate 817 is a multi-cohort, open-label phase 3b/4 study investigating safety and efficacy of flat-dose nivolumab plus weight-based low-dose ipilimumab in advanced NSCLC. Here we evaluate this regimen as first-line treatment in special populations (cohort A1) and a reference population (cohort A; previously reported).

      Method

      Patients had previously untreated advanced NSCLC. Cohort A1 (n=198) had ECOG PS 2 or ECOG PS 0–1 with 1 of: asymptomatic untreated brain metastases, hepatic or renal impairment, or HIV. Cohort A (n=391) had ECOG PS 0–1. Patients with known EGFR mutations or ALK translocations sensitive to available targeted therapy were excluded from both cohorts. Nivolumab 240 mg Q2W plus ipilimumab 1 mg/kg Q6W was administered for two years or until disease progression/unacceptable toxicity. Safety and efficacy endpoints were assessed; cohort A1 analyses were exploratory.

      Result

      Cohort A1 patients were grouped as: ECOG PS 2 (n=139) and all other special populations (AOSP; n=59). Baseline characteristics were generally balanced between cohorts. Rates of grade 3–4 treatment-related adverse events (TRAEs) were similar between cohorts; within cohort A1, grade 3–4 TRAEs were numerically higher in AOSP versus the ECOG PS 2 subgroup; TRAEs leading to discontinuation were similar across populations (Table). ORR was 25% in cohort A1 (patients with ECOG PS 2, 20%; AOSP, 37%) and 35% in cohort A. PFS was numerically shorter in cohort A1 than cohort A; high TMB (≥10 mut/Mb) and higher PD-L1 expression (≥1% or ≥50%) were associated with numerically longer PFS in both cohorts (Table).

      table_v3.jpg

      Conclusion

      First-line flat-dose nivolumab plus weight-based ipilimumab showed a consistent safety profile in special populations with advanced NSCLC, including those with ECOG PS 2. Patients with either high TMB or higher tumor PD-L1 expression appeared to exhibit improved efficacy.

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    OA14 - Update of Phase 3 Trials and the Role of HPD (ID 148)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
    • +

      OA14.04 - Five-Year Outcomes From the Randomized, Phase 3 Trials CheckMate 017/057: Nivolumab vs Docetaxel in Previously Treated NSCLC (ID 894)

      11:30 - 13:00  |  Author(s): Fabrice Barlesi

      • Abstract
      • Slides

      Background

      Historically, outcomes for advanced non-small cell lung cancer (NSCLC) have been poor, with 5-year survival rates < 5% with conventional chemotherapy. Nivolumab, a programmed death-1 (PD-1) inhibitor, was approved in 2015 for patients with previously treated advanced NSCLC based on two randomized phase 3 trials, CheckMate 017 (NCT01642004; squamous) and CheckMate 057 (NCT01673867; non-squamous), which demonstrated improved overall survival (OS) vs docetaxel. We report 5-year pooled efficacy and safety from these trials, representing the longest survival follow-up for randomized phase 3 trials of an immune checkpoint inhibitor in advanced NSCLC.

      Method

      Patients (N = 854; CheckMate 017/057 pooled) with advanced NSCLC, ECOG performance status (PS) ≤ 1, and progression during or after first-line platinum-based chemotherapy, were randomized 1:1 to nivolumab 3 mg/kg Q2W or docetaxel 75 mg/m2 Q3W until progression or unacceptable toxicity. After completion of the primary analyses, patients in the docetaxel arm no longer receiving benefit could cross over to receive nivolumab. OS was the primary endpoint for both studies.

      Result

      At 5-year follow-up, 50 nivolumab patients and 9 docetaxel patients were alive. Baseline characteristics of 5-year survivors in both arms were similar to the overall population and patients who survived < 1 year, except for a higher percentage of patients with ECOG PS 0 or tumor programmed death ligand-1 (PD-L1) expression ≥ 1% on nivolumab and ECOG PS 0 and Stage IIIB NSCLC on docetaxel. Nivolumab continued to show long-term OS and progression-free survival (PFS) benefit vs docetaxel with 5-year OS rates 13% vs 3% (HR, 0.68 [95% CI, 0.59–0.78]) and PFS rates 8% vs 0% (0.79 [0.68–0.92]). OS benefit with nivolumab vs docetaxel was observed across subgroups including patients with tumor PD-L1 expression < 1%, baseline liver and adrenal metastases, neutrophil-to-lymphocyte ratio < median, lactate dehydrogenase ≥ upper limit of normal or no baseline proton-pump inhibitor use. Among patients with an objective response to nivolumab (20%) or docetaxel (11%), 32% remained in response at 5 years vs none on docetaxel, with a median duration of response of 19.9 vs 5.6 months, respectively. Of the 5-year nivolumab vs docetaxel survivors, 36% vs 0% were on study drug, 20% vs 67% received subsequent immunotherapy (on or off study), and 10% vs 0% were off study drug, progression free, with no subsequent therapy. No new safety signals were observed with longer follow-up. Between 3 and 5 years’ follow-up, 8 of the 31 (26%) nivolumab-treated patients reported a treatment-related adverse event, 1 (3%) grade 3–4. The most common select adverse events (events with a potential immunological cause) were related to skin, in 4 (13%) patients, none of which were grade 3–4.

      Conclusion

      CheckMate 017 and 057 are the first phase 3 trials to report 5-year outcomes for a PD-1 inhibitor in previously treated advanced NSCLC, demonstrating a greater than 4-fold increase in 5-year OS rates with nivolumab (13%) over docetaxel (3%). Nivolumab remained well tolerated with no new safety signals.

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    P1.01 - Advanced NSCLC (ID 158)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.01-133 - Randomized Open-Label Study of Bintrafusp Alfa (M7824) vs Pembrolizumab in Patients with PD-L1 Expressing Advanced 1L NSCLC (Now Available) (ID 741)

      09:45 - 18:00  |  Author(s): Fabrice Barlesi

      • Abstract
      • Slides

      Background

      Transforming growth factor β (TGF- β) promotes tumor progression via immune- and non–immune-related processes. Bintrafusp alfa* (M7824) is an innovative first-in-class bifunctional fusion protein composed of 2 extracellular domains of TGF-βRII (a TGF-β “trap”) fused to a human IgG1 monoclonal antibody against PD-L1. Targeting these independent and complementary pathways may restore and enhance antitumor responses. An expansion cohort of the NCT02517398 study of patients with advanced NSCLC (n=80) treated with bintrafusp alfa in the second-line setting presented at ESMO 2018 showed an objective response rate of 86% in the subgroup with high PD-L1 tumor expression at the recommended phase 2 dose (1200 mg intravenously [IV] every 2 weeks [Q2W]). Observed data support the hypothesis that bintrafusp alfa may be superior to other PD-(L)1 inhibitors, including pembrolizumab, for the treatment of NSCLC. Based on the promising antitumor activity and manageable safety profile, this study will evaluate bintrafusp alfa treatment in patients with advanced NSCLC in the 1L setting.

      Method

      Here we present a global, randomized trial comparing bintrafusp alfa vs pembrolizumab in the 1L treatment of patients with metastatic NSCLC with high PD-L1 expression levels. Patients in this study must have a histologically confirmed diagnosis of advanced NSCLC with high PD-L1 expression on tumor cells (defined as either ≥80% by the Dako 73-10 pharmDx kit or ≥50% by the Dako 22C3 pharmDx kit since both assays are expected to select a similar patient population at their respective cut-offs). ECOG performance status must be 0 or 1. Patients must not have received prior systemic treatment for advanced NSCLC. Patients with tumors with actionable mutations (for which targeted therapy is locally approved) are not eligible. Patients will receive 1200 mg Q2W or pembrolizumab 200 mg Q3W as an IV infusion until confirmed disease progression, unacceptable toxicity, or trial withdrawal. Dual primary endpoints are progression-free survival and best overall response; key secondary endpoints include overall survival, duration of response, and safety. Estimated enrollment is 300 patients. Clinical trial information: NCT03631706. *Proposed INN.

      © 2019 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2019 ASCO-SITC Clinical Immuno-Oncology Meeting. All rights reserved.

      Result

      Section not applicable

      Conclusion

      Section not applicable

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    P1.04 - Immuno-oncology (ID 164)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.04-28 - COAST: Durvalumab Alone or with Novel Agents for Locally Advanced, Unresectable, Stage III Non-Small Cell Lung Cancer (ID 174)

      09:45 - 18:00  |  Author(s): Fabrice Barlesi

      • Abstract
      • Slides

      Background

      The standard of care for patients with unresectable stage III non-small cell lung cancer (NSCLC) is platinum-based chemotherapy with concurrent radiotherapy, followed by durvalumab consolidation for 12 months. When administered after completion of concurrent chemoradiotherapy (cCRT) in patients with unresectable NSCLC in the PACIFIC study, durvalumab demonstrated superior clinical outcomes vs placebo in terms of progression-free survival (PFS; hazard ratio [HR] 0.51; 95% CI: 0.41, 0.63) and overall survival (OS; HR 0.68; 99.73% CI 0.47, 0.997; p=0.0025).1 Comparing durvalumab with placebo, the 24‑month OS rate (95% CI) was 66.3% (61.7, 70.4) vs 55.6% (48.9, 61.8), median PFS was 17.2 months (13.1, 23.9) vs 5.6 months (4.6, 7.7) and objective response rate was 30.0% (25.8, 34.5) vs 17.8% (13.0, 23.6).1,2 However, despite cCRT followed by durvalumab, most patients with unresectable stage III NSCLC relapse and eventually die from NSCLC. The COAST study (NCT03822351) is a platform trial that aims to identify potential combinations of durvalumab with novel agents to improve response rates over monotherapy.

      Method

      This multidrug, randomized, phase 2 trial is evaluating the clinical activity and safety of durvalumab alone or in combination with the novel agents oleclumab (MEDI9447) and monalizumab (IPH2201) in patients with unresectable, stage III NSCLC who have not progressed following definitive cCRT. New treatment arms evaluating other durvalumab combinations may be added based on emerging preclinical and clinical data. The primary endpoint is objective response per RECIST v1.1 with monotherapy and combination therapy. Secondary endpoints include safety, efficacy (duration of response, disease control, PFS, 12-month PFS rate, OS), pharmacokinetics and immunogenicity. The COAST study is open for accrual with an estimated total target enrollment of up to 60 patients per treatment arm.

      References

      1Antonia SJ, et al. N Engl J Med 2018;379:2342–50.

      2Antonia SJ, et al. N Engl J Med 2017;377:1919–29.

      Result

      Section not applicable

      Conclusion

      Section not applicable

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      P1.04-30 - Pioneer Study: Precision Immuno-Oncology for Advanced Non-Small Cell Lung Cancer Patients with PD1/L1 ICI Resistance (ID 1865)

      09:45 - 18:00  |  Presenting Author(s): Fabrice Barlesi

      • Abstract

      Background

      In the management of advanced Non-Small Cell Lung Carcinoma (NSCLC), both PD1/L1 immune checkpoint inhibitors (ICIs) have been shown to increase overall survival (OS) over standard second-line chemotherapy. While this long-term increase in OS is driven by about 20% of patients, others display disease progression during the first weeks (w.). PIONeeR aims to understand, through a strategy based on a comprehensive biomarkers assessment, and overcome, through rescue IO strategies, the resistance to ICIs.

      Method

      Stage IV or recurrent NSCLC patients (n=450), with an archived pre-ICI tumor block, planned for a standard 2nd or 3rd line ICIs monotherapy, will be screened. If eligible, after signing an informed written consent, they will be blood-sampled, every cycle throughout the 18 w. post C1D1, and systematically be re-biopsied (primitive or metastasis tumor) at 6 w. of treatment. Efficacy of ICIs will be assessed by RECIST, after 6, 12 and 18 w. Feces will be self-collected by patients, before and during ICIs, to analyze impact of gut microbiome in resistance to ICIs. Characterization of the specific immune contexture of each patient to potentially predict the efficacy of ICIs will be based on the investigation of tumors and their microenvironment (Immunoscore® IC & Multiplex ImmunoHistoChemistry, Tumor Mutational Burden –T cell clonality- ctDNA investigation), effector immune cells, cytokines and endothelial activation (ELISA-Flow cytometry). Protocol’s legal and ethical authorizations were obtained on February 2018 (NCT03493581), patient inclusions were enhanced on April 2018 with the activation of 3 main centers; 10 satellites centers were opened at Q4 2018, inclusions are expected to be completed at Q4 2020. Patients who will progress between 6 and 18 w. (n=150) will be randomized within a precision immuno-oncology experimental masterprotocol using a Bayesian, adaptive design (4 combinations of PDL1i and NKG2Ai, STAT3i, ATRi or CD73i or a control arm). Legal authorizations were obtained on December 2018 (NCT03833440), the inclusion period is expected to last 24 months, from the beginning of Q2 2019.Descriptive statistics will be used to characterize distributions of marker’s expression and to evaluate their predictive value on treatment response and prognostic value on Progression Free Survival., in both protocols. The primary endpoint of the randomized clinical trial is the 12-week Disease Control Rate, assessed in each arm of treatment.

      Result

      Section not applicable

      Conclusion

      Section not applicable

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    P2.01 - Advanced NSCLC (ID 159)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.01-02 - CANOPY-A: A Phase 3 Study of Canakinumab as Adjuvant Therapy in Patients with Surgically Resected NSCLC (ID 1569)

      10:15 - 18:15  |  Author(s): Fabrice Barlesi

      • Abstract

      Background

      Overexpression of interleukin (IL)-1β has been described in solid tumors, including lung. IL-1β can promote angiogenesis, tumor invasiveness, and induces tumor-associated immunosuppression through myeloid-derived suppressor cell (MDSC) accumulation in tumors. Pre-clinical data has shown that IL-1β inhibition reduced tumor growth, by limiting pro-tumorigenic inflammation and polarization of MDSCs into M1 phenotype. Canakinumab is a human monoclonal antibody with high affinity and specificity for IL-1β. Recently, it was found that canakinumab was associated with a significant and dose-dependent reduction in incidence and mortality from lung cancer based on CANTOS study.

      Method

      CANOPY-A (NCT03447769) is a phase III, randomized, double-blind, placebo-controlled study designed to evaluate efficacy and safety of adjuvant canakinumab versus placebo in patients with surgically resected NSCLC. This trial will enroll adult patients, with completely resected (R0) AJCC/UICC v.8 stages II-IIIA and IIIB (T >5 cm and N2) NSCLC, who have completed standard-of-care adjuvant treatments, including cisplatin-based chemotherapy and mediastinal radiation therapy (if applicable). Prior treatment with neoadjuvant chemotherapy or neoadjuvant radiotherapy is not permitted. Approximately 1500 patients will be randomized 1:1 to receive canakinumab (200 mg Q3W, s.c) or placebo (Q3W, s.c.) for 18 cycles or until disease recurrence, unacceptable toxicity, treatment discontinuation at the discretion of the investigator or patient, death, or loss to follow-up. Randomization will be stratified by AJCC/UICC v.8 stage, tumor histology, and region. The primary objective is disease-free survival, per investigator assessment. Secondary objectives include overall survival (key secondary objective), lung cancer-specific survival, safety, pharmacokinetics and immunogenicity of canakinumab, and patient-reported outcomes. Enrollment is ongoing.CANOPY-A (NCT03447769) is a phase III, randomized, double-blind, placebo-controlled study designed to evaluate efficacy and safety of adjuvant canakinumab versus placebo in patients with surgically resected NSCLC. This trial will enroll adult patients, with completely resected (R0) AJCC/UICC v.8 stages II-IIIA and IIIB (T >5 cm and N2) NSCLC, who have completed standard-of-care adjuvant treatments, including cisplatin-based chemotherapy and mediastinal radiation therapy (if applicable). Prior treatment with neoadjuvant chemotherapy or neoadjuvant radiotherapy is not permitted. Approximately 1500 patients will be randomized 1:1 to receive canakinumab (200 mg Q3W, s.c) or placebo (Q3W, s.c.) for 18 cycles or until disease recurrence, unacceptable toxicity, treatment discontinuation at the discretion of the investigator or patient, death, or loss to follow-up. Randomization will be stratified by AJCC/UICC v.8 stage, tumor histology, and region. The primary objective is disease-free survival, per investigator assessment. Secondary objectives include overall survival (key secondary objective), lung cancer-specific survival, safety, pharmacokinetics and immunogenicity of canakinumab, and patient-reported outcomes. Enrollment is ongoing.

      Result

      Section not applicable

      Conclusion

      Section not applicable

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    P2.09 - Pathology (ID 174)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Pathology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.09-15 - PD-L1 Expression and Lymphocyte Infiltration in Resected Stage IIIAN2 NSCLC: Preliminary Data from a Lung ART Ancillary Study (ID 1344)

      10:15 - 18:15  |  Author(s): Fabrice Barlesi

      • Abstract

      Background

      Patients with resectable stage IIIA N2 NSCLC, are at high risk of both systemic and loco-regional relapse following surgical resection, necessitating neo-adjuvant or adjuvant treatments. Prognostic biological markers are needed. Parameters from the immune microenvironment, including PD-L1 expression and lymphocytic infiltration, have been poorly described in this group of patients. Thus we assessed simultaneously PD-L1 expression and TIL density in a cohort of stage IIIA N2 Lung ART patients, and correlated the results with clinical and pathological features before adjuvant treatment.

      Method

      Formalin fixed paraffin-embedded tumor surgical specimens from 247 patients included in the Lung Adjuvant Radiotherapy Trial (NCT00410683) were studied. PD-L1 immunohistochemistry was performed centrally on whole slides using a validated clinical PD-L1 assay. Expression of PD-L1 in tumor cells (TC) and immune cell (IC) was scored by a trained pathologist. Morphological assessment of TIL density (percentage of tumor area) was performed on whole hematoxylin-eosin stained slides. Surgical and pathology reports were reviewed by an independent expert committee for tumor staging. Association between immune parameters and baseline clinical characteristics were assessed in exploratory analyses in order to provide insights on immune activity in resected NSCLC patients.

      Result

      PD-L1 expression in ≥1% TC, ≥50% TC, ≥1% IC, ≥10% IC was observed in 47.8%, 21.9%, 61.5%, 7.3% of patients, respectively. In univariate analysis, high PD-L1 expression in both tumor cells and immune cells for all cut points correlated strongly with a higher TIL density (p-values ≤0.001). In 41 (16.6%) patients with preoperative chemotherapy (CT), a higher TIL density was observed (mean 28.1 vs. 17.5%, p=0.0018) as compared to patients without preoperative CT, but no difference was noted for PD-L1 expression in both TC and IC,. Skip N2 metastases were associated with a higher TIL infiltration (mean 22.9% vs. 17.4% p=0.014). We found no significant correlation between PD-L1 or TIL infiltration with the number of mediastinal lymph nodes stations involved on pathological examination and with histological tumor subtypes (squamous cell carcinoma vs. adenocarcinoma).

      Conclusion

      PD-L1 expression levels in TC and IC appeared similar in stage IIIA N2 NSCLC as compared to other stages. Expression in both TC and IC strongly correlated with TIL infiltration, suggesting a prominently immune-induced expression mechanism. Preoperative chemotherapy was associated with a higher TIL infiltration but not higher PD-L1 expression. Patients with skip N2 metastases harbored a higher level of TIL density, a finding consistent with a more active immune microenvironment in this group of patients with better prognosis. These data will be subsequently updated on a larger number of patient and correlated to clinical follow-up.

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    P2.14 - Targeted Therapy (ID 183)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.14-53 - High MET Overexpression Does Not Predict the Presence of MET Exon 14 Splice Mutations in NSCLC: Results from the IFCT Predict.amm Study (ID 2324)

      10:15 - 18:15  |  Author(s): Fabrice Barlesi

      • Abstract
      • Slides

      Background

      MET exon 14 splice site (METex14) mutations were recently described in Non Small Cell Lung Cancer (NSCLC) and reported to correlate with efficacy of MET tyrosine kinase inhibitors. High diversity of these alterations make them hard to detect by DNA sequencing in clinical practice. Because METex14 mutations induce increased stabilization of the MET receptor, it is anticipated that these mutations are associated with MET overexpression. We aim to determine whether NSCLC with high MET overexpression could define a subset of patients with a high rate of METex14 mutations.

      Method

      From the IFCT Predict.amm cohort of 843 consecutive patients with a treatment-naïve advanced NSCLC who were eligible for a first-line therapy, 108 NSCLC samples with high MET overexpression defined by an immunochemistry (IHC) score 3+ were tested for METex14 mutations using fragment length analysis combined with optimized targeted next generation sequencing (NGS). MET copy number analysis was also derived from the sequencing data.

      Result

      METex14 mutations were detected in two patients (2.2%) who also displayed a TP53 mutation and a PIK3CA mutation, respectively. A MET gene copy number increase was observed in 7 additional patients (7.7%). NGS analysis revealed inactivating mutations in TP53 (52.7%) and PTEN (1.1%) and oncogenic mutations in KRAS (28.6%), EGFR (7.7%), PIK3CA (4.4%), BRAF (4.4%), NRAS (2.2%), GNAS (1.1%) and IDH1 (1.1%).

      Conclusion

      The rate of METex14 mutations in NSCLC with high MET overexpression was similar to that found in unselected NSCLC. Moreover, we observed a high frequency of driver alterations in other oncogenes. Consequently these findings do not support the use of MET IHC as a surrogate marker for METex14 mutations.

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    P2.18 - Treatment of Locoregional Disease - NSCLC (ID 191)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Treatment of Locoregional Disease - NSCLC
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.18-01 - A Multicenter, Double-Blind, Randomized, Controlled Study of Bintrafusp Alfa (M7824) in Unresectable Stage III NSCLC (Now Available) (ID 2200)

      10:15 - 18:15  |  Author(s): Fabrice Barlesi

      • Abstract
      • Slides

      Background

      The TGF-β pathway promotes tumor immunosuppression, and its inhibition may enhance the antitumor activity of PD-(L)1 monoclonal antibodies and reduce radiation-induced lung fibrosis. Bintrafusp alfa is an innovative first-in-class bifunctional fusion protein composed of the extracellular domain of TGF-βRII (a TGF-β “trap”) fused to a human IgG1 mAb blocking PD-L1. In a phase 1 study, second-line bintrafusp alfa therapy demonstrated promising antitumor activity in advanced non-small cell lung cancer (NSCLC) (NCT02517398). In preclinical studies, bintrafusp alfa plus radiotherapy showed enhanced antitumor activity compared with radiotherapy alone in mouse models. This study is evaluating the efficacy and safety of bintrafusp alfa with concurrent chemoradiation (cCRT) followed by bintrafusp alfa vs cCRT plus placebo followed by durvalumab in patients with unresectable stage III NSCLC.

      Method

      This global, multicenter, double-blind, randomized, controlled study of bintrafusp alfa (NCT03840902) includes adults with histologically documented stage III locally advanced, unresectable NSCLC, ECOG performance status ≤1, adequate pulmonary function, and life expectancy ≥12 weeks. Patients with tumors with actionable mutations (EGFR, ALK translocation, ROS-1 rearrangement) are also eligible. Mixed small cell lung cancer and NSCLC histology; pleural effusions greater than minimal, exudative, or cytologically positive; significant acute or chronic infections; prior chemotherapy or immune checkpoint inhibitor therapy for NSCLC; and current use of immunosuppressive medication are exclusion criteria. Patients are randomized to receive either bintrafusp alfa 1200 mg IV every 2 weeks (Q2W) with cCRT for 6 weeks followed by bintrafusp alfa 1200 mg IV Q2W (arm A) or placebo with cCRT for 6 weeks followed by durvalumab 10 mg/kg IV Q2W (arm B) until confirmed disease progression, unacceptable toxicity, or treatment ≤1 year. The primary endpoint is progression-free survival; secondary endpoints include overall survival, safety, lung function assessment, objective response, duration of response, pharmacokinetics, and immunogenicity. This phase 2 trial was activated on April 2, 2019 and first patient in is anticipated for May 22, 2019. Target enrollment: 350 patients.

      Result

      Section not applicable

      Conclusion

      Section not applicable

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    PL02 - Presidential Symposium including Top 7 Rated Abstracts (ID 89)

    • Event: WCLC 2019
    • Type: Plenary Session
    • Track:
    • Presentations: 1
    • Now Available
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      PL02.08 - Registrational Results of LIBRETTO-001: A Phase 1/2 Trial of LOXO-292 in Patients with RET Fusion-Positive Lung Cancers (Now Available) (ID 964)

      08:00 - 10:15  |  Author(s): Fabrice Barlesi

      • Abstract
      • Presentation
      • Slides

      Background

      No targeted therapy is currently approved for patients with RET fusion-positive non-small cell lung cancer (NSCLC). LOXO-292 is a highly selective RET inhibitor with activity against diverse RET fusions, activating RET mutations and brain metastases. Based on initial data from LIBRETTO-001, LOXO-292 received FDA Breakthrough Designation for the treatment of RET fusion-positive NSCLC in August 2018.

      Method

      This global phase 1/2 study (87 sites, 16 countries) enrolled patients with advanced RET-altered solid tumors including RET fusion-positive NSCLC (NCT03157128). LOXO-292 was dosed orally in 28-day cycles. The phase 1 portion established the MTD/RP2D (160 mg BID). The phase 2 portion enrolled patients to one of six cohorts based on tumor type, RET alteration, and prior therapies. The primary endpoint was ORR (RECIST 1.1). Secondary endpoints included DoR, CNS ORR, CNS DoR, PFS, OS, safety and PK.

      Result

      As of 17-June 2019, 253 RET fusion-positive NSCLC patients were treated. The primary analysis set (PAS) for LOXO-292 registration, as defined with the US FDA, consists of the first 105 consecutively enrolled RET fusion-positive NSCLC patients who received prior platinum-based chemotherapy; 58 patients (55%) also received prior anti PD-1/PD-L1 agents. The majority of PAS responders have been followed for ≥6 months from first response. Of the remaining 148 patients, 79 had previously been treated with platinum-based chemotherapy, 55 did not receive prior platinum-based chemotherapy and 14 did not have measurable disease at baseline.

      Among PAS patients, the investigator-assessed ORR was 68% (95% CI 58-76%, n=71/105, 2 PRs pending confirmation). Responses did not differ by fusion partner or the type or number of prior therapies, including chemotherapy, anti PD-1/PD-L1 agents and multikinase inhibitors with anti-RET activity. The median DoR was 20.3 months (95% CI 13.8-24.0) with a median follow-up of 8 months; as evidenced by the wide confidence interval, this DoR estimate is not statistically stable due to a low number of events (16 of 69 confirmed responders). The intracranial ORR was 91% (n=10/11: 2 confirmed CRs, 8 confirmed PRs) for patients with measurable brain metastases at baseline.

      The ORR in efficacy evaluable treatment naïve RET fusion-positive NSCLC patients was 85% (95% CI 69-95%, n=29/34, 7 PRs pending confirmation). In the safety data set of all 531 patients, 5 treatment-related AEs occurred in ≥15% of patients: dry mouth, diarrhea, hypertension, increased AST and increased ALT. Most AEs were grade 1-2. Only 9 of 531 (1.7%) patients discontinued LOXO-292 for treatment-related AEs.

      Conclusion

      LOXO-292 had marked antitumor activity in RET fusion-positive NSCLC patients and was well tolerated. These data will form the basis of an FDA NDA submission later this year.

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    PR02 - Press Conference (ID 387)

    • Event: WCLC 2019
    • Type: Press Conference
    • Track: Immuno-oncology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 10:30, CC7.1 A&B
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      PR02.05 - CheckMate 817: First-Line Nivolumab + Ipilimumab in Patients with ECOG PS 2 and Other Special Populations with Advanced NSCLC (ID 3608)

      09:45 - 10:30  |  Presenting Author(s): Fabrice Barlesi

      • Abstract
      • Slides

      Abstract not provided

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