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Luis Paz-Ares

Moderator of

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    OA02 - A New Vision of Targets and Strategies (ID 120)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Targeted Therapy
    • Presentations: 8
    • Now Available
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      OA02.01 - Alectinib in Previously Treated RET-Rearranged Advanced Non-Small-Cell Lung Cancer: A Phase 1/2 Trial (ALL-RET) (Now Available) (ID 1651)

      10:30 - 12:00  |  Presenting Author(s): Noriko Yanagitani  |  Author(s): Shinji Takeuchi, Toshinori Murayama, Kenichi Yoshimura, Yasuhito Imai, Shizuko Takahara, Takahiro Kawakami, Takashi Seto, Yoshihiro Hattori, Kadoaki Ohashi, Masahiro Morise, Shingo Matsumoto, Kiyotaka Yoh, Koichi Goto, Makoto Nishio, Seiji Yano

      • Abstract
      • Presentation
      • Slides

      Background

      RET rearrangements occur in 1–2% of non-small cell lung cancers (NSCLCs). Alectinib (300 mg twice daily) has been approved for the treatment of ALK-rearranged NSCLC in Japan; it also has a high activity against RET in vitro. A global trial (ALEX study) showed the efficacy and safety of alectinib (600 mg twice daily) in ALK-rearranged NSCLC patients. We conducted a phase 1/2 study of alectinib to establish the recommended dose (RD) and examined its activity in RET-rearranged Japanese NSCLC patients.

      Method

      This study was a single-arm, open-label, multi-institutional phase 1/2 trial. RET-rearranged NSCLC patients treated with at least one regimen of chemotherapy were recruited. RET rearrangements were screened using LC-SCRUM-Japan, a nationwide genomic screening network. In phase 1, alectinib (600 or 450 mg twice daily) was administered, following a 3 + 3 design. The primary endpoint was safety. During phase 2, alectinib at the RD defined in phase 1 was administered. The primary endpoint was the objective response rate in RET inhibitor-naïve patients.

      Result

      Between March 8, 2016 and January 29, 2018, 35 patients were enrolled, and 34 patients were administered alectinib. KIF5B-RET was the most common fusion gene (22 cases [63%]), and the CCDC6-RET fusion was identified in 8 cases. The remaining 5 cases were not distinguishable. In cohort 1 (600 mg twice daily), we observed 5 DLTs (grade 3 rash, increased aspartate aminotransferase, erythema multiforme, thromboembolic event, and increased CPK) in 3 of 6 patients. In accordance with the protocol, we moved to cohort 2 (450 mg twice daily) and observed no DLTs in 3 patients. Additionally, pharmacokinetic analysis indicated that the mean exposure (AUC0–10) of 600 mg twice daily was higher than that previously reported in AF-002JG trial (global phase 1 study). Therefore, we determined 450 mg twice daily as the RD for phase 2. Twenty-five RET inhibitor-naïve patients were treated with the RD, of whom 1 achieved an objective response (4%) and 13 achieved disease control at 8 weeks (52%) as determined by central review. The median progression-free survival was 3.4 months (95% CI 2.0-5.4), and the median overall survival was 19.0 months (5.4-NE). We observed grade 3 neutropenia, pneumonitis, diarrhea, hyponatremia, increased CPK and blood bilirubin (4%) in patients treated with 450 mg alectinib twice daily; no grade 4 adverse events were observed.

      Conclusion

      Alectinib had limited activity in patients with RET-rearranged NSCLC. Further investigation of new targeted therapeutics is required to improve outcomes for these patients.

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      OA02.02 - Phase 1 Study of Safety, Tolerability, P­­K and Efficacy of AMG 510, a Novel KRAS G12C Inhibitor, Evaluated in NSCLC (ID 1020)

      10:30 - 12:00  |  Presenting Author(s): Ramaswamy Govindan  |  Author(s): Marwan G Fakih, Timothy J Price, Gerald S Falchook, Jayesh Desai, James C Kuo, John H Strickler, John C Krauss, Bob T Li, Crystal S Denlinger, Greg Durm, Jude Ngang, Haby Henary, Gataree Ngarmchamnanrith, Erik Rasmussen, Phuong Khanh Morrow, David S. Hong

      • Abstract
      • Slides

      Background

      The KRASG12C mutation is found in approximately 14% of lung adenocarcinoma and 11% of NSCLC pts. Currently, no approved therapy targets this mutation. AMG 510 is a novel small molecule that specifically and irreversibly inhibits KRASG12C by locking it in an inactive GDP-bound state.

      Method

      A phase 1, first-in-human, open-label, multicenter study (NCT03600883) is evaluating the safety, tolerability, PK, and efficacy of AMG 510 in adult pts with locally-advanced or metastatic KRASG12C mutant solid tumors, including NSCLC pts. Safety is the primary endpoint; ORR (assessed every 6 wks), DOR, PFS, and PK are key secondary endpoints. Important inclusion criteria: KRASG12C mutation identified through DNA sequencing; measurable or evaluable disease; progression on standard therapy; ECOG PS ≤2; life expectancy >3 mo. Important exclusion criteria: active brain metastases; myocardial infarction within 6 mo. The maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) will be identified during the dose exploration. Once identified, additional pts with advanced solid tumors carrying the KRASG12C mutation will be enrolled during dose expansion. AMG 510 is given PO until disease progression, intolerance, or consent withdrawal.

      Result

      As of 4 April 2019, thirteen [5 men and 8 women; median age 63 yrs (range: 53–77)] of 35 pts enrolled in 4 dose exploration cohorts have NSCLC. These pts had a median of 3 (range: 1–5) prior lines of treatment (tx). On-study tx duration had a median of 59 days (range:9–192 d). No DLTs have been reported. Six NSCLC pts reported 10 treatment-related AEs (6 grade 1; 2 grade 2; 2 grade 3). The grade 3 related AEs were anemia in a pt with baseline grade 2 anemia and diarrhea lasting 2 d in a second pt. The most frequently reported AEs were decreased appetite (n=4 subjects) and diarrhea (n=3 subjects). Best tumor response has been evaluated in 10 NSCLC pts; 3 pts have not reached their first assessment. Of these 10 evaluable pts, 5 pts had a PR (2 of which are confirmed PRs), 4 had SD and 1 had PD. Of 13 NSCLC pts, 11 pts remain on-study and continue their AMG 510 and 2 pts have discontinued treatment due to PD during study wks 6 and 26.

      Conclusion

      AMG 510 has been well tolerated at all 4 dose levels explored and has shown antitumor activity when administered as monotherapy to pts with advanced KRASG12C mutant NSCLC. Enrollment is on-going.

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      OA02.03 - The Third Generation EGFR Inhibitor (EGFR-TKI) HS-10296 in Advanced NSCLC Patients with Resistance to First Generation EGFR-TKI (Now Available) (ID 766)

      10:30 - 12:00  |  Presenting Author(s): Shun Lu  |  Author(s): Qiming Wang, Guojun Zhang, Xiaorong Dong, Cheng-Ta Yang, Yong Song, Gee-Chen Chang, You Lu, Hongming Pan, Chao-Hua Chiu, Zhehai Wang, Jifeng Feng, Jianying Zhou, Xingxiang Xu, Renhua Guo, Jianhua Chen, Haihua Yang, Yuan Chen, Zhuang Yu, Her-Shyong Shiah, Chin-Chou Wang, Nong Yang, Jian Fang, Ping Wang, Kai Wang, Yanping Hu, Jianxing He, Ziping Wang, Jianhua Shi, Shaoshui Chen, Ying Cheng, Wu-Chou Su, Te-Chun Hsia, Jiuwei Cui, yuping Sun, Chih-Hsin Yang

      • Abstract
      • Presentation
      • Slides

      Background

      HS-10296 is an oral, potent, high selective third generation EGFR tyrosine-kinase inhibitor (EGFR-TKI) for sensitizing mutations, and the EGFR Thr790Met (T790M) resistance mutation which has been demonstrated by phase I study. This phase II, open-label, multicenter single-arm study was designed to confirm the efficacy and safety of HS-10296 in a large population of non-small-cell lung cancer (NSCLC) patients with EGFR T790M mutation, who had progressed after first generation EGFR-TKI treatment.

      Method

      Patients aged at least 18 years with centrally confirmed EGFR T790M-positive mutations, locally advanced or metastatic (stage IIIB/IV) NSCLC after first generation EGFR-TKI treatment received HS-10296 110 mg orally once daily until disease progression, or intolerable toxicity, or patient withdrawal. Patients with asymptomatic, stable brain metastases not requiring steroids were allowed to enroll. The primary endpoint was the objective response rate (ORR) by independent central review using Response Evaluation Criteria in Solid Tumors, version 1.1 every 6 weeks. Response endpoints (ORR and disease control rate [DCR]) were assessed in response analysis set. Secondary end points including progression-free survival (PFS), duration of response (DoR), depth of response (DepOR), overall survival (OS) and safety were evaluated in full analysis set. The final data cutoff was on Jan 5, 2019. The study is still ongoing.

      Result

      Totally, 244 patients (median age 60.8) entered study in 36 sites in mainland China (189 patients) and Taiwan (55 patients) between May 16, 2018 to Oct 23, 2018. 2 patients were excluded from the evaluable for response analysis set (n=242) due to absence of measurable disease at baseline by independent central review. At data cutoff, 182 (74.6%) patients remained on treatment. The median duration of follow-up was 4.7 months. 160 of 242 patients achieved confirmed partial responses by independent central review. The ORR was 66.1% (95% CI: 59.8-72.1). The DCR was 93.4% (95% CI: 89.5-96.2). The most common adverse reactions (≥ 10%) were blood creatine phosphokinase increased (43 [17.6%]), aspartate aminotransferase increased (29 [11.9%]), pruritus (28 [11.5%]), rash (28 [11.5%]) and alanine aminotransferase increased (26 [10.7%]). The most common all-causality grade 3 and 4 adverse events were blood creatine phosphokinase increased (14 [5.7%]) and hyponatraemia (4 [1.6%]). Serious adverse events were reported in 30 (12.3%) patients, of which 19 (7.8%) were investigator assessed as possibly treatment-related to HS-10296. Three deaths were due to adverse events; one was related to cardiopulmonary failure, other two events occurred after disease progression. There was no interstitial lung disease during study treatment.

      Conclusion

      HS-10296 has demonstrated good clinical benefit with minimal toxicity in patients with EGFR T790M-positive NSCLC patients who have progressed after first generation EGFR-TKI treatment. The Phase III study has already launched comparing HS-10296 with gefinitib in advanced NSCLC patients with EGFR sensitizing mutations. (The study was sponsored by Jiangsu Hansoh Pharmaceutical Co., Ltd.; ClinicalTrials.gov number, NCT02981108)

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      OA02.04 - Discussant - OA02.01, OA02.02, OA02.03 (Now Available) (ID 3726)

      10:30 - 12:00  |  Presenting Author(s): Jon Zugazagoitia

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      OA02.05 - First-In-Human Phase 1/2 Trial of Anti-AXL Antibody–Drug Conjugate (ADC) Enapotamab Vedotin (EnaV) in Advanced NSCLC (Now Available) (ID 343)

      10:30 - 12:00  |  Presenting Author(s): Suresh S Ramalingam  |  Author(s): Juanita Lopez, Morten Mau-Sorensen, Fiona Thistlethwaite, Sarina Piha-Paul, Shirish Gadgeel, Yvette Drew, Pasi A Jänne, Aaron S. Mansfield, Guang Chen, Ulf Forssmann, Hrefna Kristin Johannsdottir, Nora Pencheva, Annette Ervin-Haynes, Ignace Vergote

      • Abstract
      • Presentation
      • Slides

      Background

      AXL, a transmembrane receptor tyrosine kinase, is aberrantly expressed in various cancers, and associated with poor prognosis and treatment resistance. AXL overexpression is associated with resistance to PD-1 immune checkpoint inhibitors (Hugo et al. 2016). EnaV, a novel ADC of anti-AXL human IgG1 and monomethyl auristatin E, demonstrated potent anti-tumor activity in preclinical models, including NSCLC (Boshuizen et al. 2018). In a phase 1, dose escalation, multi-cohort trial (NCT02988817) in heavily pretreated patients with relapsed or refractory solid tumors, EnaV 2.2 mg/kg once every 3 weeks (1Q3W; recommended phase 2 dose) showed preliminary anti-tumor activity. Here we present initial results from patients with NSCLC in the phase 2a, expansion phase of this trial.

      Method

      We analyzed data from EnaV 2.2 mg/kg 1Q3W, in the cohort of pretreated patients with stage III/IV NSCLC without sensitizing EGFR mutations (EGFR WT) or ALK rearrangements (ALK-) who had failed ≤4 prior lines of therapy, including platinum-based chemotherapy and PD-1/PD-L1 inhibitor (either in combination or sequentially). Endpoints include safety, objective response rate (ORR; RECIST 1.1), and AXL expression in fresh tumor biopsies (immunohistochemistry).

      Result

      In the EGFR WT/ALK- cohort, 26 patients (median age 65.5 years, range 38–74; 57.7% male) with ECOG PS of 0 (11.5%) or 1 (88.5%) have been enrolled. Most patients (23/26) were treated with a checkpoint inhibitor. At a median follow-up of 18 weeks (range: 2–54), the most common (≥20%; any grade) treatment-emergent adverse events (TEAEs) were fatigue, constipation, nausea, decreased appetite, decreased weight, diarrhea, and vomiting. Two patients had a TEAE leading to dose reduction. Grade ≥3 TEAEs occurred in 12 patients, with the most common being gastrointestinal disorders in eight patients (constipation [n=1]; colitis, diarrhea, nausea, vomiting [n=2 each]; abdominal distension [n=1]. The confirmed ORR is 19% (95% CI: 8.5%, 37.9%). The disease control rate (CR+PR+SD) is 50% (13/26). Nine of 12 (75%) evaluable fresh biopsies were positive for AXL tumor cell staining.

      Conclusion

      In this high unmet need patient population, with advanced EGFR WT and ALK- NSCLC who are pretreated with PD-1/PD-L1 inhibitors and platimum-based therapies, EnaV monotherapy demonstrated a manageable safety profile and encouraging preliminary clinical activity. This cohort has expanded to allow up to 60 patients to gain further knowledge of AXL as a potential biomarker for responsiveness to EnaV and to gather additional data on safety and efficacy. Funding: Genmab A/S

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      OA02.06 - The Sequential Therapy of Crizotinib Followed by Alectinib: Real World Data of 840 Patients with NSCLC Harboring ALK-Rearrangement (WJOG9516L) (Now Available) (ID 2145)

      10:30 - 12:00  |  Presenting Author(s): Satomi Watanabe  |  Author(s): Takeharu Yamanaka, Kentaro Ito, Shinya Sakata, Haruko Daga, Takashi Kijima, Katsuya Hirano, Isamu Okamoto, Atsushi Nakamura, TOSHIYUKI Kozuki, Mikiko Ishihara, Koichi Azuma, Takashi Seto, Toshihide Yokoyama, Yuko Oya, Haruki Kobayashi, Kazumi Nishino, Yoshihiro Hattori, Kazuhiko Nakagawa, Nobuyuki Yamamoto

      • Abstract
      • Presentation
      • Slides

      Background

      Previous clinical trials demonstrated that alectinib (ALEC) had a longer time-to-progression than crizotinib (CRZ) in 1st-line settings. Information on long-term overall survival (OS), however, is still limited with a few studies having reported that the sequential strategy of CRZ followed by other ALK-inhibitorcan provide extended OS. In Japan, ALEC was approved for a 1st-line setting earlier than in other countries.

      Method

      We reviewed the clinical data of ALK-rearranged NSCLC patients who received CRZ or ALEC between May 2012 and Dec 2016. Patients were divided into two groups according to the first-administered ALK inhibitor, the CRZ or ALEC group. In order to evaluate the efficacy of the sequential strategy of CRZ followed by ALEC, the combined time to treatment failure (TTF) was calculated in the CRZ group as defined by the sum of the TTF of CRZ plus the TTF of ALEC if patients were treated with ALEC followed by CRZ. In the ALEC group, the TTF of ALEC was calculated. The primary endpoint is the comparison between the combined TTF in the CRZ group with the TTF in the ALEC group.

      Result

      Of 864 patients enrolled from 61 institutions, 840 patients were analyzed. Median age was 61 (range, 20-94); 56% were female; and 95% had adenocarcinoma. There were 535/305 patients in the CRZ/ALEC group. In the CRZ group, 282 patients received ALEC after CRZ failure. The combined TTF in the CRZ group was significantly longer than TTF in the ALEC group; median, 34.4 vs 27.2 months (mo); hazard ratio (HR), 0.709 [95%CI;0.559- 0.899]; P=0.0044. However, there was no significant difference in OS between the patients who received ALEC after CRZ in the CRZ group and the patients in the ALEC group; median, 88.4 months vs. not reached; HR 1.048 [95%CI;0.758-1.451]; P=0.7770. In the whole population, the CRZ group had a significantly shorter OS than the ALEC group; median, 53.6 mo vs not reached HR, 1.821 [95%CI;1.372-2.415]; P<0.0001.

      Conclusion

      The combined TTF in the CRZ group was significantly longer than TTF in the ALEC group, however, OS benefit of sequential therapy of CRZ followed by ALEC was not shown.

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      OA02.07 - Phase 3 ALUR Study of Alectinib in Pretreated ALK+ NSCLC: Final Efficacy, Safety and Targeted Genomic Sequencing Analyses (Now Available) (ID 2267)

      10:30 - 12:00  |  Presenting Author(s): Juergen Wolf  |  Author(s): Åslaug Helland, In-Jae Oh, Maria Rita Migliorino, Rafal Dziadziuszko, Javier De Castro Carpeno, Julien Mazieres, Frank Griesinger, Marijana Chlistalla, Andres Cardona, Thorsten Ruf, Kerstin Trunzer, Vlatka Smoljanovic, Silvia Novello

      • Abstract
      • Presentation
      • Slides

      Background

      The ALUR (NCT02604342) primary analysis (cut-off January 2017) demonstrated improved efficacy and safety with alectinib versus chemotherapy in patients with ALK+ NSCLC previously treated with chemotherapy and crizotinib. These patients can develop crizotinib resistance through ALK secondary mutations, but limited data exist regarding alectinib’s efficacy in patients with different post-crizotinib genetic profiles. We report final data from ALUR including treatment outcomes according to genetic profile.

      Method

      Overall, 119 patients with locally determined ALK+ NSCLC were randomised 2:1 to receive alectinib 600mg bid or chemotherapy (pemetrexed 500mg/m2 or docetaxel 75mg/m2 q3w). The primary endpoint was PFS by investigator. Targeted genomic sequencing (FoundationONE® [tissue; 315 genes] and FoundationACT® [plasma; 62 genes]) was performed retrospectively using tumour tissue (n=33) and baseline plasma (n=59).

      Result

      Final efficacy data confirmed those of the primary analysis (table). Grade ≥3 treatment-emergent adverse events were lower with alectinib (37.7%) than with chemotherapy (43.2%); adverse events causing treatment discontinuation were lower with alectinib (5.2% versus 10.8% chemotherapy), despite alectinib’s longer treatment duration. ALK fusions were confirmed retrospectively in 26/33 (78.8%) tissue and 41/59 (69.5%) plasma (post-crizotinib) samples. ORR in alectinib-treated patients with ALK fusions was 72.2% (13/18, tissue) and 63.0% (17/27, plasma) versus 0% for chemotherapy (tissue [0/8], plasma [0/14]). ALK secondary mutations were detected in 16/59 (27.1%) patients (plasma, both arms). ORR in the alectinib arm (plasma) was similar in patients with ALK fusions with (60.0%, 6/10) or without (64.7%, 11/17) ALK secondary mutations, but lower in patients with gene mutations other than ALK (23.1%, 3/13).

      Conclusion

      Final data from ALUR confirm the primary analysis, demonstrating improved efficacy and safety with alectinib versus chemotherapy in post-crizotinib ALK+ NSCLC. The role of reconfirming ALK status upon sequential ALK inhibitor treatment requires further investigation, due to the limited data and known technical challenges of plasma testing.

      Funding: F. Hoffmann-La Roche Ltd.

      table.jpg

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      OA02.08 - Discussant - OA02.05, OA02.06, OA02.07 (Now Available) (ID 3727)

      10:30 - 12:00  |  Presenting Author(s): Michael Duruisseaux

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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Author of

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    JCSE01 - Joint IASLC-CSCO-CAALC Session (ID 63)

    • Event: WCLC 2019
    • Type: Joint IASLC-CSCO-CAALC Session
    • Track:
    • Presentations: 1
    • Now Available
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      JCSE01.06 - New Era Beyond PD-1/PD-L1 (Now Available) (ID 3420)

      07:00 - 11:15  |  Presenting Author(s): Luis Paz-Ares

      • Abstract
      • Presentation
      • Slides

      Abstract

      Over the past few years, targeting immune checkpoints such as PD-1/PD-L1 (and in some extend CTLA-4) has changed the landscape of lung cancer therapy and largely impacted patients with notable therapeutic benefits. However, not all lung cancer patients respond to immune checkpoint inhibitors and actually only some 15-20% of those with metastatic disease achieve long term survival, reflecting to the complexity of immune checkpoints and daunting tumor resistance. In order to broaden the possibilities of lung cancer immunotherapy, we need to seek alternative immune checkpoints beyond PD-1/ PD-L1, test novel combination strategies of immune checkpoint inhibitors and more conventional treatments, and increase the predictive potential of biomarkers to optimally guide clinical practice. Meanwhile, there are a number of unsolved questions that may require our attention for future better clinical performance.

      The wide range of immune-related adverse effects (irAEs) that accompany immune checkpoint inhibitors can complicate this efficacious immunotherapy and restrict its use in cancer patients. The precise pathophysiology underlying irAEs is frequently unknown, but may be related to breaking the balance of immunologic homeostasis. Although any organ system is possibly influenced, irAEs most commonly involve the gastrointestinal tract, endocrine glands, and skin. Most of the toxic effects are reversible, but deaths due to severe irAEs such as myocarditis and pneumonitis can occur. The serious problem of irAEs particularly requires to define optimal strategies for multidisciplinary and collaborative management, and ad-hoc education programs. Of note, recent data suggest that prophylactic TNF blockade uncouples efficacy and toxicity in dual CTLA-4 and PD-1 immunotherapy.

      The clinical therapeutic efficacy of immune checkpoint inhibitors remains controversial. Tumor resistance, primary and acquired, is a daunting challenge that limits the responsiveness to immunotherapy, and deserves intensive investigation. Hyperprogressive disease (HPD) following immunotherapy also deserve adequate attention. Evidence suggests that MDM2 family amplification or EGFR, KEAP and LKB1 aberrations may lead to poor clinical outcomes on IO treatment and may account for the risk of HPD.

      Preclinical and clinical testing of alternative immune checkpoints is mandatory, particularly in programs that coupled a biomarker driven strategy. It is noteworthy that tumor infiltrating T cells can simultaneously express PD-1/PD-L1 along with other immune checkpoints. Also, evidence has delineated that upregulation of compensatory inhibitory molecules such as LAG-3, VISTA, and TIM-3 may mediate tumor resistance to immune checkpoint inhibitors. Understanding the precise molecular mechanisms of different immune checkpoints will benefit the design of effective combination therapies and overcome potential resistance.

      More well-designed combination strategies (antiangiogenics, targeted therapies, chemotherapeutics,...) that can yield remarkable and synergistic clinical benefits are critical for immune checkpoint therapy. To optimize the combination therapies, we should carefully explore effective and safe doses of treatments, sequencing of the agents, appropriate timing, and so on. There is a pressing need to study the indepth mechanisms of the interaction between chemo-radiotherapy or targeted therapy and the immune system. In addition, identifying more combinations of immune checkpoint inhibitors and new treatment approaches such as by-specific antibodies, chimeric antigen receptor T cell (CAR-T) immunotherapy, TILs, modulating the microbioma and tumor vaccines is a tantalizing option.

      Finally, due to the complexity of the immune system, developping and validating a multiparametic model of predictive biomarkers is much required. As mentioned earlier, PD-L1 expression can inform treatment decisions, but its clinical value still needs confirmation in different patient cohorts. Meanwhile, certain genomic tumor aberrations, TMB and TME are future directions for routine clinical practice. Different TIL phenotypes, diverse TCRs, immune gene signatures, and genetic features derived from blood monitoring or TME hold high potential, but are ready for clinical use as yet.

      References

      Kato S, Goodman A, Walavalkar V, Barkauskas DA, Sharabi A, Kurzrock R. Hyperprogressors after Immunotherapy: Analysis of Genomic Alterations Associated with Accelerated Growth Rate. Clin Cancer Res. 2017; 23: 4242-4250.

      Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med. 2018;378(2):158–68.

      Kato S, Goodman A, Walavalkar V, Barkauskas DA, Sharabi A, Kurzrock R. Hyperprogressors after immunotherapy: analysis of genomic alterations associated with accelerated growth rate. Clin Cancer Res. 2017;23(15):4242–50.

      Teixeira VH, Pipinikas CP, Pennycuick A, Lee-Six H, Chandrasekharan D, Beane J, et al. Deciphering the genomic, epigenomic, and transcriptomic landscapes of pre-invasive lung cancer lesions. Nat Med. 2019; 25: 517-525.

      Turajlic S, Sottoriva A, Graham T, Swanton C. Resolving genetic heterogeneity in cancer. Nat Rev Genet. 2019; 20:404-416.

      Rosenthal R, Cadieux EL, Salgado R, Bakir MA, Moore DA, Hiley CT, et al. Neoantigen-directed immune escape in lung cancerevolution. Nature. 2019; 567:479-485.

      Wrangle JM, Patterson A, Johnson CB, Neitzke DJ, Mehrotra S, Denlinger CE, et al. IL-2 and Beyond in Cancer Immunotherapy. J Interferon Cytokine Res. 2018; 38:45-68.

      Naing A HJ, Papadopoulos KP et al. Responses and durability of clinical benefit in renal cell carcinoma treated with pegilodecakin in combination with anti-PD-1 inhibitors (oral presentation). Presented at: European Society of Medical Oncology.2018.

      Naing A, Papadopoulos KP, Autio KA, et al. Safety, antitumor activity, and immune activation of pegylated recombinant human interleukin-10 (AM0010) in patients with advanced solid tumors. J Clin Oncol. 2016;34(29):3562–9.

      Paz-Ares L, Kim TM, Vincente D, Felip E, Lee DH, LeeKH,. Et al. Updated results of M7824 (MSB0011359C), a bifunctional fusion protein targeting TGF-B and PD-L1, in second-line (2L) NSCLC. Annals of Oncology 2018; 29 (suppl_8): viii493-viii547.

      Ben-Avi R, Farhi R, Ben-Nun A, Gorodner M, Greenberg E, Markel G, et al. Establishment of adoptive cell therapy with tumor infiltrating lymphocytes for non-small cell lung cancer patients. Cancer Immunol Immunother. 2018; 67:1221-1230.

      Lan Y, Zhang D, Xu C, Hance KW, Marelli B, Qi J, et al. Enhanced preclinical antitumor activity of M7824, a bifunctional fusion protein simultaneously targeting PD-L1 and TGF-β. Sci Transl Med. 2018; 17;10(424).

      Strauss J, Heery CR, Schlom J, Madan RA, Cao L, Kang Z, Lamping E, et al. Phase I Trial of M7824 (MSB0011359C), a Bifunctional Fusion Protein Targeting PD-L1 and TGFβ, in Advanced Solid Tumors. Clin Cancer Res; 24(6):1287-1295.

      Zitvogel L, Ma Y, Raoult D, Kroemer G, Gajewski TF. The microbiome in cance immunotherapy: Diagnostic tools and therapeutic strategies. Science. 2018; 23; 359: 1366-1370.

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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: 2
    • Now Available
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      MA14.02 - Entrectinib in Patients with ROS1-Positive NSCLC or NTRK Fusion-Positive Solid Tumors with CNS Metastases (Now Available) (ID 1631)

      15:45 - 17:15  |  Presenting Author(s): Luis Paz-Ares

      • Abstract
      • Presentation
      • Slides

      Background

      Entrectinib potently inhibits kinases encoded by NTRK and ROS1 genes. It achieves therapeutic levels in the CNS with antitumor activity in intracranial tumor models. We report integrated analysis data (31 May 2018 data cut-off) from three Phase 1/2 entrectinib trials (ALKA-372-001 [EudraCT 2012-000148-88]; STARTRK-1 [NCT02097810]; STARTRK-2 [NCT02568267]) for a large cohort of adult patients with NTRK fusion-positive solid tumors (NTRK+) or ROS1 fusion-positive NSCLC (ROS1+), with baseline CNS metastases.

      Method

      Patients had locally advanced/metastatic NTRK+ solid tumors or ROS1+ NSCLC by nucleic acid-based assays confirmation. Baseline CNS metastases were identified by CT/MRI. Tumor assessments were performed at baseline, week 4, and then every 8 weeks by blinded independent central review (RECIST v1.1). Primary endpoints were overall response rate (ORR), duration of response (DOR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), intracranial efficacy in patients with CNS metastases, safety.

      Result

      Most patients were treated first-line or after one line of prior therapy; baseline characteristics relating to measurable CNS metastases for patients with NTRK+ solid tumors and ROS1+ NSCLC are presented (Table). Intracranial outcomes for the NTRK+ solid tumors (n=54; 18% NSCLC) and ROS1+ NSCLC (n=53) efficacy evaluable populations are reported (Table). Durability of treatment effect and potential delayed progression in the CNS was observed; time to CNS progression was 17.0 months (95% CI: 14.3–NE) for NTRK+ solid tumor patients and NE (95% CI: 15.1–NE) for ROS1+ NSCLC. In the subset of patients with NTRK+ NSCLC (n=10), 6 patients had CNS metastases at baseline (by BICR); IC-ORR was 66.7% (4/6), 2 CR; IC-DOR was NE. In both the NTRK+ and ROS1+ populations, entrectinib was tolerable with a manageable safety profile; most treatment-related AEs were grade 1–2.

      Conclusion

      Entrectinib induced clinically meaningful durable responses in patients with NTRK+ solid tumors or ROS1+ NSCLC with CNS disease at baseline.

      Funding: This study was funded by F. Hoffmann-La Roche

      table.jpg

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      MA14.07 - Phase I Expansion Cohort of Ramucirumab Plus Pembrolizumab in Advanced Treatment-Naïve Non-Small Cell Lung Cancer (JVDF) (Now Available) (ID 209)

      15:45 - 17:15  |  Author(s): Luis Paz-Ares

      • Abstract
      • Presentation
      • Slides

      Background

      Emerging data suggest blockade of vascular endothelial growth factor receptor 2 (VEGFR-2) with ramucirumab (R) and programmed cell death 1 protein (PD-1) with pembrolizumab (P) has anti-tumor activity. The JVDF study (NCT02443324) evaluated the safety and efficacy of R+P in locally advanced and unresectable or metastatic gastric/gastroesophageal junction adenocarcinoma, non-small cell lung cancer (NSCLC), urothelial carcinoma, and biliary tract cancer. Data from NSCLC patients receiving R+P as first-line therapy are reported.

      Method

      Eligible patients had treatment-naïve, PD-L1 positive, histopathologically confirmed nonsquamous or squamous NSCLC and received R 10 mg/kg and P 200 mg on Day 1 every 21 days for up to 35 cycles until confirmed disease progression or discontinuation for other reasons. Response and progression were assessed using RECIST 1.1 with confirmatory scans. PD-L1 was assessed using the PD-L1 IHC 22C3 pharmDx assay; PD-L1 positivity was defined as a tumor proportion score (TPS) ≥1%.

      Result

      As of August 31, 2018, 26 patients were treated. Baseline characteristics were as expected for an advanced, treatment-naïve population. Median follow-up was 17.4 (13.4, 20.1) months. Adverse events were consistent with R+P, with no additive toxicities. Eleven (42.3%) patients experienced Grade ≥3 treatment-related adverse events (TRAEs), most commonly hypertension (15.4%) and myocardial infarction (7.7%). No patients discontinued because of TRAEs; the two on-study deaths were due to disease progression. Efficacy results are shown in the table.

      table.jpg

      Conclusion

      In previously untreated NSCLC, R+P has a manageable safety profile and is active in patients with PD-L1 expression. Updated results will be presented at the meeting. Randomized trials in this population are warranted.

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    MA25 - Precision Medicine in Advanced NSCLC (ID 352)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
    • +

      MA25.01 - Pembrolizumab Plus Chemotherapy for Advanced NSCLC Without Tumor PD-L1 Expression: Pooled Analysis of KN021G, KN189 and KN407 (Now Available) (ID 1399)

      14:30 - 16:00  |  Author(s): Luis Paz-Ares

      • Abstract
      • Presentation
      • Slides

      Background

      Randomized studies have demonstrated that pembrolizumab plus chemotherapy improves OS, PFS, and ORR compared with chemotherapy alone in patients with advanced NSCLC regardless of tumor PD-L1 expression level. We present a post hoc pooled analysis of pembrolizumab plus chemotherapy versus chemotherapy alone in patients with advanced NSCLC and no PD-L1 expression (ie, TPS <1%), representing an area of unmet need.

      Method

      Patients enrolled in KEYNOTE-021 cohort G (nonsquamous; NCT02039674), KEYNOTE-189 (nonsquamous; NCT02578680), and KEYNOTE-407 (squamous; NCT02775435) were included. Patients with nonsquamous NSCLC were randomized to pemetrexed-platinum with or without pembrolizumab; those with squamous NSCLC were randomized to carboplatin-paclitaxel/nab-paclitaxel with or without pembrolizumab. OS, PFS, and ORR were evaluated for the pooled intent-to-treat population. Response was assessed per RECIST v1.1 by blinded independent central review. Across studies, PD-L1 expression was assessed centrally using PD-L1 IHC 22C3 pharmDx assay (Agilent Technologies, Carpinteria, CA). Analyses were descriptive.

      Result

      Of 1298 patients enrolled across the 3 trials, 428 (33%) had PD-L1 TPS <1% (pembrolizumab plus chemotherapy, n=243; chemotherapy alone, n=185) and were included in this analysis. 52% had nonsquamous histology, 63% had ECOG PS of 1. Median (range) follow-up at data cutoff was 10.2 (0.1‒34.9) months. OS, PFS, and ORR were improved with pembrolizumab plus chemotherapy versus chemotherapy alone (Table). Grade ≥3 AEs (all-cause) occurred in 68% of patients receiving pembrolizumab plus chemotherapy versus 72% receiving chemotherapy alone. Immune-mediated AEs and infusion reactions occurred in 26% who received pembrolizumab plus chemotherapy versus 12% who received chemotherapy alone.

      Pembrolizumab + Chemotherapy

      n=243

      Chemotherapy
      Alone

      n=185

      Median (95% CI) OS, mo

      19.0 (15.2–24.0)

      11.0 (9.2–13.5)

      Hazard ratio (95% CI)

      0.56 (0.43–0.73)

      Median (95% CI) PFS, mo

      6.5 (6.2–8.5)

      5.4 (4.7–6.2)

      Hazard ratio (95% CI)

      0.67 (0.54–0.84)

      ORR, % (95% CI)

      46.9% (40.5%–53.4%)

      28.6% (22.3%–35.7%)

      Difference (95% CI)

      18.3% (9.0%–27.1%)

      Conclusion

      Our results highlight the clinically meaningful efficacy benefit and acceptable safety profile of pembrolizumab plus chemotherapy versus chemotherapy alone in patients with advanced NSCLC and no PD-L1 expression. Benefit was consistent with that observed in the overall study populations, suggesting pembrolizumab plus chemotherapy should be considered standard-of-care first-line therapy for all patients with NSCLC, irrespective of PD-L1 expression.

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    OA03 - Systemic Therapies for SCLC: Novel Targets and Patients' Selection (ID 121)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 1
    • Now Available
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      OA03.03 - Initial Efficacy and Safety Results of Irinotecan Liposome Injection (nal-IRI) in Patients with Small Cell Lung Cancer (Now Available) (ID 1985)

      13:30 - 15:00  |  Presenting Author(s): Luis Paz-Ares

      • Abstract
      • Presentation
      • Slides

      Background

      SCLC accounts for ~15% of lung cancers, with 5-year survival <10%. 50-90% of patients with extensive disease respond to initial treatment; many rapidly relapse due to acquired resistance to front-line platinum-based chemotherapy. Limited treatment options are available for second-line patients. nal-IRI is a liposomal formulation of irinotecan (topoisomerase-1 inhibitor), utilizing intraliposomal stabilization technology to enable high drug load and in-vivo stability.

      Method

      RESILIENT (NCT03088813) is a two-part Phase 2/3 study assessing the safety, tolerability, and efficacy of monotherapy nal-IRI in SCLC patients who progressed on/after a front-line platinum regimen: Part 1 includes dose-finding then dose-expansion. Key eligibility criteria included ECOG PS 0-1 and adequate organ function, with prior exposure to immunotherapy allowed. Eligible patients received nal-IRI 70mg/m2 or 85mg/m2 (free-base equivalent) q2w. Primary endpoints were safety and tolerability. Efficacy assessments included objective response rate (ORR), best overall response (BOR), progression-free survival (PFS), and overall survival (OS).

      Result

      30 patients were treated for >12 weeks in Part 1 (male, 43%; median age, 60.4y; platinum-resistant, 40%) with tumor assessments q6w. During dose-finding, 5 patients received nal-IRI 85mg/m2 (deemed not tolerable: dose-limiting toxicity) and 12 patients received nal-IRI 70mg/m2 (deemed tolerable: selected for dose expansion). At data cut-off** (median follow-up, 4.4mo), 25 patients had received nal-IRI 70mg/m2. Diarrhea was the most common gastrointestinal adverse events (AEs) (Gr3, 20%). Hematologic AEs included neutropenia (Gr3, 8%; Gr4, 8%), anemia (Gr3, 8%), febrile neutropenia (Gr3, 4%), thrombocytopenia (Gr3, 4%; Gr4, 4%). Preliminary efficacy identified 11 patients with partial responses (ORR 44%), BOR (PR+SD) of 72%, and 12-week disease control rate (DCR12wks PR+SD) of 48%. PFS and OS are not yet mature.

      Conclusion

      Part 1 demonstrated encouraging anti-tumor activity for nal-IRI 70mg/m2 in patients with SCLC (ORR: 44%, BOR: 72%). nal-IRI 70mg/m2 was generally well tolerated. Future research is warranted to assess nal-IRI in second-line SCLC.

      Table 1. Baseline Demographic, Patient Disposition, Safety & Tolerability, and Clinical Efficacy for Part 1 of the RESILIENT study

      Dose-Finding /
      Dose-Exploration Phase
      Irinotecan
      Liposome
      Injection
      85mg/m2
      (N=5)
      Irinotecan
      Liposome
      Injection
      70mg/m2
      (N=25)
      Baseline Characteristics
      Gender, Male, n (%) 3 (60.0) 10 (40.0)
      Age (Years, median) 62.0 59.0
      Baseline ECOG
      0 1 (20.0) 3 (12.0)
      1 4 (80.0) 22 (88.0)
      Time Since Most Recent Progression (Weeks, median) 3.4 3.2
      Disease Location, n (%)
      Locally Advanced 0 2 (8.0)
      Metastatic 5 (100.0) 23 (92.0)
      Disposition, n (%)
      Patient Completed Study 4 (80.0) 12 (48.0)
      Patient Currently Ongoing* 7 (28.0)
      Deaths 2 (40.0) 6 (24.0)
      Disease Related 1 3
      Adverse Event Not Related to Study Drug 1 1
      Cardiac Arrest 1 -
      Hepatic Failure - 1
      Adverse Event Related to Study Drug 0 2
      Abdominal Sepsis - 2
      Patient Discontinued Treatment 5 (100.0) 18 (72.0)
      Safety & Tolerability, n (%)
      Any Treatment-Emergent Adverse Event (TEAE) 5 (100.0) 25 (100.0)
      Grade 3 or Higher TEAE (≥ 2 patients) 5 (100.0) 15 (60.0)
      Neutropenia 1 (20.0) 4 (16.0)
      Anemia 2 (8.0)
      Thrombocytopenia 2 (8.0)
      Diarrhea 3 (60.0) 5 (20.0)
      Asthenia 2 (8.0)
      General Physical Health Deterioration 2 (8.0)
      Pneumonia 2 (40.0) 1 (4.0)
      Abdominal Sepsis 2 (8.0)
      Hypokalemia 1 (20.0) 2 (8.0)
      Renal Failure 2 (8.0)
      Best Overall Response
      Complete Response (CR)
      Partial Response (PR) 2 (40.0) 11 (44.0)
      Stable Disease 1 (20.0) 7 (28.0)
      Progressive Disease 1 (20.0) 5 (20.0)
      Non-evaluable 1 (20.0) 2 (8.0)
      Objective Response Rate
      CR + PR 2 (40.0) 11 (44.0)
      Non-responder 3 (60.0) 14 (56.0)
      ** Data Cut-off: May 8, 2019.
      * Per RECIST v1.1 or RANO criteria.

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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  |  Author(s): Luis Paz-Ares

      • 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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    OA08 - Advanced Models and "Omics" for Therapeutic Development (ID 133)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Biology
    • Presentations: 1
    • Now Available
    • +

      OA08.05 - Notch Inhibition Overcomes Resistance to Tyrosine Kinase Inhibitors Promoted by Gate-Keeper Mutations in EGFR-Driven Lung Adenocarcinoma  (Now Available) (ID 639)

      11:00 - 12:30  |  Author(s): Luis Paz-Ares

      • Abstract
      • Presentation
      • Slides

      Background

      EGFR mutated lung adenocarcinoma patients treated with gefitinib and osimertinib showed a therapeutic benefit limited by the appearance of secondary mutations, such as EGFRT790M and EGFRC797S. It has been generally assumed that these secondary mutations render EGFR completely unresponsive to the inhibitors, indicating that the use of single drug to treat efficiently EGFR-driven lung adenocarcinoma might have limited value while a strategy based on combinational drug therapy could be more effective at mitigating the effects of gatekeeper mutations.

      Method

      We have combined the use of EGFR-driven genetic engineered mouse models and patient-derived xenografts, adenocarcinoma cell lines and primary samples from EGFR mutated patients.

      Result

      We uncover here that gefitinib and osimertinib increase STAT3 phosphorylation (pSTAT3) in EGFRT790M and EGFRC797S tumoral cells. Interestingly, we also found that concomitant Notch inhibition with gefitinib or osimertinib treatment induces a pSTAT3-dependent strong reduction in the levels of the transcriptional repressor HES1. Importantly, we show that tyrosine kinase inhibitor resistant tumors, with EGFRT790M and EGFRC797S mutations, are highly responsive to the combined treatment of Notch inhibitors with gefitinib and osimertinib respectively. Finally, in patients with EGFR mutations treated with tyrosine kinase inhibitors, HES1 protein levels increase during relapse and correlate with shorter progression-free survival.

      Conclusion

      Our results show that the Notch pathway plays a major role in the relapse of lung adenocarcinoma patients treated with EGFR TKIs, providing a rationale to treat patients that become resistant to EGFR TKI with a combination of the same TKI and Notch inhibitors.

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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): Luis Paz-Ares

      • 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: 1
    • 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): Luis Paz-Ares

      • 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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    P1.12 - Small Cell Lung Cancer/NET (ID 179)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.12-03 - Antitumor Activity of Single Agent Lurbinectedin in Patients with Relapsed SCLC Occurring ≥30 Days After Last Platinum Dose (ID 1710)

      09:45 - 18:00  |  Author(s): Luis Paz-Ares

      • Abstract
      • Slides

      Background

      Lurbinectedin (L) inhibits activated transcription and induces DNA double-strand breaks, leading to apoptosis.

      Method

      This multicenter, single agent, phase II Basket trial treated a cohort of 105 SCLC patients (pts) with ECOG PS 0-2 who had received one prior chemotherapy line. L 3.2 mg/m2 was administered as a 1-hour i.v. infusion on Day 1 q3wk. Primary endpoint, confirmed overall response rate (ORR) by RECIST v.1.1 according to investigator assessment, was met (ORR=35.2%; 95% CI, 26.2-45.2%). A sub-analysis excluding the 21 pts with disease relapse < 30 days after last platinum dose is reported here.

      Result

      Median age of 84 evaluated pts was 60 years (range, 41-83), 58.3% were male, ECOG PS 0-1/2 in 96/4%, liver metastasis in 36.9%, history of CNS involvement in 4.8%, prior platinum in 100%, median chemotherapy-free interval (CTFI)=3.9 months (1.1-16.1); prior immunotherapy in 8.3%. A median of 5.5 cycles (range, 1-24) was administered.

      ORR, % (95% CI) (confirmed responses) (n=84)

      40.5 (29.9-51.7)*

      CTFI≥90d (n=60)

      45.0 (32.1-58.4)

      CTFI 30-89d (n=24)

      29.2 (12.6-51.1)

      Disease Control Rate at 6 months, % (n=84)

      48.8

      Median duration of response (months) (95% CI) (n=34)

      5.3 (3.5-6.4)

      CTFI≥90d (n=27)

      6.2 (3.5-7.3)

      CTFI 30-89d (n=7)

      4.1 (2.6-5.3)

      Median overall survival (months) (95% CI) (n=84)**

      10.9 (7.8-14.9)

      CTFI≥90d (n=60)**

      11.9 (9.7-16.2)

      CTFI 30-89d (n=24)**

      (4.1-7.6)

      *4 of 7 pts who failed prior immunotherapy had confirmed response

      **Preliminary data

      L was well tolerated. Neutropenia was the most common adverse event (AE) (G3:21.5% and G4:25%), whereas febrile neutropenia was reported in 2.4%. Most common non-hematological AEs included fatigue (G3: 7.1%), nausea and vomiting (all G1-2: 32.1% and 16.7%) and transaminase increase (G3:7.2%). There was no death due to treatment related AE.

      Conclusion

      L is an active agent for second-line treatment of SCLC. The highest ORR (45.0%) was reported for pts with CTFI≥90d. Notable antitumor activity (ORR=29.2%) was also observed in pts with CTFI 30-89d, for whom no therapy is currently approved. Hence, L is a valuable therapeutic option for SCLC pts with disease relapse after first-line platinum-based therapy.

      Updated trial results will be presented at the conference.

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    P2.01 - Advanced NSCLC (ID 159)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 2
    • 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): Luis Paz-Ares

      • 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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      P2.01-24 - CANOPY-2: Phase 3 Study of Canakinumab Plus Docetaxel as Second/Third Line Therapy in Locally Advanced/Metastatic NSCLC (ID 2539)

      10:15 - 18:15  |  Presenting Author(s): Luis Paz-Ares

      • Abstract

      Background

      Pembrolizumab, a PD-1 inhibitor combined with platinum-based chemotherapy is standard first-line therapy for eligible patients without a targetable mutation, stage IIIB/IV NSCLC. Currently, there is no data to guide treatment following progression on sequential/concomitant use of platinum-based chemotherapy and PD-1 inhibitors. Activation of inflammation and elevated baseline C-reactive protein (CRP) levels are associated with lower response/resistance to immunotherapies. Canakinumab is a high-affinity anti-IL-1β monoclonal antibody that demonstrated a significant reduction in incidence of fatal and nonfatal lung cancer in patients with increased CRP levels (CANTOS study).

      Method

      CANOPY-2 (NCT03626545) is a multicenter, phase 3 study evaluating safety and efficacy of docetaxel ± canakinumab in patients with squamous/non-squamous, stage IIIB-IV NSCLC. This study includes a safety run-in part (part 1 – open label) to confirm recommended phase 3 regimen (RP3R) to be used in randomized phase 3 part (part 2 – double blind, placebo-controlled). Key inclusion criteria: adult patients pretreated with one prior platinum-based chemotherapy and one prior PD-(L)1 inhibitor therapy for locally advanced/metastatic disease, either together/sequentially and then progressed; ECOG PS 0-1. In part 1, ~9 patients will be enrolled to have at least 6 evaluable patients and ~226 patients will be randomized (1:1, stratified by number of prior lines of therapy and histology) in part 2 to docetaxel ± canakinumab. Primary objectives: to confirm RP3R of canakinumab + docetaxel, as determined by incidence of DLTs in first 42 days of administration (part 1) and overall survival (part 2). Secondary objectives are to assess efficacy (overall response rate, disease control rate, duration of response, time to response, progression-free survival by investigator per RECIST v1.1), safety, pharmacokinetics, immunogenicity of canakinumab, and patient reported outcomes. Enrollment is ongoing.

      Result

      Section not applicable

      Conclusion

      Section not applicable

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    P2.12 - Small Cell Lung Cancer/NET (ID 180)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.12-13 - Lurbinectedin (L) Combined with Paclitaxel (P) or Irinotecan (I) in Relapsed SCLC. Results from Two Phase Lb Trials (ID 1588)

      10:15 - 18:15  |  Author(s): Luis Paz-Ares

      • Abstract
      • Slides

      Background

      L is a new agent that exerts antitumor activity through inhibition of trans-activated transcription and modulation of tumor microenvironment. Preclinical evidence of synergism was observed for L in combination with P and I.

      Method

      Activity of combinations with LP and LI in small cell lung cancer (SCLC) was reviewed in two phase Ib trials. Patients were enrolled following a 3+3 dose escalation design. SCLC patients with ECOG performance status (PS) 0-1 and pretreated with at least one platinum-based chemotherapy are presented. Extensive pharmacokinetic (PK) sampling for L and P or I was performed.

      Result

      19 pts were treated: 7 with LP and 12 with LI. Baseline characteristics (LP/LI) were: males, 57%/45%; median age, 55/57 years; ECOG PS score 1, 57%/92%; chemotherapy-free interval (CTFI) >90 days, 43%/67%; median (range) prior lines, 1 (1-3)/2 (1-3); liver metastases, 29%/33%.

      Lurbinectedin-Paclitaxel

      (L: 2.2 mg/m2 – 5 mg FD +

      P: 60-80 mg/m2) *

      (n=7)

      Lurbinectedin-Irinotecan

      (L: 1-2.4 mg/m2 + I: 75 mg/m2) **

      (n=12)

      ORR (CR+PR)

      CR

      PR

      71% (n=5)

      14% (n=1)

      57% (n=4)

      25% (n=3)

      0%

      25% (n=3)

      ORR in CTFI >90d

      67%

      38%

      CB (CR+PR+SD≥4m)

      71%

      67%

      Median DOR

      2.3 m 95% CI (2.0-NR)

      4.6 m 95% CI (3.0-6.8)

      Median PFS

      4.8 m 95% CI (1.8-12.5)

      5.6 m 95% CI (1.4-8.3)

      * Combination with P given for up to 6 cycles, followed by single-agent L 2.2 mg/m2.

      ** One patient received L 3 mg/m2 + I 15 mg/m2.

      CB, clinical benefit; CR, complete response; CTFI, chemotherapy-free interval; d, days; DOR, duration of response; FD, flat dose; I, irinotecan; L, lurbinectedin; m, months; NR, not reached; ORR, overall response rate; P, paclitaxel; PFS, progression-free survival; PR, partial response; SD, stable disease.

      Adverse events (AEs): grade (G) 4 neutropenia LP/LI 43%/27% of patients; no episodes of febrile neutropenia in LI, one (G3) in LP; no G4 anemia or G4 thrombocytopenia in either study. Non-hematological toxicity was mild and mainly consisted of G3 fatigue (18%) and G3 nausea (7%) in LI; no G3/4 toxicities were found in LP. No toxic deaths and no discontinuations were due to AEs. PK: mean clearance of L (12 L/h in combo with P, and 9.5 L/h in combo with I), of P (31.5 L/h) and of I (32.2 L/h) are comparable with reported data (11.2 L/h, 31.4/h and 25 L/h, respectively).

      Conclusion

      LP and LI combinations showed promising activity after first-line therapy in SCLC. This activity seems consistent with that observed in other trials with L given alone or in combination. Both combinations showed acceptable safety profile. So far, no evidence of major PK drug-drug interactions has been observed. Further development of these combinations is warranted.

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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): Luis Paz-Ares

      • 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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    PC02 - Combining with Chemo: Old School Is New Again (ID 84)

    • Event: WCLC 2019
    • Type: Pro-Con Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      PC02.04 - IO Should Be Given with Chemo (Now Available) (ID 3564)

      14:00 - 15:30  |  Presenting Author(s): Luis Paz-Ares

      • Abstract
      • Presentation
      • Slides

      Abstract

      Lung cancer is the leading cause of cancer death worldwide. Non-small-cell lung cancer (NSCLC) accounts for almost 85% of all cases. The prognosis of NSCLC patients remains quite unsatisfactory due to the frequent advanced disease stage at diagnosis and the relatively low efficacy of the available systemic treatments. Of note, over the las few years significant progress as inhibitors of programmed death-1 (PD-1) and its ligand PD-L1 have proven to be effective therapies in metastatic NSCLC lacking sensitizing EGFR or ALK mutations, initially in pretreated patients. Subsequently, in metastatic NSCLC patients with PD-L1 expression of at least 50% on tumor cells, upfront pembrolizumab improved median progression-free survival (PFS) and overall survival (OS) compared to standard platinum-based chemotherapy. However, patients with a tumor proportion score (TPS) of 50% or greater represent only some 30% of those with NSCLC, and progression during the first three months is frequent in one third of the cases. To enhance the immune response through PD-1 inhibition, several studies have combined the potential immunogenic effects of cytotoxic chemotherapy with immune checkpoint inhibitors (ICPI), particularly of some chemotherapy regimens such as those pemetrexed-based. The first study that gave some important information regarding the efficacy of combining IO and chemotherapy was Keynote 021, randomized phase II trial of carboplatin plus pemetrexed with and without pembrolizumab. It showed significantly better response rates (RR) and longer PFS with the addition of pembrolizumab to chemotherapy. Over the last two years at least 6 other phase III clinical trials with pembrolizumab (KN 189 and KN 407) have showed the benefits of combined chemotherapy plus IO therapy in terms of PFS and OS (HR 0.49-0.64). Consistent data have been achieved on atezolizumab trials, although the magnitude of the OS benefit (HR 0.78-0.93) have been somehow lower. Randomized studies with nivolumab, durvalumab and avelumab are expected to be reported in the near future. Chemo-immunotherapy combinations are associated with the expected toxicities of chemotherapy and IO on their own.

      At present, for patients with tumors with TPS >50%, there are no comparative trials of IO monotherapy (e.g. pembrolizumab) as compared to chemotherapy. Across trial comparisons may support the use of IO monotherapy for most of cases. Chemo-IO regimens may be considered for patients requiring rapid responses (e.g. symptomatic patients) or those with aggressive disease. In patients, whose tumors express PD-L1 in 1-49% of cells, chemo-IO combinations are seen as the best treatment options. Of note, in the IMPOWER 150 trial, patients with EGFR/ALK aberrations also benefitted from the addition of atezolizumab to the paclitaxel/carboplatin/bevacizumab regimen. In patients with tumors with negative expression of PD-L1 the benefits on PFS were more debatable but the pembrolizumab-based combos, and to some extend those with atezolizumab, resulted in prolonged survival. The value of certain genomic aberrations (e.g. Keap or LKB1) or low tumor mutational burden (TMB) as a predictive tool in this setting needs further validation. In addition, the results of several ongoing combination studies (CheckMate-9LA, POSEIDON ) investigating two and four drug regimens of PD-(L)1 plus CTLA-4 inhibition with/without chemotherapy are eagerly awaited and will reveal further knowledge of efficacy and tolerability in this setting.

      References

      Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. . Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. (2015) 373:1627–39.

      Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. (2016) 375:1823–33.

      Langer CJ, Gadgeel SM, Borghaei H, Papadimitrakopoulou VA, Patnaik A, Powell SF, et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. (2016) 17:1497–508.

      Gandhi L, Rodriguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. (2018) 378:2078–92.

      Paz-Ares L, Luft A, Vicente D, Tafreshi A, Gümüş M, Mazières J, et al. KEYNOTE-407 Investigators. Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer. N Engl J Med. 2018; 379: 2040-2051.

      Hellmann MD, Ciuleanu TE, Pluzanski A, Lee JS, Otterson GA, Audigier-Valette C, Minenza E, et al. Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden. N Engl J Med. 2018; 378: 2093-2104.

      Jotte RM, Cappuzzo F, Vynnychenko I, Stroyakovskiy D, Abreu DR, Hussein MA, et al. IMpower131: primary PFS and safety analysis of a randomized phase III study of atezolizumab + carboplatin + paclitaxel or nab-paclitaxel vs carboplatin + nab-paclitaxel as 1L therapy in advanced squamous NSCLC. J Clin Oncol. (2018) 36:LBA9000–LBA9000. 10.1200/JCO.2018.36.18_suppl.LBA9000.

      Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, et al.. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. (2018) 378:2288–301.

      Socinski MA, Jotte RM, Cappuzzo F, Orlandi FJ, Stroyakovskiy D, Nogami N, et al. Overall survival (OS) analysis of IMpower150, a randomized Ph 3 study of atezolizumab (atezo) + chemotherapy (chemo) ± bevacizumab (bev) vs chemo + bev in 1L nonsquamous (NSQ) NSCLC. J Clin Oncol. (2018) 36:9002.

      Papadimitrakopoulou V, Cobo M, Bordoni R, Dubray-Longeras P, Szalai Z, Ursol G, et al. IMpower132: PFS and safety results with 1L Atezolizumab + Carboplatin/Cisplatin + Pemetrexed in stage IV non-squamous NSCLC. In: International Association for the Study of Lung Cancer's (IASLC) 2018 World Conference on Lung Cancer (WCLC); 2018 Sept 23-26. Toronto, ON: (2018).

      West H, McCleod M, Hussein M, Morabito A, Rittmeyer A, Conter HJ, et al. Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019; 20: 924-937.

      Borghaei H, Hellmann MD, Paz-Ares LG, Ramalingam SS, Reck M, O'Byrne KJ, et al. Nivolumab (Nivo) + platinum-doublet chemotherapy (Chemo) vs chemo as first-line (1L) treatment (Tx) for advanced non-small cell lung cancer (NSCLC) with < 1% tumor PD-L1 expression: results from CheckMate 227. J Clin Oncol. (2018) 36:9001 10.1200/JCO.2018.36.15_suppl.900.

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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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      PL02.11 - Overall Survival with Durvalumab Plus Etoposide-Platinum in First-Line Extensive-Stage SCLC: Results from the CASPIAN Study (Now Available) (ID 2265)

      08:00 - 10:15  |  Presenting Author(s): Luis Paz-Ares

      • Abstract
      • Presentation
      • Slides

      Background

      Extensive-stage (ES)-SCLC is a recalcitrant disease associated with a median OS of ~10 months following etoposide-platinum (EP); new treatments that prolong survival are needed. CASPIAN (NCT03043872) is an open-label, phase 3 study of durvalumab (anti-PD-L1), ± tremelimumab (anti-CTLA-4), combined with EP as first-line treatment for patients with ES-SCLC. Here we report results for durvalumab + EP (D+EP) versus EP from a planned interim analysis.

      Method

      Patients with previously untreated ES-SCLC (ECOG PS 0/1) were randomised (1:1:1) to durvalumab 1500 mg + EP q3w; durvalumab 1500 mg + tremelimumab 75 mg + EP q3w; or EP q3w. Patients in immunotherapy arms received up to 4 cycles of EP followed by maintenance durvalumab until progression. Patients in the EP arm received up to 6 cycles of EP and prophylactic cranial irradiation (PCI), at the investigator’s discretion. Investigator’s choice of cisplatin or carboplatin was allowed across all arms and was a stratification factor at randomisation. The primary endpoint was OS. Data cutoff: 11 March 2019.

      Result

      268 patients were randomised to D+EP and 269 to EP. Baseline characteristics were well balanced between arms. In the EP arm, 56.8% of patients received 6 cycles of EP. At the interim analysis, D+EP significantly improved OS compared to EP with a HR of 0.73 (95% CI, 0.591-0.909; p=0.0047); mOS 13.0 versus 10.3 months, respectively. 33.9% of patients were alive at 18 months with D+EP versus 24.7% with EP. Secondary endpoints of PFS and ORR were also improved with D+EP compared to EP: PFS HR 0.78 (95% CI, 0.645-0.936); mPFS 5.1 versus 5.4 months; 12-month PFS rate 17.5% versus 4.7%; investigator-assessed ORR (RECIST v1.1; unconfirmed) 79.5% versus 70.3% (odds ratio, 1.64 [95% CI, 1.106-2.443]). The incidences of grade 3/4 AEs (61.5% versus 62.4%) and AEs leading to discontinuation (9.4% each) were similar between arms; the incidence of haematological toxicities was numerically higher in the EP arm. The durvalumab + tremelimumab + EP arm continues blinded to final analysis.

      Conclusion

      The addition of durvalumab to EP as first-line treatment for ES-SCLC significantly improved OS (27% reduction in risk of death) versus a robust control arm that permitted up to 6 cycles of EP and PCI. Of note, this chemo-immunotherapy regimen offers flexibility in platinum choice (carboplatin or cisplatin), reflecting current clinical practice for this challenging disease. No new safety signals were identified.

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    PR03 - Press Conference (ID 94)

    • Event: WCLC 2019
    • Type: Press Conference
    • Track:
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 11:00, CC7.1 A&B
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      PR03.08 - Overall Survival with Durvalumab Plus Etoposide-Platinum in First-Line Extensive-Stage SCLC: Results from the CASPIAN Study (Now Available) (ID 3619)

      10:15 - 11:00  |  Presenting Author(s): Luis Paz-Ares

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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