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Background: In the CANTOS study, treatment with canakinumab (selective IL-1β inhibitor) was associated with reduced incidence and mortality of NSCLC in patients with stable post-myocardial infarction who had elevated high-sensitivity C-reactive protein (hs-CRP) levels. The results provided a rationale to investigate the therapeutic role of canakinumab in NSCLC. Methods: The phase III, multicenter, randomized, double-blind, placebo-controlled CANOPY-A study (NCT03447769) is evaluating the efficacy and safety of canakinumab as adjuvant therapy in adult patients with completely resected NSCLC. Patients with AJCC/UICC v.8 stages II-IIIA and IIIB (T>5 cm, N2), any histology, completely resected (R0) NSCLC who have completed adjuvant cisplatin-based chemotherapy (≥2 cycles) and radiation therapy (if applicable) are eligible. Patients must not have had prior neoadjuvant chemotherapy or neoadjuvant radiotherapy. Patients (~1500) are randomized 1:1 to receive canakinumab (200 mg Q3W, SC) or placebo (Q3W, SC) for 18 cycles or until NSCLC disease recurrence as determined by investigator, unacceptable toxicity, treatment discontinuation at the discretion of the investigator or patient, start of a new antineoplastic therapy, death, or loss to follow-up. Randomization is stratified by AJCC/UICC v.8 stage (IIA vs IIB vs IIIA vs IIIB with T>5 cm, N2 disease), tumor histology (squamous vs non-squamous), and region (western Europe and North America vs eastern Asia vs rest of the world). Primary objective is disease-free survival (DFS) per local investigator assessment. Secondary objectives are overall survival (OS), lung cancer specific survival, safety, pharmacokinetics, immunogenicity, and patient reported outcomes. Adult patients with stage IIA-IIIA, IIIB (N2 disease only) NSCLC who are candidates for complete resection surgery (and therefore prospective candidates for the main study) will be asked to participate in a biomarker sub-study to understand how resection surgery may impact biomarkers involved in the IL-1β inflammatory pathway as well as mutations present in blood. For all patients participating into the sub-study, the levels of hs-CRP, other cytokines, and additional biomarkers in blood will be assessed at pre- and post-surgery (endpoint: summary statistics of hs-CRP and other pharmacodynamics [PD] biomarkers). For patients who will also enroll into the main study, possible associations between pre- and post-surgery biomarker levels with canakinumab efficacy will be determined (endpoint: DFS and OS by hs-CRP and other PD biomarkers). The CANOPY-A study is currently enrolling. As of Jan 13, 2020, there are 307 study locations. Citation Format: Edward B. Garon, Andrea Ardizzoni, Fabrice Barlesi, Byoung Chul Cho, Pedro De Marchi, Yasushi Goto, Dariusz Kowalski, Shun Lu, Luis Paz-Ares, David R. Spigel, Alexander Spira, Michael Thomas, Mimi Leung, Jason Baum, Zewen Zhu, Bijoyesh Mookerjee, James Chih-Hsin Yang. CANOPY-A: A phase III, multicenter, randomized trial evaluating canakinumab versus placebo as adjuvant therapy in patients with completely resected non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT287.

Introduction: Stereotactic radiosurgery and radiotherapy (SRS-SRT) is a valuable treatment for brain metastases (BMs) due to its specificity to the patient and reduction of toxic effects compared to whole brain radiation. Immune checkpoint inhibition (ICI) is also an important treatment option utilizing anti-cytotoxic T-lymphocyte-associated protein 4 and anti-programed cell death protein 1 receptors in cancer cells. However, few published studies are available describing how combined immunotherapy and SRS-SRT affect patient outcomes. The purpose of this study was to retrospectively analyze how SRS-SRT given in combination with immunotherapy affects toxicity and survivorship in patients with metastatic brain tumors. Methods: A retrospective review was completed of patients with BMs treated with linac-based SRS-SRT and ICI from 2010-2019 at a community cancer program. IRB exempt status was established. Timing of ICI in relation to SRS-SRT was characterized as prior (ended 6 months before), concurrent (delivered within 2 weeks before or during), and following (initiated more than 3 months) after radiation. Total radiation dose, fractionation, number of BMs treated, and conformality index (CI) in relation to ICI drug(s) and incidence of acute and delayed toxicities via RTOG criteria, were analyzed to identify predictors of toxicity and tumor control. Progression free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier survival curves and Cox proportional hazards models were used for multivariate analysis. Brain MRI with contrast was completed every 3 months post-radiation. Patients were evaluated via ROS and physical exam q2-3 months until death. Results: The final sample consisted of 417 patients, 178M, 239F, with the mean age of 62.6 years (range 17-90). Primary tumor sites of BMs were lung (NSCLC and SCLC) 56%, Other 16.6%, breast 12.9%, melanoma 8.8%, and colon 5.5%. There were a total of 986 BMs treated, median dose was 2000 cGy in 3 fractions. A total of 71 pts (17%) received ICIs concurrent with SRS-SRT. Median RTOG toxicity score was 0.73, (SD 1.049). Neurotoxicity grade 3 occurred in 6.2% of all patients. Concurrent use of either Ipilimumab or Pembrolizumab with SRS-SRT showed significantly increased acute RTOG toxicity scores compared to either pre or post radiation ICI use of any drug. No grade 4 or 5 toxicities occurred. PFS and OS were not significantly associated with use of concurrent ICI with radiotherapy. Conclusions: The use of ICI prior to, during or after SRS-SRT for BMs appears to be safe in both acute and delayed toxicity evaluation. However a small but statistically significant increase in acute toxicities was observed when concurrent Ipilimumab or Pembrolizumab were given. Citation Format: Sonal Khedkar, Andrew S. Kennedy, D Edward Hunt, James Gray, Melissa L. Johnson, Casey Chollet-Lipscomb, Meredith McKean, Brian J. Stevens, David Spigel. Impact of immune checkpoint inhibition combined with stereotactic radiotherapy in treatment of brain metastases [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6502.

Background: In the CANTOS study, treatment (tx) with Cana (selective IL-1β inhibitor) was associated with reduced incidence and mortality of NSCLC in stable post-myocardial infarction pts with elevated high-sensitivity C-reactive protein levels. The results provided a rationale to investigate the therapeutic role of Cana in NSCLC. Methods: The phase (ph) 2, open-label CANOPY-N study (NCT03968419) is evaluating Cana or pembrolizumab (pembro) alone or in combination as neoadjuvant tx in stage IB-IIIA, tx-naive NSCLC pts eligible for primary resection (except N2 and T4 tumors) with planned surgery in 4-6 weeks (wks) from the 1st dose of study tx. Pts (~110) are randomized 2:2:1 to Cana (2 doses 200 mg SC Q3W), Cana + pembro, or pembro (2 doses 200 mg iv Q3W) for 2 three-wk cycles. Randomization (R) stratification: histology (squamous [sq] vs non-sq). Primary endpoint: major pathological response rate at time of surgery.CANOPY-A (NCT03447769), CANOPY-1 (NCT03631199), and CANOPY-2 (NCT03626545) are ph 3, multicenter, double-blind studies. In CANOPY-A (Cana in adjuvant setting), pts (~1500) with stages IIA-IIIA and IIIB (T>5 cm N2), any histology, completely resected (R0) NSCLC post cisplatin-based chemotherapy (CTx) and radiation therapy (if applicable) are randomized 1:1 to Cana (200 mg SC Q3W)/placebo (PBO; SC Q3W) for 18 cycles. R stratification: AJCC/UICC v.8 stage (IIA vs IIB vs IIIA vs IIIB with T>5 cm, N2 disease), histology (sq vs non-sq), region (western Europe and North America vs eastern Asia vs rest of the world). Primary endpoint: disease-free survival. CANOPY-1 and CANOPY-2 consist of Part 1 (open-label, safety run-in; enrollment complete) and Part 2 (randomized 1:1, PBO-controlled, efficacy & safety; ongoing). CANOPY-1 eligibility: pts with previously untreated stages IIIB/IIIC or IV NSCLC and known PD-L1 status (for Part 2), without EGFR sensitizing mutations and/or ALK rearrangements. Part 1 (3 cohorts of ~9 pts each, based on different platinum-CTx): to confirm the recommended phase 3 regimen (RP3R) for Cana. In Part 2, pts (~600) are randomized to Cana (200 mg SC Q3W)/PBO + pembro + CTx for 4 cycles, followed by maintenance tx (Cana/PBO + pembro ± pemetrexed) until progressive disease (PD). R stratification: PD-L1 status (tumor proportion score Citation Format: Luis Paz-Ares, Edward B. Garon, Tony Mok, Andrea Ardizzoni, Fabrice Barlesi, Byoung Chul Cho, Gilberto de Castro, Pedro De Marchi, Enriqueta Felip, Yasushi Goto, Alastair Greystoke, Shun Lu, Darren Wan-Teck Lim, Martin Reck, Benjamin J. Solomon, David R. Spigel, Daniel SW Tan, Michael Thomas, James Chih-Hsin Yang, Jay M. Lee, Pilar Garrido, Edward Kim, Bruce E. Johnson. CANOPY program clinical trials: Canakinumab (Cana) in patients (pts) with non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT286.

TPS9075 Background: In the CANTOS study, canakinumab (selective IL-1β inhibitor) treatment was associated with reduced incidence and mortality from NSCLC in pts with stable post-myocardial infarction with elevated high-sensitivity C-reactive protein (hs-CRP) levels. In CANOPY-A study, we investigate the therapeutic role of canakinumab in NSCLC. Methods: The CANOPY-A study (NCT03447769) is evaluating the efficacy and safety of canakinumab as adjuvant therapy in adult pts with completely resected NSCLC. Pts with AJCC/UICC v.8 stages II–IIIA and IIIB (T > 5 cm, N2), any histology, completely resected (R0) NSCLC who completed adjuvant cisplatin-based chemotherapy (≥2 cycles) and radiotherapy (if applicable) are eligible. Pts must not have had prior neoadjuvant chemotherapy or radiotherapy. Pts (~1500) are randomized 1:1 to receive canakinumab (200 mg Q3W, SC) or placebo (Q3W, SC) for 18 cycles or until disease recurrence as determined by investigator, unacceptable toxicity, treatment discontinuation at the discretion of the investigator or patient, start of a new antineoplastic therapy, death, or loss to follow-up. Randomization is stratified by AJCC/UICC v.8 stage (IIA vs IIB vs IIIA vs IIIB with T > 5 cm, N2 disease), tumor histology (squamous vs non-squamous), and region (western Europe and North America vs eastern Asia vs rest of the world). Primary objective: disease-free survival (DFS) per local investigator assessment. Secondary objectives: overall survival (OS), lung cancer specific survival, safety, pharmacokinetics, immunogenicity, and patient reported outcomes. Adult pts with stage IIA–IIIA, IIIB (N2 disease only) NSCLC who are candidates for complete resection surgery (and therefore prospective candidates for the main study) will be asked to participate in a biomarker sub-study to understand how resection may impact biomarkers involved in the IL-1β inflammatory pathway and mutations present in blood. In the sub-study, the levels of hs-CRP, other cytokines, and additional biomarkers in blood will be assessed at pre- and post-surgery (endpoint: summary statistics of hs-CRP and other pharmacodynamics [PD] biomarkers). For pts who will enroll in the main study, possible associations between pre- and post-surgery biomarker levels with canakinumab efficacy will be assessed (endpoint: DFS and OS by hs-CRP and other PD biomarkers). The CANOPY-A study is currently enrolling. As of Jan 13, 2020, there are 307 study locations. Clinical trial information: NCT03447769.

e21623 Background: IMpower110 evaluated atezo mono in PD-L1–selected, chemo-naive patients (pts) with nonsquamous (nsq) or squamous (sq) NSCLC. At the interim analysis, IMpower110 met its primary OS endpoint, with a statistically significant and clinically meaningful improvement for atezo vs chemo in TC3 or IC3 wild-type ( EGFR/ALK-negative) pts. We report on the safety profile of atezo vs chemo in IMpower110. Methods: 572 pts with stage IV nsq or sq NSCLC, PD-L1 expression ≥ 1% on TC or IC and ECOG PS 0-1 were randomized 1:1 to receive atezo (1200 mg IV q3w) or chemo (4 or 6 21-day cycles). In the chemo arm, nsq pts received cisplatin (cis) 75 mg/m2 or carboplatin (carbo) AUC 6 + pemetrexed (pem) 500 mg/m2 IV q3w; sq pts received cis 75 mg/m2 + gemcitabine (gem) 1250 mg/m2 or carbo AUC 5 + gem 1000 mg/m2 IV q3w. Safety was assessed in all treated pts (safety evaluable [SE] population [pop]), regardless of PD-L1 expression or EGFR/ALK status. AEs were summarized per MedDRA v22.0 and severity graded per NCI CTCAE v4.0. Immune-mediated AEs (imAEs) were defined per a sponsor-specified list of terms, regardless of whether the events led to systemic glucocorticoid, endocrine therapy, or other immunosuppressants use. Results: At data cutoff (Sep 10, 2018) within the ITT pop, treatment (tx) was ongoing in 90 (atezo: 31.6%) and 25 (chemo: 8.7%) pts, with 13.7 mo of follow-up. Within the SE pop (atezo: n = 286, chemo: n = 263), atezo pts had longer tx exposure (5.3 mo) vs chemo pts (pem, 3.5 mo; gem, 2.6 mo; carbo, 2.3 mo; cis, 2.1 mo). Atezo had a favorable safety profile vs chemo (table); safety data were consistent with data from a pooled atezo mono pop. imAEs occurred in 40.2% (atezo) and 16.7% (chemo) of pts and were Grade (Gr) 3-4 in 6.6% and 1.5%, respectively. Conclusions: Atezo was better tolerated than chemo and imAEs were generally low grade. Overall, the safety experience with atezo mono in IMpower110 was consistent with its known safety profile; no new safety signals were identified. Clinical trial information: NCT02409342. [Table: see text]

9560 Background: In Part 1 of the phase II CheckMate 568 study (NCT02659059), NIVO + IPI was active and tolerable in patients (pts) with advanced NSCLC. The addition of chemo to dual immune checkpoint inhibitor therapy may further improve initial disease control. We report results from Part 2 of CheckMate 568, which evaluates NIVO + IPI combined with 2 cycles of chemo in pts with advanced treatment-naive NSCLC. Methods: Adult pts with untreated stage IV NSCLC received NIVO 360 mg Q3W + IPI 1 mg/kg Q6W combined with 2 cycles of histology-based platinum-doublet chemo, followed by NIVO + IPI without chemo until disease progression/unacceptable toxicity for ≤ 2 years. The primary endpoints were dose-limiting toxicity (DLT) within the first 9 weeks and safety/tolerability. Treatment was considered safe if ≤ 25% of at least 22 evaluable pts had a DLT. DLTs included but were not limited to: uncontrolled grade 3 non-skin treatment-related adverse events (TRAEs), grade 4 TRAEs, grade 2 treatment-related pneumonitis not resolved within 14 days, and treatment-related hepatic function abnormalities. Results: In total, 36 pts received treatment; 97% of pts completed 2 cycles of chemo combined with NIVO + IPI. Three pts discontinued IPI while continuing NIVO. Minimum follow-up was 14.9 months. Only 1 (3%) pt experienced a DLT (transient, asymptomatic grade 3 AST and ALT elevation) within the first 9 weeks. The elevation occurred on cycle 1, day 21 and resolved 2 weeks later with discontinuation of IPI, delay of NIVO, and treatment with prednisone; chemo was continued throughout and NIVO was restarted thereafter without recurrent toxicity. Grade 3–4 TRAEs occurred in 21 (58%) pts. Eight (22%) pts experienced a TRAE leading to discontinuation, most commonly colitis, encephalopathy, pneumonitis, and arthralgia (each in 2 [6%] pts); these events occurred outside of the 9-week window for DLT assessment. The most common select TRAEs (defined as AEs of potential immunologic causes) were skin related (18 [50%] pts); the most common grade 3–4 select TRAEs were endocrine (3 [8%] pts), skin related, gastrointestinal, and pulmonary (each in 2 [6%] pts). No treatment-related deaths occurred. Updated safety in addition to efficacy data will be presented. Conclusions: In pts with untreated advanced NSCLC, the addition of 2 cycles of platinum-doublet chemo to NIVO + tumor-optimized IPI was tolerable. No unexpected safety signals were observed. Clinical trial information: NCT02659059 .

9613 Background: MET is a validated oncogene for molecular targeted therapy in non-small-cell lung cancer (NSCLC), and METex14 mutations result in MET overexpression. Studies with MET-targeting therapies have demonstrated high objective response rates and prolonged disease control. There are few clinical and genomic analyses of patients with METex14-positive NSCLC in the community setting. We herein characterize key clinical and genomic findings for patients harboring METex14 mutations. Methods: Sarah Cannon provides clinical research to partnering medical oncology practices who order broad-based NGS, from both tissue and blood, as a part of standard of care. Genospace, a clinico-genomic software tool, was used for identification of patients for clinical trials and analysis of clinical and genomic data. Results: Of 6521 lung cancer patients with NGS results, 66 (1.01%) harbored METex14 mutations (45.5% from blood and 54.5% from in tissue). The mean age at diagnosis was 75.7 and 21.2% developed brain metastases. Of the 66 patients with METex14 mutations, 69.5% are current/former smokers. Nineteen percent of former/current smokers and 7.6% of never smokers had PD-L1 scores of > 50%, respectively. The majority of METex14-positive patients either received standard of care (66.7%) or were unable to take (19.7%) 1st-line therapy. Patients who received chemotherapy (Chemo), immunotherapy (IO), and Chemo/IO in the first and second line settings responded to SOC treatment, and patients receiving anti-MET therapy benefited from therapy even after front-line SOC (table). Genomic analysis revealed the most common co-occurring mutations to be EGFR, MET, NF1, KRAS, and BRCA2 (Freq = 8.7%, 8.7%, 8.7%, and 7.6%, respectively). Conclusions: Genospace enables real-time patient identification of METex14-positive NSCLC cases and analysis of these cases indicates that anti-MET therapy may be effective at any line of treatment. Genospace’s clinico-genomic database was used to analyze treatment history, clinical correlates, and co-occurring mutations that may reveal novel treatment combination strategies or resistance mechanisms. [Table: see text]

9069 Background: Most patients with extensive SCLC develop drug resistance to platinum-based 1L therapy or discontinue for other reasons, and second-line (2L) therapies are limited. RESILIENT (NCT03088813) is a two-part phase 2/3 study assessing the safety, tolerability and efficacy of 2L liposomal irinotecan monotherapy in adults with SCLC who progressed with platinum-based 1L therapy. Preliminary data from RESILIENT part 1 (cut-off May 8 2019; ≥ 12 weeks follow-up) showed that liposomal irinotecan 70 mg/m2 free base every 2 weeks was generally well tolerated and had encouraging antitumor activity (Paz-Ares et al. WCLC 2019 OA03.03). Objective response rate (ORR; secondary endpoint) was 44% (11/25). Here we report efficacy analyses in post hoc subgroups by platinum sensitivity. Methods: RESILIENT part 1 was an open-label, single-arm study comprising dose-finding and dose-expansion phases. Eligible patients were aged ≥ 18 y, with an ECOG performance status score of 0/1 and adequate organ function; a single line of prior immunotherapy was allowed. Participants received liposomal irinotecan 70 mg/m2 or 85 mg/m2 free base every 2 weeks, with tumor assessments every 6 weeks (RECIST v1.1). Analyses were undertaken for the dose-finding phase recommended dose (RD) in subgroups of platinum-resistant/sensitive patients (with/without progression within 90 days from completion of 1L therapy). Results: During dose finding, 5 patients received liposomal irinotecan 85 mg/m2 (deemed not tolerable; dose-limiting toxicity) and 12 received 70 mg/m2 (deemed tolerable; RD for dose-expansion phase in which 13 more patients were included). Analyses included all 25 patients receiving the RD (mean exposure, 13.95 weeks [median 14.86; SD 7.222]). In the platinum-sensitive subgroup (33.3% men; median age 62.0 y) ORR was 53.3% (8/15) and 12-week disease control rate (DCR12wks) was 60% (9/15); in the platinum-resistant subgroup (50% men, median age 58.0 y) both ORR and DCR12wks were 30% (3/10). Overall and progression-free survival (secondary endpoints) are not yet mature. Conclusions: ORR and DCR12wks were numerically higher in platinum-sensitive than in platinum-resistant patients with SCLC who had progressed with platinum-based 1L therapy before receiving 2L liposomal irinotecan 70 mg/m2 in this phase 2 study. RESILIENT part 2, an ongoing, phase 3, randomized controlled trial vs topotecan, will provide further data. Clinical trial information: NCT03088813.

9563 Background: Pembrolizumab (P) is an immune checkpoint inhibitor (CPI) approved to treat 1L advanced NSCLC pts with high PD-L1 expression. PEG + CPI has demonstrated promising efficacy in NSCLC pts in a phase I trial (IVY; NCT02009449; Naing et al., 2019 Lancet Oncol), providing rationale for this randomized phase II trial (CYPRESS 1; NCT03382899). Methods: CYPRESS 1 was an open label phase II trial, for treatment-naïve, ECOG 0-1, PD-L1 high (22C3 clone TPS ≥ 50%), Stage IV NSCLC pts, without known EGFR/ALK mutations. Pts were randomized 1:1 to arm P (received 200mg IV on day 1 of a 21-day cycle) v. arm PEG+P (received P as above + PEG daily of 0.8 mg if weight ≤80kg and 1.6mg if weight> 80 kg up to 35 cycles in each arm). Pts were stratified by tumor histology and must have no prior history of cancer or prior CPI therapy. Primary endpoint was ORR (per RECIST v1.1 by investigator) Secondary endpoints included PFS, OS, and safety. Exploratory endpoints included ORR and PFS by blinded independent central review (BICR). Immune activation biomarkers (baseline and change from baseline) were assessed by serum immunoassay, IHC, and sequencing. Results: As of Dec 6, 2019, 101 pts were randomized to PEG+P (n=51) or P (n=50). Median follow-up time was 10.0 months (95% CI [8.4, 11.1]). Results for PEG+P versus P were: ORR per investigator was 47% v. 44% (p=0.76), ORR per BICR was 53% v. 46%(p=0.78), mPFS per investigator was 6.3 v. 6.1 months with HR = 0.94 (95% CI [0.54, 1.63];p=0.82), mPFS per BICR was 6.4 v. 7.2 months with HR = 1.10 (95%CI [0.62, 1.96]; p=0.74), and mOS was 16.3 months v. not reached with HR = 1.36 (95% CI [0.66, 2.77]; p-value=0.40). Gr ≥3 treatment related adverse events (TRAEs) were 62% for PEG+P versus 19% for P. Gr ≥3 TRAEs with ≥10% incidence included anemia (20% vs. 0%) and thrombocytopenia (12% vs. 2%). Biomarker data on immunostimulatory signals of the IL-10R pathway will be included. Conclusions: Adding PEG to P did not lead to improvement in ORR, PFS, or OS, in 1L advanced NSCLC with high PD-L1 expression. PEG+P arm demonstrated expected safety profile but overall higher toxicity compared to pembrolizumab alone. Clinical trial information: NCT03382899 .

TPS9081 Background: Although small cell lung cancer (SCLC) is often sensitive to established first-line therapies, many patients relapse and develop drug resistance, and second-line therapies are limited. RESILIENT (NCT03088813) is a two-part phase 2/3 study assessing the safety, tolerability, and efficacy of liposomal irinotecan monotherapy in patients with SCLC who progressed with platinum-based first-line therapy. Preliminary data from the dose-ranging part of the study (part 1) showed that liposomal irinotecan 70 mg/m2 administered every 2 weeks was well tolerated and had promising antitumor activity (Paz-Ares et al. ASCO 2019; poster 318). Here, we present the design of the second, larger part of the study, which will evaluate the efficacy and safety of liposomal irinotecan versus topotecan in the same patient population. Methods: Part 2 of RESILIENT is a phase 3, open-label study with a planned sample size of 450. Patients are randomly allocated 1:1 to intravenous liposomal irinotecan or intravenous topotecan. Liposomal irinotecan is administered every 2 weeks at 70 mg/m2 (free-base equivalent) and topotecan is administered for 5 consecutive days every 3 weeks at 1.5 mg/m2. As of January 2020, 80 patients have been enrolled in part 2 of the trial. Tumor assessments are performed using the Response Evaluation Criteria in Solid Tumors version 1.1 and the Response Assessment in Neuro-oncology criteria for CNS lesions; symptom improvement is measured using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30. Safety assessments include monitoring for adverse events. The primary endpoint is overall survival (OS) and secondary endpoints are progression-free survival (PFS), objective response rate, and proportion of patients reporting symptom improvement. Patients will continue study treatment until disease progression, unacceptable toxicity or study withdrawal and will then be followed for survival until death or study end (when all patients have died, withdrawn consent or are lost to follow-up). Clinical trial information: NCT03088813.

9594 Background: IMpower110 (NCT02409342) evaluated atezo (anti–PD-L1) monotherapy as 1L treatment in PD-L1–selected patients (pts) with metastatic NSCLC and met its primary endpoint with statistically significant and clinically meaningful OS benefit in TC3 or IC3 wild-type (WT; EGFR/ALK-negative) pts. PROs were prespecified endpoints to assess pt perspectives on overall clinical benefit. Methods: Pts were randomized 1:1 to receive atezo 1200 mg IV q3w (Arm A) or platinum-based chemo (Arm B; 4 or 6 21-day cycles). Arm B non-squamous pts received cisplatin (cis) 75 mg/m2 or carboplatin (carbo) AUC 6 + pemetrexed 500 mg/m2 IV q3w; Arm B squamous pts received cis 75 mg/m2 + gemcitabine (gem) 1250 mg/m2 or carbo AUC 5 + gem 1000 mg/m2 IV q3w. PROs were assessed by the EORTC Quality of Life Questionnaire Core 30 (QLQ-C30) and lung cancer module QLQ-LC13. Time to confirmed deterioration (TTD) in QLQ-LC13 lung cancer symptoms (secondary endpoint) and change from baseline (BL) in global health status (GHS), functioning and lung cancer symptoms (exploratory endpoints) were analyzed in TC3 or IC3-WT pts. Clinically meaningful change was defined as a ≥10-point deterioration from BL. Results: Completion rates at BL (atezo, n = 107; chemo, n = 98) were high in both arms for the QLC-C30 (90% atezo, 86% chemo) and the QLC-LC13 (89% atezo, 85% chemo), and remained > 80% at most visits. Mean BL scores for GHS, physical functioning, and role functioning were moderate, symptom burden was low, and all were similar in both arms. No differences in TTD were seen between arms for cough (HR, 0.98; 95% CI: 0.48, 2.03), chest pain (HR, 1.02; 95% CI: 0.47, 2.22), dyspnea (HR, 0.96, 95% CI: 0.57, 1.60), and 3-symptom composite score (HR, 0.92; 95% CI: 0.59, 1.44). Mean change in physical function from BL to wk 42 was modestly improved with atezo and greater than or similar to chemo. No clinically meaningful worsening in dyspnea, cough or chest pain was seen with atezo vs chemo. Mean change in cough and chest pain from BL numerically improved immediately after start of treatment and was maintained to wk 48 with atezo. Fatigue and nausea/vomiting scores numerically improved immediately with atezo and were maintained to wk 48. Conclusions: QLQ-C30 and QLQ-LC13 completion rates were high at BL and most study visits. TTD of lung cancer-related symptoms was similar in both arms, indicating pts’ low BL symptom burden was maintained for a similar duration. Pts receiving atezo vs chemo sustained numerical improvements in physical function and no worsening in lung cancer-related symptoms. Clinical trial information: NCT02409342 .

BACKGROUND. The VeriStrat test provides accurate predictions of outcomes in all lines of therapy for patients with non‐small cell lung cancer (NSCLC). We investigated the predictive and prognostic role of VeriStrat in patients enrolled on the MARQUEE phase III trial of tivantinib plus erlotinib (T+E) versus placebo plus erlotinib (P+E) in previously treated patients with advanced NSCLC. METHODS. Pretreatment plasma samples were available for 996 patients and were analyzed by matrix‐assisted laser desorption/ionization‐time of flight mass spectrometry to generate VeriStrat labels (good, VS‐G, or poor, VS‐P). RESULTS. Overall, no significant benefit in overall survival (OS) and progression‐free survival (PFS) were observed for the addition of tivantinib to erlotinib. Regardless of treatment arm, patients who were classified as VS‐G had significantly longer PFS (3.8 mo for T+E arm, 2.0 mo for P+E arm) and OS (11.6 mo for T+E, 10.2 mo for P+E arm) than patients classified as VS‐P (PFS: 1.9 mo for both arms, hazard ratio [HR], 0.584; 95% confidence interval [CI], 0.468–0.733; p < .0001 for T+E, HR, 0.686; 95% CI, 0.546–0.870; p = .0015 for P+E; OS: 4.0 mo for both arms, HR, 0.333; 95% CI, 0.264–0.422; p < .0001 for T+E; HR, 0.449; 95% CI, 0.353–0.576; p < .0001 for P+E). The VS‐G population had higher OS than the VS‐P population within Eastern Cooperative Oncology Group (ECOG) performance score (PS) categories. VS‐G patients on the T+E arm had longer PFS, but not OS, than VS‐G patients on the P+E arm (p = .0108). Among EGFR mutation‐positive patients, those with VS‐G status had a median OS more than twice that of any other group (OS: 31.6 mo for T+E and 22.8 mo for P+E), whereas VS‐P patients had similar survival rates as VS‐G, EGFR‐wild type patients (OS: 13.7 mo for T+E and 6.5 mo for P+E). CONCLUSION. In these analyses, VeriStrat showed a prognostic role within EGOC PS categories and regardless of treatment arm and EGFR status, suggesting that VeriStrat could be used to identify EGFR mutation‐positive patients who will have a poor response to EGFR tyrosine kinase inhibitors. IMPLICATIONS FOR PRACTICE. This study suggests that VeriStrat testing could enhance the prognostic role of performance status and smoking status and replicates findings from other trials that showed that the VeriStrat test identifies EGFR mutation‐positive patients likely to have a poor response to EGFR tyrosine kinase inhibitors (TKIs). Although these findings should be confirmed in other populations, VeriStrat use could be considered in EGFR mutation‐positive patients as an additional prognostic tool, and these results suggest that EGFR mutation‐positive patients with VeriStrat “poor” classification could benefit from other therapeutic agents given in conjunction with TKI monotherapy.

283 Background: Cancers of the esophagus, stomach, pancreas, gallbladder, liver, bile duct, colon and rectum will account for 17% of incident cancer diagnoses and 26% of cancer-related deaths in the US in 2019. We developed a methylation-based cfDNA early multi-cancer detection test that also can predict the tissue of origin (TOO) of these and other cancers types; performance of this test for gastrointestinal (GI) tract cancers is reported here. Methods: The Circulating Cell-free Genome Atlas (CCGA; NCT02889978) study is a prospective, multi-center, observational, case-control study with longitudinal follow-up, enrolling individuals with cancer ( > 20 cancers, all stages, newly diagnosed) and without cancer. Plasma cfDNA was subjected to a cross-validated targeted methylation (TM) sequencing assay. Methylation fragments were combined across targeted genomic regions and assigned a probability of cancer and a predicted TOO. GI cancer classes were upper GI (esophagus/stomach, n = 67), pancreas/gallbladder/extrahepatic bile duct (n = 95), liver/intrahepatic bile duct (n = 29), and colon/rectum (n = 121). Results: Detection across all GI cancers was 82% (95% CI 77-86) at a > 99% pre-set specificity. Overall predicted TOO accuracy was 92% (88-95) among the samples for which TOO was predicted (6/255 had indeterminate predicted TOO). The table shows performance by GI cancer type. Conclusions: Simultaneous detection at high specificity ( > 99%) of multiple cancer types, including GI cancers across stages at high sensitivity (82%), was shown using TM analysis of cfDNA. Accurate (92%) localization of cancers to specific regions of the GI tract was also achieved. Detection of multiple GI cancers from a single noninvasive blood test could be a practical method for detecting GI and other cancers, and may facilitate diagnostic work-ups. Clinical trial information: NCT02889978. [Table: see text]

Introduction Nivolumab est approuve a la dose de 240 mg Q2S dans l’Union europeenne dans le traitement de 2e ligne du CBNPC avance. La modelisation pharmacocinetique dans diverses tumeurs predit que l’exposition, l’efficacite et la tolerance peuvent etre maintenues avec une dose Q4S. Nous presentons ici une analyse intermediaire des donnees d’efficacite et de tolerance de l’etude de phase 3b/4 CheckMate 384. Methodes Des pts deja traites pour un CBNPC de stade IIIb/IV histologiquement confirme ou recurrent, avec un statut de performance ECOG de 0 a 2, un traitement anterieur par nivolumab 3 mg/kg ou 240 mg Q2S ≤ 12 mois et un minimum de 2 evaluations consecutives mettant en evidence une reponse complete/partielle ou une maladie stable, ont ete randomises (1 :1) en 2 bras : nivolumab 480 mg Q4S ou 240 mg Q2S. Les criteres principaux d’evaluation etaient les taux de survie sans progression (SSP) post-randomisation a 6 mois et a 1 an. La tolerance etait un critere de jugement secondaire. En raison des changements dans les algorithmes de traitement du CBNPC, les analyses statistiques ont ete modifiees pour reduire la taille de l’echantillon. Les analyses presentees sont descriptives. Resultats Sur 166 et 163 pts randomises aux doses de 480 mg Q4S et de 240 mg Q2S, 164 et 161 ont ete respectivement traites. Le suivi median etait de 9,5 mois (480 mg Q4S) et de 10,2 mois (240 mg Q2S). Les caracteristiques a l’inclusion etaient equilibrees entre les 2 bras de traitement. Les taux de SSP stratifiee post-randomisation a 6 mois et a 1 an etaient comparables entre les 2 bras de traitement (voir le Tableau 1 ). Les effets indesirables de tous grades lies au traitement et ceux ayant entraine l’arret du traitement ont ete rapportes respectivement chez 48 % vs 61 % et 6 % vs 9 % des patients. Aucun deces lie au traitement n’a ete rapporte. Conclusion Nivolumab 480 mg Q4S presente une efficacite et une tolerance similaires a celles de nivolumab 240 mg Q2S chez les patients avec une maladie controlee par nivolumab, soutenant l’utilisation potentielle de 480 mg Q4S comme dose de nivolumab plus pratique dans le traitement du CBNPC avance de 2e ligne.

Introduction Historiquement, la survie des patients atteints de CBNPC avance etait mediocre, avec des taux a 5 ans Methodes Les patients (n = 854 ; CM 017/057 regroupes) atteints d’un CBNPC avance, avec un ECOG PS ≤ 1 et dont la maladie avait progresse pendant ou apres une premiere ligne de chimiotherapie ont ete randomises 1 :1 pour recevoir nivolumab 3 mg/kg toutes les 2 semaines ou docetaxel 75 mg/m2 toutes les 3 semaines jusqu’a progression ou toxicite inacceptable. La SG etait le critere principal d’evaluation pour les deux etudes. Resultats A 5 ans de suivi, 50 patients dans le bras nivolumab et 9 patients dans le bras docetaxel etaient en vie. Les caracteristiques initiales des survivants a 5 ans dans les deux bras etaient similaires a celles de la population globale et a celles des patients ayant survecu Conclusion Les CM 017 et CM 057 sont les premiers essais de phase III a rapporter les resultats a 5 ans d’un anti-PD1 dans le CBNPC avance prealablement traite et font etat d’une augmentation de plus de 4 fois des taux de SG a 5 ans avec nivolumab (13 %) par rapport au docetaxel (3 %). Le traitement par nivolumab reste bien tolere, sans nouveau signal de toxicite.

Significance Programmed death-ligand 1 (PD-L1) expression on tumor cells and tumor-infiltrating immune cells is regulated by distinct mechanisms and has nonredundant roles in regulating anticancer immunity, and PD-L1 on both cell types is important for predicting best response to atezolizumab in non-small cell lung cancer., Programmed death-ligand 1 (PD-L1) expression on tumor cells (TCs) by immunohistochemistry is rapidly gaining importance as a diagnostic for the selection or stratification of patients with non-small cell lung cancer (NSCLC) most likely to respond to single-agent checkpoint inhibitors. However, at least two distinct patterns of PD-L1 expression have been observed with potential biological and clinical relevance in NSCLC: expression on TC or on tumor-infiltrating immune cells (ICs). We investigated the molecular and cellular characteristics associated with PD-L1 expression in these distinct cell compartments in 4,549 cases of NSCLC. PD-L1 expression on IC was more prevalent and likely reflected IFN-γ–induced adaptive regulation accompanied by increased tumor-infiltrating lymphocytes and effector T cells. High PD-L1 expression on TC, however, reflected an epigenetic dysregulation of the PD-L1 gene and was associated with a distinct histology described by poor immune infiltration, sclerotic/desmoplastic stroma, and mesenchymal molecular features. Importantly, durable clinical responses to atezolizumab (anti–PD-L1) were observed in patients with tumors expressing high PD-L1 levels on either TC alone [40% objective response rate (ORR)] or IC alone (22% ORR). Thus, PD-L1 expression on TC or IC can independently attenuate anticancer immunity and emphasizes the functional importance of IC in regulating the antitumor T cell response.

BACKGROUND: An earlier analysis in this phase 3 trial showed that durvalumab significantly prolonged progression-free survival, as compared with placebo, among patients with stage III, unresectable non-small-cell lung cancer (NSCLC) who did not have disease progression after concurrent chemoradiotherapy. Here we report the results for the second primary end point of overall survival. METHODS: We randomly assigned patients, in a 2:1 ratio, to receive durvalumab intravenously, at a dose of 10 mg per kilogram of body weight, or matching placebo every 2 weeks for up to 12 months. Randomization occurred 1 to 42 days after the patients had received chemoradiotherapy and was stratified according to age, sex, and smoking history. The primary end points were progression-free survival (as assessed by blinded independent central review) and overall survival. Secondary end points included the time to death or distant metastasis, the time to second progression, and safety. RESULTS: Of the 713 patients who underwent randomization, 709 received the assigned intervention (473 patients received durvalumab and 236 received placebo). As of March 22, 2018, the median follow-up was 25.2 months. The 24-month overall survival rate was 66.3% (95% confidence interval [CI], 61.7 to 70.4) in the durvalumab group, as compared with 55.6% (95% CI, 48.9 to 61.8) in the placebo group (two-sided P=0.005). Durvalumab significantly prolonged overall survival, as compared with placebo (stratified hazard ratio for death, 0.68; 99.73% CI, 0.47 to 0.997; P=0.0025). Updated analyses regarding progression-free survival were similar to those previously reported, with a median duration of 17.2 months in the durvalumab group and 5.6 months in the placebo group (stratified hazard ratio for disease progression or death, 0.51; 95% CI, 0.41 to 0.63). The median time to death or distant metastasis was 28.3 months in the durvalumab group and 16.2 months in the placebo group (stratified hazard ratio, 0.53; 95% CI, 0.41 to 0.68). A total of 30.5% of the patients in the durvalumab group and 26.1% of those in the placebo group had grade 3 or 4 adverse events of any cause; 15.4% and 9.8% of the patients, respectively, discontinued the trial regimen because of adverse events. CONCLUSIONS: Durvalumab therapy resulted in significantly longer overall survival than placebo. No new safety signals were identified. (Funded by AstraZeneca; PACIFIC ClinicalTrials.gov number, NCT02125461 .). ispartof: NEW ENGLAND JOURNAL OF MEDICINE vol:379 issue:24 pages:2342-2350 ispartof: location:United States status: published

Introduction For patients with recurrent SCLC, topotecan remains the only approved second-line treatment, and the outcomes are poor. CheckMate 032 is a phase 1/2, multicenter, open-label study of nivolumab or nivolumab plus ipilimumab in SCLC or other advanced/metastatic solid tumors previously treated with one or more platinum-based chemotherapies. We report results of third- or later-line nivolumab monotherapy treatment in SCLC. Methods In this analysis, patients with limited-stage or extensive-stage SCLC and disease progression after two or more chemotherapy regimens received nivolumab monotherapy, 3 mg/kg every 2 weeks, until disease progression or unacceptable toxicity. The primary end point was objective response rate. Secondary end points included duration of response, progression-free survival, overall survival, and safety. Results Between December 4, 2013, and November 30, 2016, 109 patients began receiving third- or later-line nivolumab monotherapy. At a median follow-up of 28.3 months (from first dose to database lock), the objective response rate was 11.9% (95% confidence interval: 6.5–19.5) with a median duration of response of 17.9 months (range 3.0–42.1). At 6 months, 17.2% of patients were progression-free. The 12-month and 18-month overall survival rates were 28.3% and 20.0%, respectively. Grade 3 to 4 treatment-related adverse events occurred in 11.9% of patients. Three patients (2.8%) discontinued because of treatment-related adverse events. Conclusions Nivolumab monotherapy provided durable responses and was well tolerated as a third- or later-line treatment for recurrent SCLC. These results suggest that nivolumab monotherapy is an effective third- or later-line treatment for this patient population.

Introduction The phase II ABOUND.PS2 study (NCT02289456) assessed safety/tolerability of a first-line modified nab-paclitaxel/carboplatin regimen for patients with advanced non-small cell lung cancer (NSCLC) and Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2. Methods Chemotherapy-naive patients with stage IIIB/IV NSCLC and ECOG PS 2 received four cycles of nab-paclitaxel 100 mg/m2 days 1 and 8 plus carboplatin area under the curve 5 day 1 q3w (induction). Patients without progression received nab-paclitaxel monotherapy (100 mg/m2 days 1 and 8 q3w) until progression/unacceptable toxicity. Primary endpoint: percentage of patients discontinuing induction due to treatment-emergent adverse events (TEAEs). Results 11/40 treated patients (27.5%; 95% CI, 14.60–43.89) discontinued chemotherapy induction due to TEAEs; 16/40 (40.0%) continued nab-paclitaxel monotherapy. Median progression-free and overall survival were 4.4 (95% CI, 2.99–7.00) and 7.7 (95% CI, 4.93–13.17) months. Grade 3/4 TEAEs during induction included neutropenia (22.5%), anemia (17.5%), thrombocytopenia (5.0%), and peripheral neuropathy (2.5%). Conclusion This nab-paclitaxel–based regimen was tolerable in patients with advanced NSCLC and ECOG PS 2, with efficacy comparable to historical chemotherapy data.

Background Checkpoint Inhibitors (CPIs), are now part of standard treatment in many advanced solid tumors, including metastatic non-small cell lung cancer (mNSCLC). However, novel, more effective CPI combinations are needed to broaden, deepen, and prolong responses, especially for pts with poor prognostic features or negative predictive clinical factors for CPI benefit, including PD-L1 negative (-) status. Bempegaldesleukin (BEMPEG; NKTR-214) is a CD122-preferential IL-2 pathway agonist designed to provide sustained signaling through the IL-2 βγ receptor. BEMPEG + CPI has demonstrated promising efficacy and can convert PD-L1(-) tumors to PD-L1(+) in pts with multiple solid tumors (Diab A, ASCO 2018; Siefker-Radtke A, ASCO-GU 2019). Given the early efficacy data and favorable safety profile of BEMPEG + nivolumab, PROPEL will evaluate the clinical benefit, safety and tolerability of BEMPEG combined with another CPI, pembrolizumab (PEMBRO). Trial Design This phase I/II multinational trial evaluates BEMPEG + PEMBRO in pts with locally advanced or metastatic solid tumors. There are two key components to the study: 1) Dose optimization: which includes 3 + 3 and step-up dosing (U.S. enrollment only) and will include ∼40 pts with first- and second-line melanoma, NSCLC, urothelial carcinoma, head and neck squamous cell carcinoma, and hepatocellular carcinoma, regardless of PD-L1 status; 2) Dose expansion: which includes ∼58 first-line mNSCLC pts (enrolling globally). The expansion cohort will evaluate the preliminary anti-tumor activity of BEMPEG, in combination with PEMBRO, in first-line mNSCLC, regardless of PD-L1 status ( 50%). The primary objectives in the dose optimization cohorts are safety and tolerability of the combination and to determine the maximum tolerated dose, recommended phase II dose and optimal dosing schedule of BEMPEG in combination with PEMBRO in locally advanced or metastatic solid tumors. The primary objective in the dose expansion cohort is objective response rate by RECIST 1.1. Enrollment is ongoing. Clinical trial identification NCT03138889. Legal entity responsible for the study Nektar Therapeutics. Funding Nektar Therapeutics. Disclosure M. Reck: Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck Sharp & Dohme; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony: Celgene. F. Cappuzzo: Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: Clovis Oncology; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Roche/Genentech; Advisory / Consultancy: Lilly. D. Rodriguez-Abreu: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Hoffmann-La Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Boehringer-Ingelheim. D.C. Cho: Advisory / Consultancy: Puretech; Advisory / Consultancy: Nektar Therapeutics; Advisory / Consultancy: HUYA; Advisory / Consultancy: Prometheus; Advisory / Consultancy: Genentech; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Exelixis. M.J. Riese: Advisory / Consultancy: Abbvie; Advisory / Consultancy, Research grant / Funding (self): Bristol-Myers Squibb; Advisory / Consultancy: Exelixis; Advisory / Consultancy, Research grant / Funding (self): Incyte. A. Gupta: Leadership role, Employed by Nektar: Nektar Therapeutics. T. Chan: Leadership role, Employed by Nektar: Nektar Therapeutics. R. Saab: Leadership role, Employed by Nektar: Nektar Therapeutics. S. Singel: Leadership role, Employed by Nektar: Nektar Therapeutics. W. Lin: Leadership role, Employed by Nektar: Nektar Therapeutics. M. Tagliaferri: Advisory / Consultancy, Leadership role, Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Licensing / Royalties, Employed by Nektar: Nektar Therapeutics; Advisory / Consultancy, Travel / Accommodation / Expenses: Bluebird Bio. D.R. Spigel: Honoraria (institution), Research grant / Funding (institution): Abbvie; Honoraria (institution), Research grant / Funding (institution): Aeglea; Honoraria (institution), Research grant / Funding (institution): Amgen; Honoraria (institution), Research grant / Funding (institution): AstraZeneca; Honoraria (institution), Research grant / Funding (institution): Boehringer Ingelheim; Honoraria (institution), Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (institution), Research grant / Funding (institution): Celgene; Honoraria (institution): Evelo; Honoraria (institution), Research grant / Funding (institution): Foundation Medicine; Honoraria (institution), Research grant / Funding (institution): Genentech/Roche; Honoraria (self), Research grant / Funding (institution): GlaxoSmithKline; Honoraria (institution): Illumina; Honoraria (institution), Research grant / Funding (institution): Ipsen; Honoraria (institution), Research grant / Funding (institution): Lilly; Honoraria (institution), Research grant / Funding (institution): Merck; Honoraria (institution): Moderna Therapeutics; Honoraria (institution), Research grant / Funding (institution): Nektar; Honoraria (institution), Research grant / Funding (institution): Novartis; Honoraria (institution): PharmaMar; Honoraria (institution), Research grant / Funding (institution): Pfizer; Honoraria (institution), Research grant / Funding (institution): Takeda; Research grant / Funding (institution): Tesaro; Research grant / Funding (institution): Transgene; Research grant / Funding (institution): Neon Therapeutics; Research grant / Funding (institution): Transgene; Honoraria (institution): Armo; Honoraria (institution): Precision Oncology; Research grant / Funding (institution): Acerta; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): CellDex; Research grant / Funding (institution): Clovis; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): EMD Serono; Research grant / Funding (institution): G1 Therapeutics; Research grant / Funding (institution): Grail; Research grant / Funding (institution): Millennium; Research grant / Funding (institution): OncoGenex. All other authors have declared no conflicts of interest.

Background An ongoing open-label, multiarm, multicenter, phase I study of the anti–CTLA-4 antibody MK-1308 in combination with pembrolizumab in advanced solid tumors (NCT03179436) revealed manageable safety and promising efficacy in patients (pts) with advanced non-small cell lung cancer receiving first-line therapy [Perets et al. J Clin Oncol. 2019;37(suppl):2558]. Here we report data from the small cell lung cancer (SCLC) cohort of this study. Methods In the dose confirmation phase, pts with advanced SCLC received MK-1308 at 75 mg Q6W + pembrolizumab 200 mg Q3W (up to 35 cycles). The primary end point was safety, and the secondary end point was ORR based on blinded independent central review (BICR) per RECIST v1.1. PFS based on BICR per RECIST v1.1 and OS were exploratory end points. The database cutoff date for this analysis was June 3, 2019. Results Forty pts with previously treated advanced SCLC (second-line or beyond) were enrolled and dosed; median duration of follow-up was 11 mo. At data cutoff, 32 pts (80%) discontinued study treatment—23 (58%) due to progressive disease, 4 (10%) due to AE, 2 (5.0%) due to clinical progression—and 3 (7.5%) withdrew consent. Median age was 66 years; 60% of pts were male and 65% had ECOG PS 1 at baseline. Seven pts achieved partial response according to BICR assessment, for an ORR of 18% (95% CI, 7.3-33). Eight pts (20%) had a best overall response of stable disease and 21 (53%) had progressive disease. Response duration ranged from 2.9 to 8.4+ mo. At the time of the data cutoff, 5 of 7 responses (71%) were ongoing. Median time to response was 2.1 mo (range, 1.1-12). Median PFS was 2.0 mo (95% CI, 1.9-3.9), and the 6-mo PFS rate was 26%. Median OS was 11 mo (95% CI, 5.9-not reached), and the 6-mo OS rate was 66%. Treatment-related adverse events (TRAEs) as determined by the investigator occurred in 32 pts (80%). Grade 3 TRAEs were reported in 11 pts (28%); no grade 4-5 events were reported. Three pts (7.5%) discontinued treatment due to TRAEs. Conclusion In heavily pretreated pts with SCLC, MK-1308 + pembrolizumab was generally well tolerated with encouraging antitumor activity. Clinical trial identification NCT03179436. Editorial acknowledgement Medical writing and/or editorial assistance was provided by Holly C. Cappelli, PhD, CMPP, and Dana Francis, PhD, of the ApotheCom pembrolizumab team (Yardley, PA, USA) and funded by Merck Sharp & Dohme Corp, a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Legal entity responsible for the study Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Funding Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Disclosure B.C. Cho: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Novartis; Honoraria (self), Research grant / Funding (self): Bayer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Honoraria (self), Research grant / Funding (self): MOGAM Institute; Honoraria (self), Research grant / Funding (self): Dong-A ST; Honoraria (self), Research grant / Funding (self), Licensing / Royalties: Champions Oncology; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Janssen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Yuhan; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Ono; Honoraria (self), Research grant / Funding (self): Dizal Pharma; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): MSD; Advisory / Consultancy: Boehringer-Ingelheim; Advisory / Consultancy: Roche; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Takeda; Shareholder / Stockholder / Stock options: TheraCanVac Inc; Shareholder / Stockholder / Stock options: Bridgebio Therapeutics; Shareholder / Stockholder / Stock options: Gencurix Inc. K. Yoh: Research grant / Funding (institution): MSD. J. Bar: Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: MSD; Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy: Takeda; Advisory / Consultancy, Research grant / Funding (institution): Abbvie; Advisory / Consultancy: OncoHost; Advisory / Consultancy: VBL; Research grant / Funding (institution): Pfizer. A. Nagrial: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): MSD; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AZ; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Research grant / Funding (institution): Beigene; Research grant / Funding (institution): Incyte. D.R. Spigel: Leadership role: Centennial Medical Center; Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: Boehringer-Ingelheim; Travel / Accommodation / Expenses: Celgene; Travel / Accommodation / Expenses: Eli Lilly; Travel / Accommodation / Expenses: EMD Serono; Travel / Accommodation / Expenses: Bristol-Myers Squibb; Travel / Accommodation / Expenses: Genentech; Travel / Accommodation / Expenses: Genzyme; Travel / Accommodation / Expenses: Intuitive Surgical; Travel / Accommodation / Expenses: Merck; Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Purdue Pharma; Travel / Accommodation / Expenses: Spectrum Pharmaceuticals; Travel / Accommodation / Expenses: Sysmex. M. Gutierrez: Shareholder / Stockholder / Stock options: COTA; Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lilly; Advisory / Consultancy: Esanex; Advisory / Consultancy: Guardant 360; Speaker Bureau / Expert testimony: Merck; Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Speaker Bureau / Expert testimony: Foundation Medicine. D-W. Kim: Research grant / Funding (institution): Alpha Biopharma; Research grant / Funding (institution): AstraZeneca/Medimmune; Research grant / Funding (institution): Hanmi; Research grant / Funding (institution): Janssen; Research grant / Funding (institution): Merus; Research grant / Funding (institution): Mirati Therapeutics; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): ONO Pharmaceutical; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche/Genentech; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): TP Therapeutics; Research grant / Funding (institution): Xcovery; Research grant / Funding (institution): Yuhan. D. Rasco: Research grant / Funding (institution): Merck; Research grant / Funding (institution): Regeneron. M. Satouchi: Honoraria (self), Research grant / Funding (institution): MSD. M-J. Ahn: Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: ONO; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Takeda; Advisory / Consultancy: Lilly; Advisory / Consultancy: Alpha Pharm. D.H. Lee: Honoraria (self): AbbVie; Honoraria (self): AstraZeneca; Honoraria (self): Boehringer-Ingelheim; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): ChongKunDang; Honoraria (self): CJ Healthcare; Honoraria (self): Eli Lilly; Honoraria (self): Janssen; Honoraria (self): Menarini; Honoraria (self): Merck; Honoraria (self): MSD; Honoraria (self): Mundipharma; Honoraria (self): Novartis; Honoraria (self): Ono; Honoraria (self): Pfizer; Honoraria (self): Roche; Honoraria (self): Samyang Biopharm; Honoraria (self), Advisory / Consultancy: ST Cube; Honoraria (self): Takeda. C. Maurice-Dror: Travel / Accommodation / Expenses: Janssen; Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Roche. S. Siddiqi: Full / Part-time employment: Merck & Co., Inc.. X. Li: Full / Part-time employment: Merck & Co., Inc.. J. Cyrus: Leadership role, Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc.. R.A. Altura: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc.. R. Perets: Advisory / Consultancy: Karyopharm; Advisory / Consultancy: BiolineRx. All other authors have declared no conflicts of interest.

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. Trial design CANOPY-A (NCT03447769) is a phase III, randomized, double-blind, placebo-controlled study designed to evaluate efficacy and safety of adjuvant canakinumab vs placebo in pts with surgically resected NSCLC. This trial will enroll adult pts, 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 pts 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 pt, death, or loss to follow-up. Randomization will be stratified by AJCC/UICC v.8 stage, tumor histology, and region. In the amended protocol, a sub-study was included to determine the biomarker levels in the blood at pre- and post-surgery, and to establish their association with canakinumab efficacy. 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 pt-reported outcomes. Enrollment is ongoing. Clinical trial identification CACZ885T2301. Legal entity responsible for the study Novartis. Funding Novartis. Disclosure B.C. Cho: Honoraria (self): Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, MSD; Advisory / Consultancy: Novartis, AstraZeneca, Boehringer Ingelheim, Roche, BMS, Ono, Yuhan, Pfizer, Eli Lilly, Janssen, Takeda, MSD; Research grant / Funding (self): Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, MSD; Shareholder / Stockholder / Stock options: TheraCanVac Inc; Licensing / Royalties: Champions Oncology. G-C. Chang: Honoraria (self): F. Hoffmann–La Roche, Ltd, Eli Lilly and Company Oncology, AstraZeneca, Pfizer, Boehringer Ingelheim, Bristol-Myers Squibb, and Merck Sharp & Dohme. Y-C. Kim: Honoraria (self): AstraZeneca, Roche, Boehringer Ingelheim; Research grant / Funding (self): AstraZeneca, Roche, Boehringer Ingelheim. S. Geater: Honoraria (self): AstraZeneca, Boehringer Ingelheim, Roche; Advisory / Consultancy: Boehringer Ingelheim; Research grant / Funding (institution): AstraZeneca, Boehringer Ingelheim, Roche, MSD; Travel / Accommodation / Expenses: AstraZeneca, Boehringer Ingelheim, Roche. S. Saeteng: Honoraria (self): AstraZeneca, Novartis : Speaker. Y. Goto: Speaker Bureau / Expert testimony: AstraZeneca, Eli Lilly, Chugai, Taiho Pharmaceutical, Boehringer Ingelheim, Ono Pharmaceutical, Bristol-Myers Squibb, Pfizer, MSD, Shionogi Pharma, Novartis; Advisory / Consultancy: Eli Lilly, Chugai, Taiho Pharmaceutical, Boehringer Ingelheim, Pfizer, Novartis, AstraZeneca, Glaxo Smith Kline; Research grant / Funding (self): AbbVie, Eli Lilly, Taiho Pharmaceutical, Bristol-Myers Squibb, Ono Pharmaceutical, Daiichi Sankyo, Pfizer, Novartis, Kyorin. S. Lu: Research grant / Funding (self): AstraZeneca, Hutchison, Roche; Advisory / Consultancy: AstraZeneca, Boehringer Ingelheim, Hutchison MediPharma, Simcere, Roche; Honoraria (self): AstraZeneca, Roche. A. Ardizzoni: Advisory / Consultancy: MDS, Roche; Honoraria (self): MSD, BMS, Pfizer, Lilly; Research grant / Funding (self): BMS, Celgene, Roche; Leadership role: Member Educational Committee. F. Barlesi: Honoraria (self): AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly Oncology,. P. De Marchi: Advisory / Consultancy: Roche, Bayer, Msd, BMS, Pfizer, AstraZeneca; Speaker Bureau / Expert Testimony: Roche, Bayer, MSD, BMS, Pfizer, AstraZeneca; Travel / Accommodation / Expenses: Roche, MSD, BMS, AstraZeneca. L. Paz-Ares: Advisory / Consultancy: Roche, Lilly, Novartis, Pfizer, BMS, MSD, Takeda, AstraZeneca, Boehringer Ingelheim, Bayer, Janssen, Celgene; Honoraria (self): Roche, Lilly, Novartis, Pfizer, BMS, MSD, Amgen, Merck, Sanofi, Takeda, AstraZeneca, Boehringer Ingelheim, Bayer, Janssen, PharmaMar, Celgene. D.R. Spigel: Advisory / Consultancy: AbbVie (Inst); Amgen (Inst); AstraZeneca (Inst); Boehringer Ingelheim (Inst); Bristol-Myers Squibb (Inst); Celgene (Inst); Evelo Therapeutics (Inst); Foundation Medicine (Inst); Genentech/Roche (Inst); GlaxoSmithKline (Inst); Illumina (Inst); Lilly (Inst); Research grant / Funding (institution): AbbVie (Inst); Acerta Pharma (Inst); Aeglea Biotherapeutics (Inst); Amgen (Inst); ARMO BioSciences (Inst); Astellas Pharma (Inst); AstraZeneca (Inst); Boehringer Ingelheim (Inst); Bristol-Myers Squibb (Inst); Celgene (Inst); Celldex (Inst); Clovis Oncolog; Travel / Accommodation / Expenses: AstraZeneca; Boehringer Ingelheim; Bristol-Myers Squibb; Celgene; EMD Serono; Genentech; Genzyme; Intuitive Surgical; Lilly; Merck; Pfizer; Purdue Pharma; Spectrum Pharmaceuticals; Sysmex. M. Thomas: Advisory / Consultancy: Novartis, Lilly, Pfizer, Bristol-Myers Squibb, Roche, AstraZeneca, Boehringer Ingelheim, MSD; Honoraria (self): Roche, Bristol-Myers Squibb, Lilly, AstraZeneca, Novartis, Pfizer, Boehringer Ingelheim, MSD; Research grant / Funding (self): Roche, BMS, MSD, AstraZeneca, Takeda. E.B. Garon: Advisory / Consultancy: Dracen, EMD Serono; Research grant / Funding (self): AstraZeneca, BMS, Eli Lilly, Genentech, Merck, Novartis, Neon, Iovance, Dynavax, Mirati. M. Leung: Shareholder / Stockholder / Stock options: Novartis; Full / Part-time employment: Novartis. J. Baum: Shareholder / Stockholder / Stock options: Novartis stock; Full / Part-time employment: Novartis. Spouse (Lauren Baum) – Abbot Laboratories. Z. Zewen: Full / Part-time employment: Novartis; Shareholder / Stockholder / Stock options: Novartis. B. Mookerjee: Full / Part-time employment: Novartis; Shareholder / Stockholder / Stock options: Novartis, GlaxoSmithKline, Incyte, AstraZeneca. J.C-H. Yang: Advisory / Consultancy: Boehringer Ingelheim, Eli Lilly, Bayer, Roche/Genentech, Chugai Pharmaceutical, MSD, Merck Serono, Pfizer, Novartis, Celgene, Merrimack, Yuhan Pharmaceuticals, BMS, Ono Pharmaceuticals, Daiichi-Sankyo, Hansoh Pharmaceuticals, Takeda Pharmaceuticals, Bluep; Honoraria (self): Boehringer Ingelheim, Eli Lilly, Bayer, Roche/Genentech, Chugai Pharmaceutical, MSD, Merck Serono, Pfizer, Novartis, Celgene, Merrimack, Yuhan Pharmaceuticals, BMS, Ono Pharmaceuticals, Daiichi-Sankyo, Hansoh Pharmaceuticals, Takeda Pharmaceuticals, Bluep; Leadership role: IASLC CME activity: Author/Board of Directors/Presenter/Reviewer. All other authors have declared no conflicts of interest.

Background Avelumab, a human IgG1 anti–PD-L1 monoclonal antibody, is an approved treatment for metastatic Merkel cell carcinoma and platinum-treated urothelial carcinoma. We performed descriptive post hoc analyses to explore characteristics of patients with NSCLC from the JAVELIN Solid Tumor phase I trial (NCT01772004) who received long-term avelumab treatment (>2-yrs) as a surrogate for long-term clinical benefit. Methods Patients with NSCLC were pooled from 2 dose-expansion cohorts enrolled with no prior treatment for metastatic/recurrent disease (first-line [1L]) or with disease progression after prior platinum doublet therapy (second-line [2L]). PD-L1 expression in tumor cells was assessed using the Dako 73-10 assay. Results As of 24 Oct 2018, duration of avelumab treatment was >2-yrs in 35 of 340 patients (10.3%) and ≤2-yrs in 305 of 340 (89.7%). At baseline (data cutoff: 15 Feb 2017), patients who subsequently received >2-yr vs≤2-yr treatment had a higher proportion with prior radiotherapy (51.4% vs 37.0%), better performance status (ECOG PS 0 in 37.1% vs 28.9%), a lower proportion with liver (11.4% vs 19.0%) or bone (14.3% vs 22.3%) metastases, and a smaller tumor burden (median, 52 vs 70mm). A higher proportion of patients with >2-yr vs≤2-yr treatment had clinical benefit (response or stable disease) on prior chemotherapy (40.0% vs 25.9%, respectively; not applicable in 31.4% vs 39.7%; not evaluable in 17.1% vs 8.2%). The proportion with PD-L1+ tumors was comparable in those with >2-yr or≤2-yr treatment using PD-L1 cutoffs of≥1% (68.6% vs 61.0%) and ≥80% (25.7% vs 23.0%), although a high proportion were nonevaluable for PD-L1 expression (25.6%). Of patients with >2-yr treatment, 18 continued treatment after RECIST-defined progression and had a decrease in tumor burden or maintained clinical benefit. Conclusions Retrospective post hoc analyses suggest that patients with NSCLC who had long-term benefit with 1L or 2L avelumab had better performance status, less aggressive disease, prior radiotherapy, and previous benefit on chemotherapy at baseline. Clinical trial identification NCT01772004. Editorial acknowledgement ClinicalThinking; funded by Merck Healthcare KGaA and Pfizer Inc. Legal entity responsible for the study Merck Healthcare KGaA. Funding Merck Healthcare KGaA and Pfizer Inc. Disclosure B. Hrinczenko: Research grant / Funding (institution): EMD Serono; Research grant / Funding (institution): Merrimack Pharma; Research grant / Funding (institution): Endocyte; Research grant / Funding (institution): Amgen. D. Spigel: Leadership role: Cetennial Medical Center; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Genentech/Roche; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Celgene; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Boehringer Ingelheim; Advisory / Consultancy, Research grant / Funding (institution): AbbVie; Advisory / Consultancy, Research grant / Funding (institution): Foundation Medicine; Advisory / Consultancy, Research grant / Funding (institution): GlaxoSmithKline; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Lilly; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck & Co.; Advisory / Consultancy: Moderna Therapeutics; Advisory / Consultancy, Research grant / Funding (institution): Nektar; Advisory / Consultancy, Research grant / Funding (institution): Takeda; Advisory / Consultancy, Research grant / Funding (institution): Amgen; Advisory / Consultancy: TRM Oncology; Advisory / Consultancy: Precision Oncology; Advisory / Consultancy: Evelo Therapeutics; Advisory / Consultancy: Illumina; Advisory / Consultancy: PharmaMar; Research grant / Funding (institution): University of Texas Southwestern Medical Center - Simmons Cancer Center; Research grant / Funding (institution): G1 Therapeutics; Research grant / Funding (institution): Neon Therapeutics; Research grant / Funding (institution): Celldex; Research grant / Funding (institution): Clovis Oncology; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution), Travel / Accommodation / Expenses: EMD Serono; Research grant / Funding (institution): Acerta Pharma; Research grant / Funding (institution): Oncogenex; Research grant / Funding (institution): Astellas Pharma; Research grant / Funding (institution): GRAIL; Research grant / Funding (institution): Transgene; Research grant / Funding (institution): Aeglea Biotherapeutics; Research grant / Funding (institution): Tesaro; Research grant / Funding (institution): Ipsen; Research grant / Funding (institution): ARMO BioSciences; Research grant / Funding (institution): Millennium; Travel / Accommodation / Expenses: Genzyme; Travel / Accommodation / Expenses: Intuitive Surgical; Travel / Accommodation / Expenses: Purdue Pharma; Travel / Accommodation / Expenses: Spectrum Pharmaceuticals; Research grant / Funding (institution): Sysmex. M.H. Taylor: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Eisai ; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Blueprint; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Loxo; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Array ; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: ArQule, Inc. J. Bennouna: Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Research grant / Funding (institution): Merck KGaA. S. Goel: Research grant / Funding (institution): EMD Serono. J. Leach: Full / Part-time employment, Employed as of Sep 2016 to Sep 2017: PRA Health Sciences ; Research grant / Funding (institution): Dynarax ; Research grant / Funding (institution): Geistlich . D.J. Wong: Research grant / Funding (institution): EMD Serono; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Merck & Co.; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): KURA Oncology; Research grant / Funding (institution): Roche-Genentech; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Regeneron; Research grant / Funding (institution): FSTAR; Research grant / Funding (institution): Astellas. K. Kelly: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Merck & Co.; Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: AbbVie; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Research grant / Funding (self): EMD Serono; Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Genentech; Advisory / Consultancy: Pfizer; Advisory / Consultancy, Research grant / Funding (self): Regeneron; Research grant / Funding (self): Five Prime; Travel / Accommodation / Expenses: Lilly; Licensing / Royalties: UpToDate. M. Bajars: Full / Part-time employment: EMD Serono. J. Manitz: Full / Part-time employment: EMD Serono. M. Ruisi: Full / Part-time employment: EMD Serono. J.L. Gulley: Research grant / Funding (institution): EMD Serono; Research grant / Funding (institution): Bavarian Nordic; Research grant / Funding (institution): Astellas Medivation; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): NantBioScience; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Merck & Co. All other authors have declared no conflicts of interest.

Background JAVELIN Lung 200, a randomized, open-label, phase III study, did not meet its primary endpoint of significantly improving overall survival (OS) with avelumab vs docetaxel in patients with PD-L1+ NSCLC. However, OS may have been affected by the larger proportion of patients in the docetaxel arm who received a subsequent CPI. We present post hoc analyses assessing the effect of subsequent CPIs on OS in the JAVELIN Lung 200 study. Methods Patients with stage IIIB/IV NSCLC and disease progression after platinum doublet treatment were randomized 1:1 to receive avelumab 10mg/kg every 2 weeks or docetaxel 75mg/m2 every 3 weeks. The primary analysis population for OS was patients with PD-L1+ tumors (≥1% PD-L1 expression in tumor cells using the IHC 73-10 assay); OS was also analyzed in the full analysis set (FAS). To assess the impact of subsequent CPI treatment (after discontinuation of randomly assigned study treatment) on OS, a preplanned naive sensitivity analysis and a post hoc inverse probability of censoring weighted (IPCW) analysis were performed. Results A subsequent CPI (anti–PD-1, anti–PD-L1, or anti–CTLA-4) was received by 16/396 (4.0%) in the avelumab arm and 104/396 (26.3%) in the docetaxel arm in the FAS, including 15/264 (5.7%) and 70/265 (26.4%) in the PD-L1+ population, respectively. Median time to subsequent CPI was shorter in the docetaxel arm than the avelumab arm (5.68 vs 10.53 months; FAS). Hazard ratios for OS with avelumab vs docetaxel were lower in the IPCW model than in the primary analysis and naive sensitivity analysis, both in the FAS and in the PD-L1+ population (Table).Table1492PTableFull Analysis SetPD-L1+ PopulationAvelumab (n=396)Docetaxel (n=396)Avelumab (n=264)Docetaxel (n=265)OS events248207161137Subsequent CPI events161041570Primary analysis (intent to treat)mOS (95% CI)10.5 (9.2-12.9)9.9 (8.1- 11.8)11.4 (9.4-13.9)10.3 (8.5- 13.0)HR (95% CI)0.90 (0.76-1.07)0.90 (0.73-1.11)Naive sensitivity analysis (patients censored at subsequent CPI)mOS (95% CI)10.5 (9.1-12.8)9.5 (8.4- 11.3)10.8 (9.4-13.8)10.3 (8.5- 13.0)HR (95% CI)0.89 (0.74-1.07)0.86 (0.68-1.09)IPCW adjusted modelHR (95% CI)0.85 (0.70-1.05)0.80 (0.62-1.04) Conclusions IPCW analyses suggest that the primary OS analysis in this study was impacted by the relatively high proportion of patients in the docetaxel arm who received a subsequent CPI. Clinical trial identification NCT02395172. Editorial acknowledgement ClinicalThinking; funded by Merck Healthcare KGaA and Pfizer Inc. Legal entity responsible for the study Merck Healthcare KGaA. Funding Merck Healthcare KGaA and Pfizer Inc. Disclosure F. Barlesi: Honoraria (self), Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Honoraria (institution), Advisory / Consultancy: Boehringer–Ingelheim; Honoraria (self), Honoraria (institution), Advisory / Consultancy: Eli Lilly; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): F. Hoffmann–La Roche Ltd; Honoraria (self), Honoraria (institution), Advisory / Consultancy: Novartis; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Merck; Honoraria (self), Honoraria (institution), Advisory / Consultancy: MSD; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Pierre Fabre; Honoraria (self), Honoraria (institution), Advisory / Consultancy: Pfizer; Honoraria (self), Honoraria (institution), Advisory / Consultancy: Takeda; Honoraria (institution): AbbVie; Honoraria (institution): ACEA; Honoraria (institution): Amgen; Honoraria (institution): Bayer; Honoraria (institution): Eisai; Honoraria (institution): Genentech; Honoraria (institution): Ipsen; Honoraria (institution): Ignyta; Honoraria (institution): Innate Pharma; Honoraria (institution): Loxo; Honoraria (institution): Sanofi-Aventis. M. Ozguroglu: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen; Honoraria (self), Advisory / Consultancy: Astellas; Travel / Accommodation / Expenses: Bristol-Myers Squibb. J.F. Vansteenkiste: Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Roche; Advisory / Consultancy: Apotex. D. Spigel: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche/Genentech; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Celgene; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Boehringer Ingelheim; Advisory / Consultancy, Research grant / Funding (institution): AbbVie; Advisory / Consultancy, Research grant / Funding (institution): Foundation Medicine; Advisory / Consultancy, Research grant / Funding (institution): GSK; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Eli Lilly; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck KGaA; Advisory / Consultancy: Moderna Therapeutics; Advisory / Consultancy, Research grant / Funding (institution): Nektar; Advisory / Consultancy, Research grant / Funding (institution): Takeda; Advisory / Consultancy, Research grant / Funding (institution): Amgen; Advisory / Consultancy: TRM Oncology; Advisory / Consultancy: Precision Oncology; Advisory / Consultancy: Evelo Therapuetics; Advisory / Consultancy: Illumina; Advisory / Consultancy: PharmaMar; Research grant / Funding (institution): University of Texas Southwestern Medical Center - Simmons Cancer Center; Research grant / Funding (institution): G1 Therapeutics; Research grant / Funding (institution): Neon Therapeutics; Research grant / Funding (institution): Celldex; Research grant / Funding (institution): Clovis Oncology; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution), Travel / Accommodation / Expenses: EMD Serono, Inc; Research grant / Funding (institution): Acerta Pharma; Research grant / Funding (institution): Oncogenex; Research grant / Funding (institution): Astellas Pharma; Research grant / Funding (institution): GRAIL; Research grant / Funding (institution): Transgene; Research grant / Funding (institution): Aeglea Biotherapeutics; Research grant / Funding (institution): Tesaro; Research grant / Funding (institution): Ipsen; Research grant / Funding (institution): ARMO Biosciences; Research grant / Funding (institution): Millenium; Travel / Accommodation / Expenses: Genzyme; Travel / Accommodation / Expenses: Intuitive Surgical; Travel / Accommodation / Expenses: Purdue Pharma; Travel / Accommodation / Expenses: Spectrum Pharmaceuticals; Travel / Accommodation / Expenses: Sysmex. J.C. Yang: Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy: Eli Lilly; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Roche/Genentech; Honoraria (self), Advisory / Consultancy: Chugai Pharmaceutical; Honoraria (self), Advisory / Consultancy: MSD; Advisory / Consultancy: Merck Serono; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Novartis; Advisory / Consultancy: Celgene; Advisory / Consultancy: Merrimack; Advisory / Consultancy: Yuhan Pharmaceuticals; Honoraria (institution), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Ono Pharmaceuticals; Advisory / Consultancy: Daiichi-Sankyo; Advisory / Consultancy: Hansoh Pharmaceuticals; Advisory / Consultancy: Takeda Pharmaceuticals; Advisory / Consultancy: Blueprint Medicines; Honoraria (self), Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: G1 Therapeutics. M. Bajars: Full / Part-time employment: EMD Serono, Inc. M. Ruisi: Full / Part-time employment: EMD Serono, Inc. J. Manitz: Full / Part-time employment: EMD Serono, Inc. K. Park: Advisory / Consultancy: AMGEN; Advisory / Consultancy: Astellas Pharma; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: BluePrint; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim; Advisory / Consultancy: Clovis Oncology; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: GSK; Advisory / Consultancy: Hanmi; Advisory / Consultancy: Kyowa Hakko Kirin; Advisory / Consultancy: Merck KGaA; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy: Novartis; Advisory / Consultancy: Ono Pharmaceuticals; Advisory / Consultancy: Roche.

Purpose Bevacizumab used in combination with first-line chemotherapy confers an overall survival (OS) benefit for patients with non-squamous non–small-cell lung cancer (NSCLC). This analysis from the ARIES observational cohort study (OCS) was initiated to evaluate the effect of bevacizumab use beyond disease progression (BBP) on clinical outcomes in patients with NSCLC receiving first-line treatment with bevacizumab and chemotherapy. Methods The ARIES OCS prospectively enrolled patients from 2006 to 2009 in the United States who had advanced non-squamous NSCLC, received bevacizumab with chemotherapy in the first-line setting, and survived progressive disease (PD). A dichotomous landmark analysis examined post-PD OS (ppOS) in patients who received BBP versus no BBP within 30 days post PD. A time-dependent Cox model assessed the effect of cumulative BBP exposure on ppOS. Results The ARIES OCS enrolled 1967 patients with first-line NSCLC; 1358 patients had first PD and were alive at the 30-day landmark (351 patients with BBP and 1007 patients with no BBP). The landmark analysis showed that BBP was associated with a lower risk of death (BBP versus No-BBP); hazard ratio [HR], 0.75; 95% confidence interval 0.65–0.86. In the cumulative exposure analysis of 1461 patients who had PD, HRs for ppOS decreased by approximately 4% for each additional 21-day interval of bevacizumab received. Protocol-specified bevacizumab-select adverse events occurred in 14% of BBP patients. Conclusions BBP was associated with a lower risk of death in patients with NSCLC treated with first-line bevacizumab and chemotherapy. Copyright © 2016 John Wiley & Sons, Ltd.

Background Panitumumab Regimen In Second-line Monotherapy of Head and Neck Cancer (PRISM) trial evaluated the safety and efficacy of panitumumab as second-line monotherapy in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). Methods This was an open-label, single-arm, multicenter trial that enrolled patients with progressive disease or intolerance to first-line systemic chemotherapy for recurrent or metastatic SCCHN. Patients received panitumumab 9 mg/kg Q3W. The primary endpoint was overall response rate; secondary endpoints included disease control rate, overall survival (OS), progression-free survival (PFS), and safety. Results The overall response rate was 4% (2 of 51 patients) and the disease control rate was 39% (20 of 51 patients). Median PFS was 1.4 months (95% confidence interval [CI] = 1.3–2.4 months). Median OS was 5.1 months (95% CI = 4.3–8.3 months). The most common adverse events were rash/dermatitis acneiform (69%), fatigue (33%), dry skin (21%), and hypomagnesemia (21%). There was one treatment-related death (angioedema). Conclusion Panitumumab monotherapy had limited activity in previously treated patients with recurrent or metastatic SCCHN. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1756–E1761, 2016

Purpose Epidermal growth factor receptor (EGFR) –tyrosine kinase inhibitors have proven efficacy in advanced non–small-cell lung cancer (NSCLC). We hypothesized that erlotinib would be efficacious in the adjuvant setting. Patients and Methods An international randomized, double-blind, placebo-controlled study was conducted in patients with completely resected IB to IIIA NSCLC whose tumors expressed EGFR protein by immunohistochemistry or EGFR amplification by fluorescence in situ hybridization. Patients were assigned 2:1 to erlotinib 150 mg once per day or placebo for 2 years. Stratification factors were stage, histology, previous adjuvant chemotherapy, smoking status, EGFR amplification status, and country. The primary end point was disease-free survival (DFS); key secondary end points were overall survival (OS) and DFS and OS in patients whose tumors had EGFR-activating mutations (EGFRm-positive). Results A total of 973 patients were randomly assigned (November 26, 2007, to July 7, 2010). There was no statistically significant difference in DFS (median, 50.5 months for erlotinib and 48.2 months for placebo; hazard ratio, 0.90; 95% CI, 0.74 to 1.10; P = .324). Among the 161 patients (16.5%) in the EGFRm-positive subgroup, DFS favored erlotinib (median, 46.4 v 28.5 months; hazard ratio, 0.61; 95% CI, 0.38 to 0.98; P = .039), but this was not statistically significant because of the hierarchical testing procedure. OS data are immature. Rash and diarrhea were common adverse events occurring in 528 (86.4%) and 319 (52.2%) patients treated with erlotinib, respectively, versus 110 (32.1%) and 54 (15.7%) patients receiving placebo. The most common grade 3 adverse events in patients treated with erlotinib were rash (22.3%) and diarrhea (6.2%). Conclusion Adjuvant erlotinib did not prolong DFS in patients with EGFR-expressing NSCLC or in the EGFRm-positive subgroup. Further evaluation of erlotinib is warranted in the EGFRm-positive subgroup.

Molecularly targeted therapies, directed against the features of a given tumor, have allowed for a personalized approach to the treatment of advanced non-small-cell lung cancer (NSCLC). The reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib had undergone turbulent clinical development until it was discovered that these agents have preferential activity in patients with NSCLC harboring activating EGFR mutations. Since then, a number of phase 3 clinical trials have collectively shown that EGFR-TKI monotherapy is more effective than combination chemotherapy as first-line therapy for EGFR mutation-positive advanced NSCLC. The next generation of EGFR-directed agents for EGFR mutation-positive advanced NSCLC is irreversible TKIs against EGFR and other ErbB family members, including afatinib, which was recently approved, and dacomitinib, which is currently being tested in phase 3 trials. As research efforts continue to explore the various proposed mechanisms of acquired resistance to EGFR-TKI therapy, agents that target signaling pathways downstream of EGFR are being studied in combination with EGFR TKIs in molecularly selected advanced NSCLC. Overall, the results of numerous ongoing phase 3 trials involving the EGFR TKIs will be instrumental in determining whether further gains in personalized therapy for advanced NSCLC are attainable with newer agents and combinations. This article reviews key clinical trial data for personalized NSCLC therapy with agents that target the EGFR and related pathways, specifically based on molecular characteristics of individual tumors, and mechanisms of resistance.

Purpose Programmed death 1 is an immune checkpoint that suppresses antitumor immunity. Nivolumab, a fully human immunoglobulin G4 programmed death 1 immune checkpoint inhibitor antibody, was active and generally well tolerated in patients with advanced solid tumors treated in a phase I trial with expansion cohorts. We report overall survival (OS), response durability, and long-term safety in patients with non–small-cell lung cancer (NSCLC) receiving nivolumab in this trial. Patients and Methods Patients (N = 129) with heavily pretreated advanced NSCLC received nivolumab 1, 3, or 10 mg/kg intravenously once every 2 weeks in 8-week cycles for up to 96 weeks. Tumor burden was assessed by RECIST (version 1.0) after each cycle. Results Median OS across doses was 9.9 months; 1-, 2-, and 3-year OS rates were 42%, 24%, and 18%, respectively, across doses and 56%, 42%, and 27%, respectively, at the 3-mg/kg dose (n = 37) chosen for further clinical development. Among 22 patients (17%) with objective responses, estimated median response duration was 17.0 months. An additional six patients (5%) had unconventional immune-pattern responses. Response rates were similar in squamous and nonsquamous NSCLC. Eighteen responding patients discontinued nivolumab for reasons other than progressive disease; nine (50%) of those had responses lasting > 9 months after their last dose. Grade 3 to 4 treatment-related adverse events occurred in 14% of patients. Three treatment-related deaths (2% of patients) occurred, each associated with pneumonitis. Conclusion Nivolumab monotherapy produced durable responses and encouraging survival rates in patients with heavily pretreated NSCLC. Randomized clinical trials with nivolumab in advanced NSCLC are ongoing.

Introduction African Americans have a greater incidence of lung cancer than whites and have been underrepresented in clinical trials. In the PointBreak trial (pemetrexed-carboplatin-bevacizumab and maintenance pemetrexed-bevacizumab [PemCBev] vs. paclitaxel-carboplatin-bevacizumab and maintenance bevacizumab [PacCBev]), 10% of the patients were African American. PointBreak had negative findings; PemCBev did not demonstrate superior overall survival (OS). Materials and Methods PointBreak subgroup efficacy and safety data were retrospectively analyzed: African Americans versus whites for PemCBev; PemCBev versus PacCBev in African Americans; and academic versus community settings for African Americans. Hazard ratios (HRs) and P values were derived from a multivariate Cox proportional hazards model after adjusting for covariates. Results Of 939 intent-to-treat (ITT) patients, 94 were African American and 805 were white. African-American enrollment was uniform across the study sites (median, 1 African American per site). In the PemCBev arm, OS (HR, 1.125; P = .525), progression-free survival (PFS) (HR, 1.229; P = .251), response ( P = .607), and toxicity profiles were similar in African Americans versus whites. For African Americans, OS (HR, 1.375; P = .209), PFS (HR, 0.902; P = .670), response ( P = 1.000), and toxicity profiles were similar in the PemCBev versus PacCBev arm. For African Americans, no significant differences were seen in OS (HR, 0.661; P = .191) or PFS (HR, 0.969; P = .915) in academic versus community practice settings. Conclusion In the PemCBev arm, this exploratory analysis showed no significant differences between African Americans and whites for the efficacy outcomes or toxicity profiles. Consistent with the ITT population negative trial result, for African Americans, the median OS was not superior for either arm. For African Americans, PFS and OS were similar in the academic and community settings. Additional outcomes data for African Americans should be collected in lung cancer studies.

IntroductionTreatment impact on quality of life (QoL) informs treatment management decisions in advanced nonsquamous non–small-cell lung cancer (NS NSCLC). QoL outcomes from the phase III PointBreak trial are reported.MethodsChemonaive patients (n = 939) with stage IIIB/IV nonsquamous non–small-cell lung cancer and Eastern Cooperative Oncology Group performance status 0 to 1 were randomized (1:1) to pemetrexed-carboplatin-bevacizumab (pemetrexed arm) or paclitaxel-carboplatin-bevacizumab (paclitaxel arm). Patients without progressive disease received maintenance pemetrexed-bevacizumab (pemetrexed arm) or bevacizumab (paclitaxel arm). QoL was assessed using Functional Assessment of Cancer Therapy (FACT)-General (FACT-G), FACT-Lung (FACT-L), and FACT/Gynecologic Oncology Group-Neurotoxicity (FACT-Ntx) instruments. Subscale scores, total scores, and trial outcome indices were analyzed using linear mixed-effects models. Post hoc analyses examined the association between baseline FACT scores and overall survival (OS).ResultsMean score differences in change from baseline significantly favored the pemetrexed arm for the neurotoxicity subscale score, FACT-Ntx total scores, and FACT-Ntx trial outcome index. They occurred at cycle 2 (p < 0.001) and persisted through induction cycles 2 to 4 and six maintenance cycles. Investigator-assessed, qualitative, drug-related differences in grade 2 (1.6% versus 10.6%) and grade 3 (0.0% versus 4.1%) sensory neuropathy and grade 3/4 fatigue (10.9% versus 5.0%, p = 0.0012) were observed between the pemetrexed and paclitaxel arms. Baseline FACT-G, FACT-L, and FACT-Ntx scores were significant prognostic factors for OS (p < 0.001).ConclusionsRandomized patients reported similar changes in QoL, except for less change from baseline in neurotoxicity on the pemetrexed arm; investigators reported greater neurotoxicity on the paclitaxel arm and greater fatigue on the pemetrexed arm. Higher baseline FACT scores were favorable prognostic factors for OS.

Imetelstat, a novel telomerase inhibitor, failed to improve significantly median PFS and OS as maintenance therapy (±bevacizumab) in advanced NSCLC. Telomere length (TL) biomarker results were consistent with the hypothesis that telomerase inhibition is of greater benefit to patients with tumors possessing shorter telomeres; the patients with shorter TL had a trend toward longer median PFS and OS. Background Continuation or ‘switch’ maintenance therapy is commonly used in patients with advancd non-small-cell lung cancer (NSCLC). Here, we evaluated the efficacy of the telomerase inhibitor, imetelstat, as switch maintenance therapy in patients with advanced NSCLC. Patients and methods The primary end point of this open-label, randomized phase II study was progression-free survival (PFS). Patients with non-progressive, advanced NSCLC after platinum-based doublet (first-line) chemotherapy (with or without bevacizumab), any histology, with Eastern Cooperative Oncology Group performance status 0–1 were eligible. Randomization was 2 : 1 in favor of imetelstat, administered at 9.4 mg/kg on days 1 and 8 of a 21-day cycle, or observation. Telomere length (TL) biomarker exploratory analysis was carried out in tumor tissue by quantitative PCR (qPCR) and telomerase fluorescence in situ hybridization. Results Of 116 patients enrolled, 114 were evaluable. Grade 3/4 neutropenia and thrombocytopenia were more frequent with imetelstat. Median PFS was 2.8 and 2.6 months for imetelstat-treated versus control [hazard ratio (HR) = 0.844; 95% CI 0.54–1.31; P = 0.446]. Median survival time favored imetelstat (14.3 versus 11.5 months), although not significantly (HR = 0.68; 95% CI 0.41–1.12; P = 0.129). Exploratory analysis demonstrated a trend toward longer median PFS (HR = 0.43; 95% CI 0.14–1.3; P = 0.124) and overall survival (OS; HR = 0.41; 95% CI 0.11–1.46; P = 0.155) in imetelstat-treated patients with short TL, but no improvement in median PFS and OS in patients with long TL (HR = 0.86; 95% CI 0.39–1.88; and HR = 0.51; 95% CI 0.2–1.28; P = 0.145). Conclusions Maintenance imetelstat failed to improve PFS in advanced NSCLC patients responding to first-line therapy. There was a trend toward a improvement in median PFS and OS in patients with short TL. Short TL as a predictive biomarker will require further investigation for the clinical development of imetelstat.

Purpose Detection of specific molecular alterations in tumors guides the selection of effective targeted treatment of patients with several types of cancer. These molecular alterations may occur in other tumor types for which the efficacy of targeted therapy remains unclear. The MyPathway study evaluates the efficacy and safety of selected targeted therapies in tumor types that harbor relevant genetic alterations but are outside of current labeling for these treatments. Methods MyPathway ( ClinicalTrials.gov identifier: NCT02091141) is a multicenter, nonrandomized, phase IIa multiple basket study. Patients with advanced refractory solid tumors harboring molecular alterations in human epidermal growth factor receptor-2, epidermal growth factor receptor, v-raf murine sarcoma viral oncogene homolog B1, or the Hedgehog pathway are treated with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. The primary end point is investigator-assessed objective response rate within each tumor-pathway cohort. Results Between April 1, 2014 and November 1, 2016, 251 patients with 35 different tumor types received study treatment. The efficacy population contains 230 treated patients who were evaluated for response or discontinued treatment before evaluation. Fifty-two patients (23%) with 14 different tumor types had objective responses (complete, n = 4; partial, n = 48). Tumor-pathway cohorts with notable objective response rates included human epidermal growth factor receptor-2–amplified/overexpressing colorectal (38% [14 of 37]; 95% CI, 23% to 55%) and v-raf murine sarcoma viral oncogene homolog B1 V600-mutated non–small-cell lung cancer (43% [six of 14]; 95% CI, 18% to 71%). Conclusion The four currently approved targeted therapy regimens in the MyPathway study produced meaningful responses when administered without chemotherapy in several refractory solid tumor types not currently labeled for these agents.

Introduction Crizotinib, an anaplastic lymphoma kinase (ALK) inhibitor, is a first-line treatment for ALK translocation–positive advanced non–small cell lung cancer (NSCLC); however, patients eventually progress. Immunotherapies, including the programmed death-1 inhibitor nivolumab, have resulted in durable responses and long-term overall survival in patients with NSCLC. We hypothesized that combining targeted therapy with immunotherapy could result in more patients with responses and/or more durable responses. Herein we report data from a study assessing nivolumab plus crizotinib in patients with previously untreated advanced ALK translocation–positive NSCLC. Methods Group E in CheckMate 370 was a single-arm cohort designed to evaluate the safety of first-line nivolumab (240 mg every 2 weeks) plus crizotinib (250 mg twice daily) in patients with ALK translocation–positive NSCLC. The primary endpoint of safety would be met if ≤20% of patients discontinued treatment due to treatment-related adverse events by week 17. Objective response rate was a secondary endpoint. A planned safety review occurred in November 2016; the data cutoff was May 26, 2017. Results Of the first 13 patients treated with nivolumab plus crizotinib, 5 (38%) developed severe hepatic toxicities leading to the discontinuation of the combination. Of these, two patients died and the presence of severe hepatic toxicities may have contributed to death. Enrollment was closed and combination treatment discontinued due to observed grade ≥3 hepatic toxicities. Five patients (38%) had a partial response. Conclusions These findings do not support further evaluation of nivolumab 240 mg every 2 weeks plus crizotinib 250 mg twice daily.

Summary Background Antibodies targeting the immune checkpoint molecules PD-1 or PD-L1 have demonstrated clinical efficacy in patients with metastatic non-small-cell lung cancer (NSCLC). In this trial we investigated the efficacy and safety of avelumab, an anti-PD-L1 antibody, in patients with NSCLC who had already received platinum-based therapy. Methods JAVELIN Lung 200 was a multicentre, open-label, randomised, phase 3 trial at 173 hospitals and cancer treatment centres in 31 countries. Eligible patients were aged 18 years or older and had stage IIIB or IV or recurrent NSCLC and disease progression after treatment with a platinum-containing doublet, an Eastern Cooperative Oncology Group performance status score of 0 or 1, an estimated life expectancy of more than 12 weeks, and adequate haematological, renal, and hepatic function. Participants were randomly assigned (1:1), via an interactive voice-response system with a stratified permuted block method with variable block length, to receive either avelumab 10 mg/kg every 2 weeks or docetaxel 75 mg/m2 every 3 weeks. Randomisation was stratified by PD-L1 expression (≥1% vs Findings Between March 24, 2015, and Jan 23, 2017, 792 patients were enrolled and randomly assigned to receive avelumab (n=396) or docetaxel (n=396). 264 participants in the avelumab group and 265 in the docetaxel group had PD-L1-positive tumours. In patients with PD-L1-positive tumours, median overall survival did not differ significantly between the avelumab and docetaxel groups (11·4 months [95% CI 9·4–13·9] vs 10·3 months [8·5–13·0]; hazard ratio 0·90 [96% CI 0·72–1·12]; one-sided p=0·16). Treatment-related adverse events occurred in 251 (64%) of 393 avelumab-treated patients and 313 (86%) of 365 docetaxel-treated patients, including grade 3–5 events in 39 (10%) and 180 (49%) patients, respectively. The most common grade 3–5 treatment-related adverse events were infusion-related reaction (six patients [2%]) and increased lipase (four [1%]) in the avelumab group and neutropenia (51 [14%]), febrile neutropenia (37 [10%]), and decreased neutrophil counts (36 [10%]) in the docetaxel group. Serious treatment-related adverse events occurred in 34 (9%) patients in the avelumab group and 75 (21%) in the docetaxel group. Treatment-related deaths occurred in four (1%) participants in the avelumab group, two due to interstitial lung disease, one due to acute kidney injury, and one due to a combination of autoimmune myocarditis, acute cardiac failure, and respiratory failure. Treatment-related deaths occurred in 14 (4%) patients in the docetaxel group, three due to pneumonia, and one each due to febrile neutropenia, septic shock, febrile neutropenia with septic shock, acute respiratory failure, cardiovascular insufficiency, renal impairment, leucopenia with mucosal inflammation and pyrexia, infection, neutropenic infection, dehydration, and unknown causes. Interpretation Compared with docetaxel, avelumab did not improve overall survival in patients with platinum-treated PD-L1-positive NSCLC, but had a favourable safety profile. Funding Merck and Pfizer.

Background: Bavituximab is a monoclonal antibody that targets phosphatidylserine in the presence of β2 glycoprotein 1 (β2GP1) to exert an antitumor immune response. This phase III trial determined the efficacy of bavituximab combined with docetaxel in patients with previously treated advanced non-small-cell lung cancer (NSCLC). Patients and methods: Key eligibility criteria included advanced non-squamous NSCLC with disease progression after treatment with platinum-based doublet chemotherapy, evidence of disease control after at least two cycles of first-line therapy, presence of measurable disease, ECOG performance status 0 or 1, adequate bone marrow and organ function, and no recent history of clinically significant bleeding. Eligible patients were randomized 1: 1 to receive up to six 21-day cycles of docetaxel plus either weekly bavituximab 3 mg/kg or placebo until progression or toxicity. The primary end point was overall survival (OS). Results: A total of 597 patients were enrolled. Median OS was 10.5 months in the docetaxel+bavituximab arm and was 10.9 months in the docetaxel+placebo arm (HR 1.06; 95% CI 0.88-1.29; P=0.533). There was no difference in progression-free survival (HR 1.00; 95% CI 0.82-1.22; P=0.990). Toxicities were manageable and similar between arms. In subset analysis, among patients with high baseline serum β2GP1 levels≥200 μg/ml, a nonsignificant OS trend favored the bavituximab arm (HR 0.82; 95% CI 0.63-1.06; P=0.134). Among patients who received post-study immune checkpoint inhibitor therapy, OS favored the bavituximab arm (HR 0.46; 95% CI 0.26-0.81; P=0.006). Conclusions: The combination of bavituximab plus docetaxel is not superior to docetaxel in patients with previously treated advanced NSCLC. The addition of bavituximab to docetaxel does not meaningfully increase toxicity. The potential benefit of bavituximab observed in patients with high b2GP1 levels and in patients subsequently treated with immune checkpoint inhibitors requires further investigation. Clinical trial number: NCT01999673. © VC The Author(s) 2018. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved

Introduction PRONOUNCE compared the efficacy and safety of pemetrexed+carboplatin followed by pemetrexed (Pem+Cb) with paclitaxel+carboplatin+bevacizumab followed by bevacizumab (Pac+Cb+Bev) in patients with advanced nonsquamous non–small-cell lung cancer (NSCLC). Methods Patients ≥18 years of age with stage IV nonsquamous NSCLC (American Joint Committee on Cancer v7.0), and Eastern Cooperative Oncology Group performance status 0/1 were randomized (1:1) to four cycles of induction Pem+Cb (pemetrexed, 500 mg/m 2 , carboplatin, area under the curve=6) followed by Pem maintenance or Pac+Cb+Bev (paclitaxel, 200 mg/m 2 , carboplatin, area under the curve=6, and bevacizumab, 15 mg/kg) followed by Bev maintenance in the absence of progressive disease or discontinuation. The primary objective was progression-free survival (PFS) without grade 4 toxicity (G4PFS). Secondary end points were PFS, overall survival (OS), overall response rate (ORR), disease control rate (DCR), and safety. Resource utilization was also assessed. Results Baseline characteristics of the patients randomized to Pem+Cb (N = 182) and Pac+Cb+Bev (N = 179) were well balanced between the arms. Median (months) G4PFS was 3.91 for Pem+Cb and 2.86 for Pac+Cb+Bev (hazard ratio=0.85, 90% confidence interval, 0.7–1.04; p = 0.176); PFS, OS, ORR, or DCR did not differ significantly between the arms. Significantly more drug-related grade 3/4 anemia (18.7% versus 5.4%) and thrombocytopenia (24.0% versus 9.6%) were reported for Pem+Cb. Significantly more grade 3/4 neutropenia (48.8% versus 24.6%), grade 1/2 alopecia (28.3% versus 8.2%), and grade 1/2 sensory neuropathy were reported for Pac+Cb+Bev. Number of hospitalizations and overall length of stay did not differ significantly between the arms. Conclusions Pem+Cb did not produce significantly better G4PFS compared with Pac+Cb+Bev. Pem+Cb was not superior in PFS, OS, ORR, or DCR compared with Pac+Cb+Bev. Both regimens were well tolerated, although, toxicity profiles differed.

BACKGROUND Patients with advanced squamous-cell non-small-cell lung cancer (NSCLC) who have disease progression during or after first-line chemotherapy have limited treatment options. This randomized, open-label, international, phase 3 study evaluated the efficacy and safety of nivolumab, a fully human IgG4 programmed death 1 (PD-1) immune-checkpoint-inhibitor antibody, as compared with docetaxel in this patient population. METHODS We randomly assigned 272 patients to receive nivolumab, at a dose of 3 mg per kilogram of body weight every 2 weeks, or docetaxel, at a dose of 75 mg per square meter of body-surface area every 3 weeks. The primary end point was overall survival. RESULTS The median overall survival was 9.2 months (95% confidence interval [CI], 7.3 to 13.3) with nivolumab versus 6.0 months (95% CI, 5.1 to 7.3) with docetaxel. The risk of death was 41% lower with nivolumab than with docetaxel (hazard ratio, 0.59; 95% CI, 0.44 to 0.79; P

There have been significant advances in the understanding of the biology and treatment of non-small cell lung cancer (NSCLC) over the past few years. A number of molecularly targeted agents are in the clinic or in development for patients with advanced NSCLC (Table 1). We are beginning to understand the mechanisms of acquired resistance following exposure to tyrosine kinase inhibitors in patients with oncogene addicted NSCLC. The advent of next generation sequencing has enabled to study comprehensively genomic alterations in lung cancer. Finally, early results from immune checkpoint inhibitors are very encouraging. This review summarizes recent advances in the area of cancer genomics, targeted therapies and immunotherapy.

Introduction Metastatic non-small cell lung cancer (NSCLC) is a recognized risk factor for VTE. Some systemic treatments may increase this risk further. Here, we present the risk of VTE and its prognostic significance for patients treated with chemotherapy (chemo) and the EGFR monoclonal antibody necitumumab (neci) for metastatic NSCLC. Methods Four trials of 1st-line treatment for Stage IV NSCLC were analyzed: two randomized phase 3 studies of cisplatin/gemcitabine ±neci in squamous NSCLC (SQUIRE: N = 1079) and cisplatin/pemetrexed ±neci in non-squamous NSCLC (INSPIRE: N = 616); JFCL (N = 161), a randomized phase 2 trial of carboplatin/paclitaxel ±neci in squamous NSCLC; and JFCK (N = 61), a single arm phase 2 trial of cisplatin/gemcitabine +neci in squamous NSCLC. A Cox proportional hazards model with VTE as a time-dependent covariate was used for overall survival (OS) analyses. Results Neci + chemo was associated with an increased risk of VTE (Relative Risk [RR]: 1.579; 95% CI: 1.155–2.158). History of VTE (RR: 1.899; 95% CI: 1.142–3.156) and prior cardiac/cardiovascular events (RR: 1.514; 95% CI: 1.102–2.082) were associated with increased risk of VTE. Decreased VTE risk was seen with: male sex (RR: 0.696; 95% CI: 0.502–0.964), eastern European geographic region (RR: 0.387; 95% CI: 0.267–0.562) and squamous cell pathology (RR: 0.653; 95% CI: 0.483–0.883). VTE occurrence showed no association with OS (HR: 1.121; 95% CI: 0.930–1.351). Conclusion Our data suggest that certain patient characteristics such as prior history of VTE and non-squamous histology might be associated with an increased risk of on-treatment VTE in NSCLC, although in this study, overall survival was not affected. Further studies to develop measures for identifying high-risk patients are needed to inform treatment decisions as well as VTE management and prophylaxis.

Purpose First-line treatment for patients with extensive-stage small cell lung cancer (SCLC) includes treatment with platinum-based combination chemotherapy. Amrubicin is a synthetic anthracycline with single-agent activity in relapsed/refractory SCLC. In an attempt to improve treatment efficacy, we evaluated amrubicin/carboplatin as first-line therapy for extensive-stage SCLC. Patients and methods In this multicenter phase II trial, patients received amrubicin (30 mg/m2 daily on Days 1, 2, and 3) and carboplatin (AUC = 5 on Day 1); cycles were repeated every 21 days for 4 cycles. Pegfilgrastim (6 mg subcutaneously) was administered on Day 4 of all cycles. Overall survival (OS) proportion at 1 year was the primary endpoint. The target 1-year OS rate was 47%, an improvement of 35% from historical results with carboplatin/etoposide. Results Eighty patients received study treatment, and 62% completed the planned 4 courses. The overall response rate was 74% (13% complete responses). The 1-year survival rate was 38% (95% CI: 25, 50). The median survival was 10 months. Myelosuppression was severe but manageable. Conclusions The combination of amrubicin/carboplatin was an active first-line treatment for extensive stage SCLC, but showed no indication of increased efficacy compared to standard treatments. Severe myelosuppression was common with this regimen, in spite of prophylactic pegfilgrastim. These results are consistent with those of other trials in showing no role for amrubicin in the first-line treatment of SCLC.