Efficacy and safety of nivolumab (nivo) monotherapy versus chemotherapy (chemo) in recurrent small cell lung cancer (SCLC): Results from CheckMate 331

Background: Despite high initial response rates, most patients (pts) with SCLC relapse soon after first-line (1L) treatment (tx), with limited tx options and a poor prognosis. Nivo is approved in the US for tx of metastatic SCLC with progression after platinum-based chemo and ≥1 other line of tx. We report results from CheckMate 331 (NCT02481830), a global, open-label, phase 3 trial of nivo vs chemo in pts with relapsed SCLC after 1L platinum-based chemo. Methods: Pts (N = 569) with limited- or extensive-disease SCLC and recurrence/progression after 1L platinum-based chemo were randomized 1:1 to receive nivo (n = 284) or chemo (n = 285; topotecan or amrubicin where locally approved; see Table for all dosages), stratified by platinum sensitivity (90 days) and CNS metastases. Pts were treated until progression (or no longer deriving clinical benefit with nivo) or unacceptable toxicity. Primary endpoint was overall survival (OS) with nivo vs chemo. Approximately 482 events were expected, providing 90% power to detect a hazard ratio (HR) of 0.745 favoring nivo (2-sided alpha, 0.05). Results: Minimum follow-up was 15.8 months. Baseline characteristics were balanced between arms. No statistically significant improvement in OS was seen with nivo vs chemo (HR, 0.86 [95% CI, 0.72–1.04]); however OS curves showed delayed separation after month 12. HR for OS with nivo vs chemo in pts with platinum-resistant SCLC was 0.71 (95% CI, 0.54–0.94). Other efficacy outcomes are shown in the table. All-grade (grade 3–4) tx-related adverse events (AE) occurred in 55% (14%) of nivo- and 90% (73%) of chemo-treated pts. There were 2 tx-related deaths with nivo and 3 with chemo.TableLBA5 Efficacy outcomes with nivolumab vs chemotherapy in recurrent SCLCNivoa240 mg IV Q2W. (n = 284)ChemobTopotecan 1.5 mg/m2 IV or 2.3 mg/m2 oral daily on days 1–5 of a 21-day cycle or amrubicin 40 mg/m2 IV daily on days 1–3 of a 21-day cycle. (n = 285)Overall survivalEvents, n (%)225 (79)245 (86)Median, months (95% CI)7.5 (5.7–9.2)8.4 (7.0–10.0)HR (95% CI)0.86 (0.72–1.04) P = 0.11cP value calculated from log-rank test stratified by response to 1L platinum-based therapy (sensitive vs refractory/resistant) and baseline CNS metastases (yes vs no) per interactive voice response system.1-year OS rate, % (95% CI)37 (31–42)34 (29–40)Progression-free survivalEvents, n (%)258 (91)235 (82)Median, months (95% CI)1.4 (1.4–1.5)3.8 (3.0–4.2)HR (95% CI)1.41 (1.18–1.69)1-year PFS rate, % (95% CI)11 (8–15)10 (7–14)Objective response rate, n (%)39 (14)47 (16)Odds ratio (95% CI)0.80 (0.50–1.27)Duration of responsen events/n responders (%)28/39 (72)43/47 (92)Median, months (95% CI)8.3 (7.0–12.6)4.5 (4.1–5.8)a 240 mg IV Q2W.b Topotecan 1.5 mg/m2 IV or 2.3 mg/m2 oral daily on days 1–5 of a 21-day cycle or amrubicin 40 mg/m2 IV daily on days 1–3 of a 21-day cycle.c P value calculated from log-rank test stratified by response to 1L platinum-based therapy (sensitive vs refractory/resistant) and baseline CNS metastases (yes vs no) per interactive voice response system. Open table in a new tab Conclusions: CheckMate 331 did not meet the primary endpoint of OS for nivo vs chemo in 2L SCLC. However, late separation of curves and potential activity in the platinum-refractory setting suggests possible long-term benefit for some pts. There were no new safety signals, with lower AE rates observed with nivo. Editorial acknowledgement: Writing and editorial assistance was provided by Nicole Draghi, PhD, of Caudex, funded by Bristol-Myers Squibb. Clinical trial identification: NCT02481830. Legal entity responsible for the study: Bristol-Myers Squibb. Funding: Bristol-Myers Squibb. Disclosure: M. Reck: Lecture and consultant fees: AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Lilly, Merck, MSD, Novartis, Pfizer, Roche. T. Ciuleanu: Advisory role: Amgen, Astellas, AZ, BMS, Boehringer Ingelheim, Eli Lilly, GSK, Janssen, Merck Serono, MSD, Novartis, Pfizer, Roche, Sanofi. Personal fees: Amgen, Boehringer Ingelheim, Ipsen, Janssen, Merck Serono, Pfizer, Roche, Sanofi, Servier. S. Gettinger: Non-financial support: Millennium Pharmaceuticals, Inc.; Grants and personal fees: Ariad/Takeda, Bristol-Myers Squibb; Personal fees: Janssen; Grants: Genentech/Roche, Incyte, Iovance. S. Peters: Honoraria or consultation fees: AbbVie, Amgen, AstraZeneca, Bayer, Biocartis, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, F. Hoffmann-La Roche, Foundation Medicine, Illumina, Janssen, Merck Sharp and Dohme, Merck Serono, Merrimack, Novartis, Pharma Mar, Pfizer, Regeneron, Sanofi, Seattle Genetics, Takeda; Talk in company's organized public event: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Merck Sharp and Dohme, Novartis, Pfizer, Takeda; Grants/research supports: (Sub)investigator in trials (institutional financial support for clinical trials) sponsored by Amgen, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Clovis, F. Hoffmann-La Roche, Illumina, Merck Sharp and Dohme, Merck Serono, Novartis, Pfizer. L. Horn: Personal fees: AbbVie, AstraZeneca, Merck, Incyte, Xcovery, Genentech, EMD Serono. C. Audigier-Valette: BMS, Roche, AstraZeneca, AbbVie, MSD, Novartis, Pfizer, Takeda, Lilly. N. Pardo: Pzifer, Boeheringer Ingelheim, Roche. O. Juan-Vidal: Honoraria or advisory role: Boehringer Ingelheim, Bristol-Myers Squibb, Merck Sharp & Dohme, Roche/Genetech, AstraZeneca, Pfizer, Eli Lilly, AbbVie. Institutional research funding: Bristol-Myers Squibb, AstraZeneca. J. Wolf: Advisory boards and lecture fees: AbbVie, AstraZeneca, BMS, Boehringer Ingelheim, Chugai, Ignyta, Lilly, MSD, Novartis, Pfizer, Roche; Research support (to institution): BMS, MSD, Novartis, Pfizer. S.J. Antonia: Personal fees: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Merck; Stock ownership: Cellular Biomedicine Group. K. Nakagawa: Grants and personal fees: Daiichi Sankyo, Astellas Pharma, AstraZeneca, EPS Holdings, Ono, Kyowa Hakko Kirin, Chugai, Nippon Boehringer Ingelheim, Eli Lilly, Pfizer, Bristol-Myers Squibb, Novartis, Taiho; Grants: Quintiles, Japan Clinical Research Operations, Eisai, PPD-SNBL K.K., Takeda, AbbVie, Yakult Honsha, Parexel, Otsuka, AC Medical, Merck Serono; Personal fees: Showa Yakuhin Kako, SymBio Pharmaceuticals, MSD K.K., Ayumi Pharmaceutical Corporation. G. Selvaggi, C. Baudelet, H. Chang: Employment: Bristol-Myers Squibb. D.R. Spigel: Research grants: AstraZeneca; Advisory role (paid to institution): AstraZeneca; Research and advisory role (paid to institution): Bristol-Myers Squibb, Roche/Genentech, Pfizer, Merck. All other authors have declared no conflicts of interest.