Nivolumab (nivo) plus ipilimumab (ipi), nivo, or placebo (pbo) as maintenance therapy in patients (pts) with extensive disease small cell lung cancer (ED-SCLC) after first-line (1L) platinum-based chemotherapy (chemo): results from the double-blind, randomized phase 3 CheckMate 451 study

Background

In pts with ED-SCLC, response rates to 1L platinum-based chemo are high but lack durability. Treatments (txs) that prolong response duration and improve survival are needed. CheckMate 451 (NCT02538666) is a global, double-blind, phase 3 study of nivo+ipi or nivo vs pbo as maintenance therapy in pts with ED-SCLC who did not progress on 1L platinum-based chemo.

Methods

Pts (N = 834) with ED-SCLC, ECOG performance status (PS) ≤ 1 and response or stable disease after 4 cycles of 1L platinum-based chemo were randomized 1:1:1 (3–9 weeks from last dose of 1L chemo or 3–11 weeks for pts who received prophylactic cranial irradiation [PCI]) to nivo 1 mg/kg + ipi 3 mg/kg Q3W intravenously (IV; 4 doses followed by nivo 240 mg Q2W IV; n = 279), nivo 240 mg Q2W IV (n = 280), or pbo (n = 275), stratified by PS, sex and prior PCI. Pts were treated up to 2 years or until progression or unacceptable toxicity. Primary endpoint was overall survival (OS) for nivo+ipi vs pbo. Secondary endpoints included OS for nivo vs pbo and progression-free survival (PFS) per blinded independent central review for nivo+ipi vs pbo and nivo vs pbo.

Results

Minimum study follow-up was 9 months. Baseline characteristics were balanced between arms. OS was not significantly prolonged with nivo+ipi vs pbo (HR, 0.92; 95% CI 0.75–1.12; P = 0.3693). OS was also not prolonged for nivo vs pbo (HR, 0.84; 95% CI 0.69–1.02), although not formally tested due to statistical hierarchy. PFS HRs vs pbo were: nivo+ipi, 0.72 (0.60–0.87); nivo, 0.67 (0.56–0.81). Rates of all-grade (grade 3–4) tx-related adverse events were: nivo+ipi, 86% (52%); nivo, 61% (12%); pbo, 50% (8%). Rates of discontinuation due to tx toxicity were: nivo+ipi, 31%; nivo, 9%; pbo, <1%. Tx-related deaths were: nivo+ipi, 7 (2.5%); nivo, 1 (<1%); pbo, 1 (<1%).

Conclusions

In CheckMate 451, maintenance therapy with nivo+ipi (primary endpoint) or nivo did not prolong OS vs pbo for ED-SCLC patients who did not progress on 1L chemo. Safety profiles of nivo+ipi and nivo were consistent with previous reports at this dose/schedule in SCLC.

Clinical trial identification

NCT02538666; Release date: 2 September 2015.

Editorial acknowledgement

Writing and editorial assistance was provided by Cristina Tomas, PhD, of Caudex and funded by Bristol-Myers Squibb.

Legal entity responsible for the study

Bristol-Myers Squibb.

Funding

Bristol-Myers Squibb.

Disclosure

T.K. Owonikoko: Research support: AbbVie, Adaptimmune, Amgen, AstraZeneca, Bristol-Myers Squibb, Corvus, G1 Therapeutics, Novartis, Pfizer, Regeneron/Sanofi; Advisory board: AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Lilly/Armo, PharmaMar, Xcovery; IRC/DSMB: EMD Serono, Roche/Genentech; Co-founder: Cambium Oncology. H.R. Kim: Speakers bureau, honoraria: AstraZeneca, ONO/Bristol-Myers Squibb; Consultant: Roche. R. Govindan: Consultant/advisory committees: AbbVie, Adaptimmune, AstraZeneca, Celgene, Ignyta, Inivata, Merck, Nektar, Pfizer, Roche. N. Ready: Advisor: AbbVie, G1 therapeutics, Merck, Novartis; Advisor/speaker: Bristol-Myers Squibb, Celgene; Education: AstraZeneca, EMD Serrano, Tesaro. M. Reck: Honoraria for lectures and consultancy: AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Lilly, Merck, MSD, Novartis, Pfizer, Roche. S. Peters: Honoraria, education grants, consultancy, attended advisory boards, and/or provided lectures: 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, PharmaMar, Pfizer, Regeneron, Sanofi, Seattle Genetics, Takeda. A. Navarro: Advisory role: Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Roche; Safety committee member: Oryzon Genomics; Travel support: Boehringer Ingelheim, Pfizer. J. Rodriguez-Cid: Investigational resources: AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, MSD, Novartis, Roche, Takeda; Advisory role: AbbVie, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eisai, MSD, Novartis, Pfizer, Roche, Takeda; Speaker role: AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, MSD, Novartis, Pfizer, Roche, Takeda. M. Schenker: For clinical trial participation (as PI/SI) my institution and I have received funds from: AbbVie, Amgen, Astellas, AstraZeneca, Bayer, Bioven, Bristol-Myers Squibb, Eisai, Eli Lilly, Gilead, Merck Serono, MSD, Mylan, Nano Carrier, Novartis, Pfizer, PharmaMar, Regeneron, Roche, Samsung D. Morgensztern: Advisory board: AbbVie, Bristol-Myers Squibb, PharmaMar, Takeda. J. Fairchild: Stock ownership: Bristol-Myers Squibb. C. Baudelet: Employee: Bristol-Myers Squibb. K. Park: Advisor: Bristol-Myers Squibb. All other authors have declared no conflicts of interest.