Nivolumab and Ipilimumab as Maintenance Therapy in Extensive-Disease Small-Cell Lung Cancer: CheckMate 451

Abstract

Purpose: In extensive-disease small-cell lung cancer (ED-SCLC), response rates to first-line platinum-based chemotherapy are robust, but responses lack durability. CheckMate 451, a double-blind phase III trial, evaluated nivolumab plus ipilimumab and nivolumab monotherapy as maintenance therapy following first-line chemotherapy for ED-SCLC.

Methods: Patients with ED-SCLC, Eastern Cooperative Oncology Group performance status 0-1, and no progression after ≤ 4 cycles of first-line chemotherapy were randomly assigned (1:1:1) to nivolumab 1 mg/kg plus ipilimumab 3 mg/kg once every 3 weeks for 12 weeks followed by nivolumab 240 mg once every 2 weeks, nivolumab 240 mg once every 2 weeks, or placebo for ≤ 2 years or until progression or unacceptable toxicity. Primary end point was overall survival (OS) with nivolumab plus ipilimumab versus placebo. Secondary end points were hierarchically tested.

Results: Overall, 834 patients were randomly assigned. The minimum follow-up was 8.9 months. OS was not significantly prolonged with nivolumab plus ipilimumab versus placebo (hazard ratio [HR], 0.92; 95% CI, 0.75 to 1.12; P = .37; median, 9.2 v 9.6 months). The HR for OS with nivolumab versus placebo was 0.84 (95% CI, 0.69 to 1.02); the median OS for nivolumab was 10.4 months. Progression-free survival HRs versus placebo were 0.72 for nivolumab plus ipilimumab (95% CI, 0.60 to 0.87) and 0.67 for nivolumab (95% CI, 0.56 to 0.81). A trend toward OS benefit with nivolumab plus ipilimumab was observed in patients with tumor mutational burden ≥ 13 mutations per megabase. Rates of grade 3-4 treatment-related adverse events were nivolumab plus ipilimumab (52.2%), nivolumab (11.5%), and placebo (8.4%).

Conclusion: Maintenance therapy with nivolumab plus ipilimumab did not prolong OS for patients with ED-SCLC who did not progress on first-line chemotherapy. There were no new safety signals.

Trial registration: ClinicalTrials.gov NCT02538666.

Conflict of interest statement

Taofeek K. OwonikokoStock and Other Ownership Interests: Cambium Medical TechnologiesConsulting or Advisory Role: Novartis, Celgene, Lilly, Sandoz, Abbvie, Eisai, G1 Therapeutics, Takeda, Seattle Genetics, Bristol-Myers Squibb, MedImmune, BerGenBio, Amgen, AstraZeneca, PharmaMar, Boehringer Ingelheim, EMD Serono, Xcovery, Bayer, Heron Pharmaceutical, ARMO BioSciences, MerckSpeakers' Bureau: AbbvieResearch Funding: Novartis, Astellas Pharma, Celgene, Bayer, Stem CentRx, Regeneron, AstraZeneca/MedImmune, Abbvie, G1 Therapeutics, Bristol-Myers Squibb, Corvus Pharmaceuticals, United Therapeutics, Amgen, Loxo/Lilly, Fujifilm, Pfizer, Aeglea Biotherapeutics, Incyte, MerckPatents, Royalties, Other Intellectual Property: Overcoming acquired resistance to chemotherapy treatments through suppression of STAT3, Selective chemotherapy treatments and diagnostic methods related thereto, DR4 modulation and its implications in EGFR-target cancer therapy ref:18089 PROV (CSP) United States patent application no. 62/670,210 June 26, 2018 (Co-Inventor), Soluble FAS ligand as a biomarker of recurrence in thyroid cancer; provisional patent 61/727,519 (Inventor)Other Relationship: Roche/Genentech, EMD SeronoUncompensated Relationships: Reflexion Medical Keunchil ParkConsulting or Advisory Role: AstraZeneca, Lilly, Ono Pharmaceutical, Bristol-Myers Squibb, MSD, Blueprint Medicines, Amgen, Merck KGaA, LOXO, Abbvie, Daiichi Sankyo, Boehringer Ingelheim, JNJ, Eisai, Puma BiotechnologySpeakers' Bureau: Boehringer Ingelheim, AZDResearch Funding: AstraZeneca, MSD Oncology Ramaswamy GovindanHonoraria: Genentech/Abbvie, Abbvie, GeneplusConsulting or Advisory Role: GlaxoSmithKline, Genentech/Roche, Abbvie, Celgene, AstraZeneca/MedImmune, Merck Serono, Pfizer, Bristol-Myers Squibb, EMD Serono, Lilly, Ignyta, Nektar, Phillips Gilmore Oncology, Jounce Therapeutics, Roche, Janssen, Amgen, Achilles Therapeutics Neal ReadyConsulting or Advisory Role: Bristol-Myers Squibb, Novartis, Merck, Abbvie, Celgene, Merck Serono, AstraZeneca, G1 Therapeutics, Jazz Pharmaceuticals, RemeronSpeakers' Bureau: Bristol-Myers SquibbResearch Funding: Bristol-Myers Squibb, Merck Martin ReckConsulting or Advisory Role: Lilly, MSD Oncology, Merck Serono, Bristol-Myers Squibb, AstraZeneca, Boehringer Ingelheim, Pfizer, Novartis, Roche/Genentech, Abbvie, Amgen, Mirati Therapeutics, Samsung BioepisSpeakers' Bureau: Roche/Genentech, Lilly, MSD Oncology, Merck Serono, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Pfizer, Novartis, Amgen, Mirati Therapeutics Solange PetersHonoraria: Roche, Bristol-Myers Squibb, Novartis, Pfizer, MSD, AstraZeneca, Takeda, IlluminaConsulting or Advisory Role: Roche/Genentech, Novartis, Bristol-Myers Squibb, Pfizer, MSD, Amgen, AstraZeneca, Janssen, Regeneron, Merck Serono, Boehringer Ingelheim, Takeda, Lilly, Abbvie, Bayer, Biocartis, Debiopharm Group, Illumina, PharmaMar, Sanofi, Seattle Genetics, Blueprint Medicines, Daiichi Sankyo, Incyte, Bioinvent, Clovis Oncology, VaccibodyResearch Funding: Roche, Bristol-Myers Squibb, MSD, Amgen, Lilly, AstraZeneca, Pfizer, Illumina, Merck Serono, Novartis, Biodesix, Boehringer Ingelheim, Iovance BiotherapeuticsTravel, Accommodations, Expenses: Roche, Bristol-Myers Squibb, MSD, Sanofi, IncyteUncompensated Relationships: Journal of Thoracic Oncology, ESMO, European Thoracic Oncology Platform (ETOP), Annals on Oncology associate editor Alejandro NavarroHonoraria: Pfizer, Roche, AstraZenecaConsulting or Advisory Role: Boehringer IngelheimExpert Testimony: Oryzon Genomics, MedsirTravel, Accommodations, Expenses: Boehringer Ingelheim, Pfizer Jerónimo Rodríguez-CidConsulting or Advisory Role: Roche, Bristol-Myers Squibb (Mexico), MSD Oncology, Takeda, BayerSpeakers' Bureau: MSD Oncology, Bristol-Myers Squibb (Mexico), Roche, Boehringer Ingelheim, Novartis, Bayer, Lilly, AstraZenecaResearch Funding: MSD, Bristol-Myers Squibb (Mexico), Roche, Celltrion, Lilly, BeiGene, AstraZenecaTravel, Accommodations, Expenses: Roche, MSD Oncology, AstraZeneca, Boehringer Ingelheim Michael SchenkerResearch Funding: Bristol-Myers Squibb, Roche, Amgen, MSD, Pfizer/EMD Serono, Lilly, Astellas Pharma, AstraZeneca, GlaxoSmithKline, Regeneron, Novartis, Abbvie, Gilead SciencesTravel, Accommodations, Expenses: Bristol-Myers Squibb Jong-Seok LeeConsulting or Advisory Role: AstraZeneca, Ono Pharmaceutical Ivor PercentConsulting or Advisory Role: Bristol-Myers Squibb, Abbvie, Takeda, PharmaMar, Gilead Sciences, G1 TherapeuticsResearch Funding: Heat Biologics, Merck, Celgene, AstraZeneca, Baxter, Incyte, Abbvie, Bristol-Myers Squibb, EpicentRx, Pfizer, Roche, Lilly, Altum Pharmaceuticals, Array BioPharma Carlos H. BarriosStock and Other Ownership Interests: Biomarker, MedSIR, TummiHonoraria: Novartis, Roche/Genentech, Pfizer, GlaxoSmithKline, Sanofi, Boehringer Ingelheim, Eisai, MSD, Lilly, Bayer, AstraZeneca, Zodiac PharmaConsulting or Advisory Role: Boehringer Ingelheim, Roche/Genentech, Novartis, GlaxoSmithKline, Eisai, Pfizer, AstraZeneca, Libbs, MSD Oncology, United Medical, LillyResearch Funding: Pfizer, Novartis, Amgen, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Roche/Genentech, Lilly, Sanofi, Taiho Pharmaceutical, Mylan, Merrimack, Merck, Abbvie, Astellas Pharma, Biomarin, Bristol-Myers Squibb, Daiichi Sankyo, Abraxis BioScience, AB Science, Asana Biosciences, Medivation, Exelixis, ImClone Systems, LEO Pharma, Millennium, Janssen, Clinica Atlantis, INC Research, Halozyme, Covance, Celgene, inVentiv Health, Merck KGaA, Shanghai Henlius Biotech, Polyphor, PharmaMarTravel, Accommodations, Expenses: Roche/Genentech, Novartis, Pfizer, BMS Brazil, AstraZeneca, MSD Oncology, Lilly Laurent GreillierHonoraria: AstraZeneca, Boehringer Ingelheim, Roche, Bristol-Myers Squibb, MSD, Takeda, Abbvie, Novartis, PfizerConsulting or Advisory Role: Roche, Boehringer Ingelheim, Bristol-Myers Squibb, Takeda, MSD, AstraZeneca, Abbvie, NovartisTravel, Accommodations, Expenses: Boehringer Ingelheim, Roche, MSD Sofia BakaConsulting or Advisory Role: MSD Oncology, Roche, Boehringer Ingelheim, AstraZeneca, Bristol-Myers Squibb, NovartisResearch Funding: Boehringer Ingelheim, Novartis, MSD Oncology, Bristol-Myers Squibb, AstraZeneca, Lilly, Takeda, Genesis PharmaceuticalsTravel, Accommodations, Expenses: Bristol-Myers Squibb, Boehringer Ingelheim, MSD, Demo Pharmaceutical Wen Hong LinEmployment: Bristol-Myers Squibb Giovanni SelvaggiEmployment: Xcovery Holdings IncOther Relationship: Xcovery Holdings Inc Christine BaudeletEmployment: Bristol-Myers SquibbStock and Other Ownership Interests: Bristol-Myers Squibb Jonathan BadenEmployment: Bristol-Myers Squibb, Johnson & JohnsonStock and Other Ownership Interests: Bristol-Myers Squibb, Johnson & Johnson Dimple PandyaEmployment: Bristol-Myers SquibbStock and Other Ownership Interests: Bristol-Myers SquibbPatents, Royalties, Other Intellectual Property: Bristol-Myers Squibb Parul DoshiEmployment: Bristol-Myers SquibbStock and Other Ownership Interests: Bristol-Myers SquibbTravel, Accommodations, Expenses: Bristol-Myers Squibb Hye Ryun KimSpeakers' Bureau: Ono Pharmaceutical, Roche/GenentechNo other potential conflicts of interest were reported.

Figures

FIG 1.

(A) OS with nivolumab plus ipilimumab versus placebo, (B) nivolumab monotherapy versus placebo, (C) PFS per blinded independent central review with nivolumab plus ipilimumab versus placebo, and (D) nivolumab monotherapy versus placebo. HRs were based on a stratified three-arm Cox proportional hazards model, and the P value for the primary end point was calculated from a stratified log-rank test. HR, hazard ratio; OS, overall survival; PFS, progression-free survival.

FIG 2.

(A) OS by predefined subgroups with nivolumab plus ipilimumab versus placebo and (B) nivolumab monotherapy versus placebo. aNot reported for three patients in the nivolumab plus ipilimumab arm, four patients in the nivolumab arm, and three patients in the placebo arm. bNot evaluated for one patient in the placebo arm. CR, complete response; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; LDH, lactate dehydrogenase; OS, overall survival; PCI, prophylactic cranial irradiation; PR, partial response; SD, stable disease; ULN, upper limit of normal.

FIG 3.

OS with nivolumab plus ipilimumab versus nivolumab versus placebo by (A) TMB ≥ 13 mut/Mb and (B)