Nivolumab Plus Ipilimumab vs Nivolumab for Previously Treated Patients With Stage IV Squamous Cell Lung Cancer The Lung-MAP S1400I Phase 3 Randomized Clinical Trial

• Type of Material: Article
• Authors: Scott N Gettinger, Yale Cancer Center; Mary W Redman, SWOG Statistical Center; Lyudmila Bazhenova, University of California San Diego; Fred R Hirsch, Mt Sinai Hlth Syst; Philip C Mack, University of California Davis; Lawrence H Schwartz, Columbia University; Jeffrey Bradley, Emory University; Thomas E Stinchcombe, Duke University; Natasha B Leighl, Princess Margaret Hosp; Suresh Ramalingam, Emory University; Susan S Tavernier, Idaho State University; Hui Yu, Mount Sinai Health System; Joseph M Unger, SWOG Statistical Center; Katherine Minichiello, SWOG Statistical Center; Louise Highleyman, SWOG Statistical Center; Vassiliki A Papadimitrakopoulou, The University of Texas MD Anderson Cancer Center; Karen Kelly, University of California Davis; David R Gandara, University of California Davis; Roy S Herbst, Yale Cancer Center
• Language: English
• Date: 2021-09-01
• Publisher: AMER MEDICAL ASSOC
• Publication Version: Final Published Version
• Copyright Statement: 2021 Gettinger SN et al. JAMA Oncology.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1001/jamaoncol.2021.2209
• Title of Journal or Parent Work: JAMA ONCOLOGY
• Volume: 7
• Issue: 9
• Start Page: 1368
• End Page: 1377
• Grant/Funding Information: The funder had no role in the conduct of the study; collection, management, analysis, and interpretation of the data; preparation or approval of the manuscript; and decision to submit the manuscript for publication.; This study was supported by grants from the Foundation for the National Institutes of Health to SWOG.
• Keywords: SURVIVAL; THERAPIES; CHEMOTHERAPY; ATEZOLIZUMAB; DOCETAXEL; OPEN-LABEL; Life Sciences & Biomedicine; Oncology; Science & Technology
• Research Categories: Health Sciences, Oncology

Abstract

Importance: Nivolumab plus ipilimumab is superior to platinum-based chemotherapy in treatment-naive advanced non-small cell lung cancer (NSCLC). Nivolumab is superior to docetaxel in advanced pretreated NSCLC. Objective: To determine whether the addition of ipilimumab to nivolumab improves survival in patients with advanced, pretreated, immunotherapy-naive squamous (Sq) NSCLC. Design, Setting, and Participants: The Lung Cancer Master Protocol (Lung-MAP) S1400I phase 3, open-label randomized clinical trial was conducted from December 18, 2015, to April 23, 2018, randomizing patients in a 1:1 ratio to nivolumab alone or combined with ipilimumab. The median follow-up in surviving patients was 29.5 months. The trial was conducted through the National Clinical Trials Network and included patients with advanced immunotherapy-naive SqNSCLC and a Zubrod score of 0 (asymptomatic) to 1 (symptomatic but completely ambulatory) with disease progression after standard platinum-based chemotherapy. Randomization was stratified by sex and number of prior therapies (1 vs 2 or more). Data were analyzed from May 3, 2018, to February 1, 2021. Interventions: Nivolumab, 3 mg/kg intravenously every 2 weeks, with or without ipilimumab, 1 mg/kg intravenously every 6 weeks, until disease progression or intolerable toxic effects. Main Outcomes and Measures: The primary end point was overall survival (OS). Secondary end points included investigator-assessed progression-free survival (IA-PFS) and response per Response Evaluation Criteria in Solid Tumors (RECIST) guidelines, version 1.1. Results: Of 275 enrolled patients, 252 (mean age, 67.5 years [range 41.8-90.3 years]; 169 men [67%]; 206 White patients [82%]) were deemed eligible (125 randomized to nivolumab/ipilimumab and 127 to nivolumab). The study was closed for futility at a planned interim analysis. Overall survival was not significantly different between the groups (hazard ratio [HR], 0.87; 95% CI, 0.66-1.16; P =.34). Median survival was 10 months (95% CI, 8.0-14.4 months) in the nivolumab/ipilimumab group and 11 months (95% CI, 8.6-13.7 months) in the nivolumab group. The IA-PFS HR was 0.80 (95% CI, 0.61-1.03; P =.09); median IA-PFS was 3.8 months (95% CI, 2.7-4.4 months) in the nivolumab/ipilimumab group and 2.9 months (95% CI, 1.8-4.0 months) in the nivolumab alone group. Response rates were 18% (95% CI, 12%-25%) with nivolumab/ipilimumab and 17% (95% CI, 10%-23%) with nivolumab. Median response duration was 28.4 months (95% CI, 4.9 months to not reached) with nivolumab/ipilimumab and 9.7 months with nivolumab (95% CI, 4.2-23.1 months). Grade 3 or higher treatment-related adverse events occurred in 49 of 124 patients (39.5%) who received nivolumab/ipilimumab and in 41 of 123 (33.3%) who received nivolumab alone. Toxic effects led to discontinuation in 31 of 124 patients (25%) on nivolumab/ipilimumab and in 19 of 123 (15%) on nivolumab. Conclusions and Relevance: In this phase 3 randomized clinical trial, ipilimumab added to nivolumab did not improve outcomes in patients with advanced, pretreated, immune checkpoint inhibitor-naive SqNSCLC. Trial Registration: ClinicalTrials.gov Identifier: NCT02785952.