Concerns and controversies regarding ipilimumab-based immunotherapy in the first-line treatment of non-small cell lung cancer

© Precision Cancer Medicine. All rights reserved. Precis Cancer Med 2021;4:7 | http://dx.doi.org/10.21037/pcm-2020-mnsclc-08 Ipilimumab is a fully human monoclonal antibody against cytotoxic T-lymphocyte antigen 4 (CTLA-4), which has shown early evidence of longer overall survival (OS) in patients with melanoma (1), renal cell carcinoma (2), and unresectable malignant pleural mesothelioma (3). Furthermore, ipilimumab plus nivolumab has shown antitumor activity in patients with small-cell lung cancer (4). The ipilimumab-based immunotherapy as a first-line treatment of non-small cell lung cancer (NSCLC) has represented a substantial change in therapeutics, particularly for patients with potential low tolerability to conventional chemotherapy. Yet, the extended long-term survival is achieved only in a minority of patients with NSCLC (5-7). Dual checkpoint blockade was associated with durable tumor responses and prolonged survival in patients with advanced NSCLC; however, a higher frequency of adverse events (AEs) was reported with the dual immunotherapy regimen (5,6,8,9). Most of the evidence regarding the development of ipilimumab-based immunotherapy in the first-line treatment of advanced NSCLC derives from two pivotal clinical trials; CheckMate-227 (5) and CheckMate-9LA (6). CheckMate-227 is a randomized, first-line, open-label, phase 3, multi-part trial that explored the efficacy and safety of nivolumab plus ipilimumab, compared with platinum-doublet chemotherapy (5). Eligible participants included patients with squamous or nonsquamous stage IV or recurrent NSCLC. CheckMate 227 is a six-arm trial, divided into two parts. In part 1a, patients with programmed cell death-1 ligand-1 (PD-L1) expression level ≥1% on tumor cells (TCs) were randomly assigned in a 1:1:1 ratio to receive nivolumab [at a dose of 3 mg per kilogram (kg) every two weeks] plus ipilimumab (at a dose of 1 mg per kg every six weeks) vs. nivolumab monotherapy (240 mg every two weeks) vs. platinum doublet chemotherapy (every three weeks for up to 4 cycles). Patients whose tumor express PDL1 <1% were allowed to enroll in the part 1b of the study. Crossover between the treatment groups was not permitted. The primary endpoint was OS (5). A total of 1,189 patients were enrolled in part 1a; 396 were assigned to receive nivolumab plus ipilimumab, 396 to nivolumab monotherapy, and 397 to chemotherapy. Of the 550 patients enrolled in part 1b, 187 were assigned to receive nivolumab plus ipilimumab, 177 nivolumab plus chemotherapy, and 186 chemotherapy. Three-year update from CheckMate-227 part 1 (at a median follow-up of 43.1 months), patients with PD-L1 level ≥1% on TCs showed a survival benefit compared to the chemotherapy arm (HR: 0.79; 95% CI, 0.67–0.93); three-year OS rates were 33% for nivolumab plus ipilimumab and 22% for the chemotherapy alone arm (10). Nivolumab plus ipilimumab also delayed disease progression among these patients, with a three-year progression-free survival (PFS) rate of 18% with the combination of ICI vs. 4% with chemotherapy alone. 38% of patients with PD-L1 level ≥1% on TCs who responded to nivolumab plus ipilimumab continue therapy at year three vs. 4% in the chemotherapy arm. In patients whose tumors expressed PD-L1 <1%, the OS rate at year three for nivolumab plus ipilimumab arm was 34% compared to 15% for chemotherapy alone (HR: 0.64; Editorial Commentary