Nivolumab in Combination With Platinum-Based Doublet Chemotherapy for First-Line Treatment of Advanced Non-Small-Cell Lung Cancer

Abstract

Purpose: Nivolumab, a fully human immunoglobulin G4 programmed death-1 immune checkpoint inhibitor antibody, has demonstrated improved survival in previously treated patients with advanced non-small-cell lung cancer (NSCLC). CheckMate 012, a phase I, multicohort study, was conducted to explore the safety and efficacy of nivolumab as monotherapy or combined with current standard therapies in first-line advanced NSCLC. Here, we report results for nivolumab plus platinum-based doublet chemotherapy (PT-DC).

Patients and methods: Patients (N = 56) received nivolumab (intravenously) plus PT-DC concurrently every 3 weeks for four cycles followed by nivolumab alone until progression or unacceptable toxicity. Regimens were nivolumab 10 mg/kg plus gemcitabine-cisplatin (squamous) or pemetrexed-cisplatin (nonsquamous) or nivolumab 5 or 10 mg/kg plus paclitaxel-carboplatin (all histologies). The primary objective was to assess safety and tolerability. Secondary objectives included objective response rate and 24-week progression-free survival rate (per Response Evaluation Criteria in Solid Tumors version 1.1); exploratory objectives included overall survival (OS) and response by tumor programmed death ligand-1 expression.

Results: No dose-limiting toxicities occurred during the first 6 weeks of treatment. Forty-five percent of patients (25 of 56 patients) reported grade 3 or 4 treatment-related adverse events (AEs); 7% of patients (n = 4) had pneumonitis. Twenty-one percent of patients (n = 12) discontinued all study therapy as a result of treatment-related AEs. Objective response rates for nivolumab 10 mg/kg plus gemcitabine-cisplatin, nivolumab 10 mg/kg plus pemetrexed-cisplatin, nivolumab 10 mg/kg plus paclitaxel-carboplatin, and nivolumab 5 mg/kg plus paclitaxel-carboplatin were 33%, 47%, 47%, and 43%, respectively; 24-week progression-free survival rates were 51%, 71%, 38%, and 51%, respectively; 2-year OS rates were 25%, 33%, 27%, and 62%, respectively. Responses were achieved regardless of tumor programmed death ligand-1 expression.

Conclusion: The safety profile of nivolumab plus PT-DC was consistent with that expected for individual agents; however, treatment discontinuation related to AEs was greater with the combination. Encouraging activity was observed, especially for the nivolumab 5 mg/kg plus paclitaxel-carboplatin group, with a 2-year OS rate of 62%.

Trial registration: ClinicalTrials.gov NCT01454102.

Conflict of interest statement

Authors’ disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article.

© 2016 by American Society of Clinical Oncology.

Figures

Fig 1.

Characteristics of objective response in patients with advanced non–small-cell lung cancer treated with nivolumab plus platinum-based doublet chemotherapy. Data are based on a September 2014 database lock. (A) Time to and duration of response (DOR). (B) Best percent change in target lesion tumor burden from baseline. Only includes patients with baseline target lesion and one or more postbaseline target lesion assessments with nonmissing value (gemcitabine [Gem]-cisplatin [Cis], n = 11; pemetrexed [Pem]-Cis, n = 15; nivolumab 10 mg/kg plus paclitaxel [Pac]-carboplatin [Carb], n = 15; nivolumab 5 mg/kg plus Pac-Carb, n = 13). Maximum percent reduction in target lesion tumor burden from baseline across all tumor assessments before subsequent therapy (including after Response Evaluation Criteria in Solid Tumors [RECIST] v1.1 progression assessments) is used. Positive change in tumor burden indicates tumor growth; negative change in tumor burden indicates tumor reduction. Horizontal lines denote 30% decrease and 20% increase. Not all reductions of 30% or greater from baseline are partial responses. (C) Percent change in target lesion tumor burden from baseline over time. Only includes patients with baseline target lesion and one or more postbaseline target lesion assessments with nonmissing value (nivolumab 10 mg/kg plus Gem-Cis, n = 11; nivolumab 10 mg/kg plus Pem-Cis, n = 15; nivolumab 10 mg/kg plus Pac-Carb, n = 15; nivolumab 5 mg/kg plus Pac-Carb, n = 13). Horizontal lines denote 30% decrease, 20% increase, and no change. Plus symbols indicate first appearance of new lesion.

Fig 1.

Characteristics of objective response in patients with advanced non–small-cell lung cancer treated with nivolumab plus platinum-based doublet chemotherapy. Data are based on a September 2014 database lock. (A) Time to and duration of response (DOR). (B) Best percent change in target lesion tumor burden from baseline. Only includes patients with baseline target lesion and one or more postbaseline target lesion assessments with nonmissing value (gemcitabine [Gem]-cisplatin [Cis], n = 11; pemetrexed [Pem]-Cis, n = 15; nivolumab 10 mg/kg plus paclitaxel [Pac]-carboplatin [Carb], n = 15; nivolumab 5 mg/kg plus Pac-Carb, n = 13). Maximum percent reduction in target lesion tumor burden from baseline across all tumor assessments before subsequent therapy (including after Response Evaluation Criteria in Solid Tumors [RECIST] v1.1 progression assessments) is used. Positive change in tumor burden indicates tumor growth; negative change in tumor burden indicates tumor reduction. Horizontal lines denote 30% decrease and 20% increase. Not all reductions of 30% or greater from baseline are partial responses. (C) Percent change in target lesion tumor burden from baseline over time. Only includes patients with baseline target lesion and one or more postbaseline target lesion assessments with nonmissing value (nivolumab 10 mg/kg plus Gem-Cis, n = 11; nivolumab 10 mg/kg plus Pem-Cis, n = 15; nivolumab 10 mg/kg plus Pac-Carb, n = 15; nivolumab 5 mg/kg plus Pac-Carb, n = 13). Horizontal lines denote 30% decrease, 20% increase, and no change. Plus symbols indicate first appearance of new lesion.

Fig 2.

Survival outcomes in patients with advanced non–small-cell lung cancer treated with nivolumab plus platinum-based doublet chemotherapy. (A) Progression-free survival (PFS). Data for PFS are based on a September 2014 database lock. Symbols denote censored observations. (B) Overall survival (OS). Data for OS are based on a March 2015 database lock. Median OS was not reached (NR) for the nivolumab 5 mg/kg plus paclitaxel (Pac)-carboplatin (Carb) group as a result of insufficient number of events and/or follow-up. Symbols denote censored observations. Cis, cisplatin; Gem, gemcitabine; Pem, pemetrexed.