Overall Survival and Long-Term Safety of Nivolumab (Anti-Programmed Death 1 Antibody, BMS-936558, ONO-4538) in Patients With Previously Treated Advanced Non-Small-Cell Lung Cancer

Abstract

Purpose: Programmed death 1 is an immune checkpoint that suppresses antitumor immunity. Nivolumab, a fully human immunoglobulin G4 programmed death 1 immune checkpoint inhibitor antibody, was active and generally well tolerated in patients with advanced solid tumors treated in a phase I trial with expansion cohorts. We report overall survival (OS), response durability, and long-term safety in patients with non-small-cell lung cancer (NSCLC) receiving nivolumab in this trial.

Patients and methods: Patients (N = 129) with heavily pretreated advanced NSCLC received nivolumab 1, 3, or 10 mg/kg intravenously once every 2 weeks in 8-week cycles for up to 96 weeks. Tumor burden was assessed by RECIST (version 1.0) after each cycle.

Results: Median OS across doses was 9.9 months; 1-, 2-, and 3-year OS rates were 42%, 24%, and 18%, respectively, across doses and 56%, 42%, and 27%, respectively, at the 3-mg/kg dose (n = 37) chosen for further clinical development. Among 22 patients (17%) with objective responses, estimated median response duration was 17.0 months. An additional six patients (5%) had unconventional immune-pattern responses. Response rates were similar in squamous and nonsquamous NSCLC. Eighteen responding patients discontinued nivolumab for reasons other than progressive disease; nine (50%) of those had responses lasting > 9 months after their last dose. Grade 3 to 4 treatment-related adverse events occurred in 14% of patients. Three treatment-related deaths (2% of patients) occurred, each associated with pneumonitis.

Conclusion: Nivolumab monotherapy produced durable responses and encouraging survival rates in patients with heavily pretreated NSCLC. Randomized clinical trials with nivolumab in advanced NSCLC are ongoing.

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.

© 2015 by American Society of Clinical Oncology.

Figures

Fig 1.

Clinical activity in patients with non–small-cell lung cancer (NSCLC) receiving nivolumab. Kaplan-Meier curves of overall survival (OS) for (A) total patient population (N = 129) and (B) patients who received nivolumab 1 (n = 33), 3 (n = 37), or 10 mg/kg (n = 59). Symbols indicate censored events, defined for OS as time to last known date alive before date of data analysis, for patients without death. (C) Tumor burden kinetics in patients with NSCLC treated with nivolumab 3 mg/kg (n = 37). Baseline tumor measurements are standardized to zero. Tumor burden was measured as sum of longest diameters of target lesions compared with baseline. Red triangles indicate first occurrence of new lesion. Horizontal dashed line at −30% indicates threshold for defining objective response (partial tumor regression) in absence of new lesions or nontarget disease progression, according to RECIST (version 1.0); vertical dashed line at 96 weeks indicates protocol-defined maximum duration of continuous nivolumab therapy. (D) Characteristics of objective responses in patients with squamous cell histology (n = 9) and nonsquamous cell histology (n = 13) treated with nivolumab. Vertical dashed line at 22 months indicates maximum planned duration of continuous nivolumab therapy. Eighteen responders discontinued nivolumab therapy for reasons other than disease progression, including: completion of maximum cycles (n = 7), adverse events (n = 8), withdrawal of consent (n = 2), and other (n = 1).

Fig 2.

Partial response of patient with metastatic squamous non–small-cell lung cancer (NSCLC) treated with nivolumab, with sustained response after drug discontinuation. Female former smoker age 57 years had widely metastatic chemotherapy-refractory squamous NSCLC after four lines of systemic therapy for stage IV disease. She received 10-mg/kg dose of nivolumab every 2 weeks and achieved partial response after 16 weeks of treatment (two cycles). Response was sustained through 96-week course of nivolumab and, as of September 2014, was ongoing 50 months after initiation of nivolumab treatment and 26 months after drug discontinuation. Computer tomography imaging shows NSCLC metastases (A) before nivolumab, (B) after 2 years with nivolumab, and (C) 2 years after stopping nivolumab therapy, involving lung and mediastinal lymph node (upper row), adrenal gland (second row), liver (third row), and myocardium (bottom row). Arrows indicate locations of metastatic disease.