Purpose: Nivolumab is a fully human IgG4 monoclonal antiprogrammed death-1 antibody with demonstrated efficacy, including durable responses and prolonged survival, in patients with previously treated, advanced non-small cell lung cancer (NSCLC). Exposure-response (E-R) analyses for efficacy and safety were conducted to inform the benefit-risk assessment of nivolumab in this patient population.Experimental Design: The analyses used clinical trial data from patients with squamous (n = 293) or nonsquamous (n = 354) NSCLC from four clinical trials who received nivolumab doses of 1 to 10 mg/kg every 2 weeks. E-R efficacy analyses were performed by investigating the relationship between time-averaged nivolumab concentration after the first dose (C_avg1) and the probability of overall survival by histology. E-R safety analyses examined relationships between nivolumab C_avg1 and hazards of adverse events leading to discontinuation or death (AEs-DC/D).Results: Nivolumab exposure was not associated with overall survival [the 95% confidence interval (CI) of effect included 1] in patients with squamous (HR, 0.802; 95% CI, 0.555-1.16) or nonsquamous NSCLC (HR, 0.94; 95% CI, 0.683-1.29). Similarly, nivolumab exposure was not associated with AEs-DC/D in the overall population (HR, 0.917; 95% CI, 0.644-1.31). The risk of AEs-DC/D was similar among patients with squamous or nonsquamous histology.Conclusions: Nivolumab monotherapy demonstrated a wide therapeutic margin, as evidenced by relatively flat E-R relationships over the range of exposures produced by doses of 1 to 10 mg/kg every 2 weeks (Q2W), supporting the use of the initially approved dose of 3 mg/kg Q2W in patients with NSCLC. Clin Cancer Res; 23(18); 5394-405. ©2017 AACR.

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