Nivolumab Exposure–Response Analyses of Efficacy and Safety in Previously Treated Squamous or Nonsquamous Non–Small Cell Lung Cancer

Abstract

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 ¼ 293) or nonsquamous (n ¼ 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 timeaveraged 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.

Nivolumab Clearance Is Stationary in Patients With Resected Melanoma on Adjuvant Therapy: Implications of Disease Status on Time‐Varying Clearance

“…The practical implications of time‐varying CL confounding nivolumab exposure–response analysis have been described, and it is recommended that exposures after the first dosing cycle be used in exposure–response analyses and using later exposure metrics that can be confounded by treatment effect be avoided. Early exposure metrics after the first cycle of therapy were used to re‐evaluate the exposure‐response (overall survival) for nivolumab, and C avg 1 (C avg after cycle 1) was determined not to be a significant predictor of overall survival, after adjusting for the effect of baseline CL . Baseline CL, independent of C avg 1, was a strong predictor of survival, and patients with MEL with higher baseline CL have a higher risk of death that is independent of systemic drug exposures.…”

A Machine‐Learning Approach to Identify a Prognostic Cytokine Signature That Is Associated With Nivolumab Clearance in Patients With Advanced Melanoma

“…Moreover, previous population pharmacokinetic analyses showed that nivolumab clearance appears to be associated with ECOG performance status and albumin level, both of which are related to a patient's disease status . In a nivolumab exposure–response analysis in NSCLC, the magnitude of clearance effect on OS seems to be different in squamous and nonsquamous patients, which may also be related to differences in baseline disease status in these two populations . In addition, among all other tested covariate effects on OS, clearance had the largest impact on OS relative to other covariates, such as ECOG performance status and albumin .…”

“…14 Similar results were reported in an exposure-response analysis in NSCLC. 15,16 The parameter estimation of clearance was not highly correlated with other tested covariates, indicating that the effect of clearance on OS was not confounded with other covariates. Furthermore, the influence of such covariates on OS was higher in a model that did not account for the effect of clearance.…”

“…The parameter estimation of clearance was not highly correlated with other tested covariates, indicating that the effect of clearance on OS was not confounded with other covariates. Furthermore, the influence of such covariates on OS was higher in a model that did not account for the effect of clearance . Such an outcome may be attributed to the fact that baseline clearance reflects the overall disease state of patients at baseline .…”

“…An increasing number of studies have reported that the clearance parameter for monoclonal antibody (mAb) immunotherapy agents is associated with overall survival (OS). [14][15][16] In recent clinical studies of nivolumab, patients with melanoma, renal cell carcinoma (RCC), or non-small cell lung cancer (NSCLC) with lower clearance had improved OS compared with patients with higher clearance. Among all evaluated covariates in an exposure-response analysis, such as age, sex, body weight, prior anticytotoxic T lymphocyte antigen 4 (CTLA-4) treatment, Eastern Cooperative Oncology Group (ECOG) performance status, baseline tumor size, and baseline lactate dehydrogenase, baseline nivolumab clearance has shown strong association with OS in patients with advanced melanoma.…”