Quantitative Characterization of the Exposure-Response Relationship for Cancer Immunotherapy: A Case Study of Nivolumab in Patients With Advanced Melanoma

Abstract

To inform the benefit–risk assessment of nivolumab in patients with advanced melanoma, analyses of efficacy and safety exposure–response (E–R) relationships were conducted with data from patients with advanced melanoma enrolled in two clinical studies (phase I and phase III) who received nivolumab 0.1–10.0 mg/kg every 2 weeks. E‐R efficacy analyses were performed by relating the nivolumab time‐averaged concentration after the first dose (Cavg1) to two endpoints: RECIST objective response (OR) and overall survival (OS). E–R safety analyses characterized the relationship between nivolumab Cavg1 and the hazard of all‐causality adverse events leading to discontinuation or death (AE‐DC/D). Nivolumab exposure represented by Cavg1 was not a significant predictor of OR, OS, or the hazard of AE‐DC/D. E–R efficacy and safety relationships were relatively flat over the exposure range.

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

“…Similar to the AEs-DC/D results, there was no apparent relationship between nivolumab exposure and any-cause or treatment-related grade !3 AEs. These results were consistent with a previous E-R analysis of the safety of nivolumab 0.1 to 10 mg/kg Q2W in patients with melanoma (18,31). In our analysis, baseline ECOG PS and line of therapy were significantly associated with the risk of AEs-DC/D in patients with NSCLC, which was not unexpected, given that ECOG PS and extensive prior treatment have been recognized as indicators of poor prognosis in patients with diverse cancer types, and may also reflect comorbidities and residual AEs associated with prior treatment regimens.…”

“…Abbreviations: CI, confidence interval; CPH, Cox proportional hazards; E-R, exposure-response; K-M, Kaplan-Meier; NSCLC, non-small cell lung cancer; OS, overall survival; PI, prediction interval; VPC, visual predictive check. were also similar to those reported in advanced melanoma, in which patients with lower baseline clearance had improved OS (18,22). The effect of exposure (C avg1 ) was not expected to be completely confounded by the effect of clearance in these analyses, because the nivolumab C avg1 values were obtained from a range of doses, and the correlation of these parameter estimates was not high (r < 0.9).…”

“…Nivolumab baseline clearance was obtained from a previously reported PPK model (22). Nivolumab baseline clearance was included in both squamous and nonsquamous OS full models, as drug clearance has been previously shown to be associated with OS in patients with advanced melanoma, in which lower baseline clearance was associated with better OS (18,23). To evaluate the confounding effects of nivolumab baseline clearance and exposure (C avg1 ) on OS, a sensitivity analysis was performed by excluding nivolumab baseline clearance from the full model.…”

“…The benefit-risk profile of nivolumab has previously been examined in E-R analyses in patients with advanced melanoma, which showed that nivolumab exposure, measured by the time-averaged concentration after the first dose (C avg1 ), was not significantly associated with objective response rate (ORR) or AEs leading to discontinuation or death (AEs-DC/D; ref. 18). The availability of data from patients with squamous and nonsquamous NSCLC from two phase III studies (9,10) and from earlier phase I (19) and phase II (14) studies allows comprehensive E-R analyses of nivolumab in 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 .…”