A real-world study of the association between nivolumab exposure and efficacy in patients with metastatic melanoma.

Abstract

e15126 Background: The pharmacokinetic/pharmacodynamic (PK/PD) relationships of immune checkpoint inhibitors are not well understood. In this real-world study, we monitored plasma concentrations of nivolumab and investigated their impact on clinical outcomes in a cohort of patients with unresectable stage III or IV melanoma. Methods: 52 adult patients (26M/26F), mean age 64.3 years (range 31-89), Performance Status 0/1 were treated with 1 mg/kg nivolumab + 3 mg/kg ipilimumab (40 patients) or single agent nivolumab 240 mg Q2W or 480 mg Q4W flat dose (12 patients). Nivolumab plasma concentrations (Cmax: end of infusion and Cmin: trough levels) were measured at the first cycle (C1). Nivolumab was analysed using a validated mass spectrometry method. PK parameters were derived using a standard population PK approach. Efficacy was evaluated according to RECIST 1.1. Patients with complete, partial response (CR/PR) or stable disease (SD) at 6 months were next categorised as having confirmed clinical benefit. Side effects were graded according to CTCAE 5.0. Statistical analyses were performed using R. Results: we observed 5.7% CR, 32% PR, 17% SD and 45.3% progressive disease (PD). There was no difference in efficacy between single-agent and combination therapy (odd ratio = 0.28, [0.06-1.087], Fisher test). Age, smoking habits or co-medications were not associated with clinical outcome, but baseline albumenia and severe toxicities were predictive of efficacy (p<0.05, t-test). After the first cycle (C1), nivolumab Cmax concentrations were 67.1 µg/mL ±64.1 (CV = 95%), and trough levels were 26.9 µg/mL ±23 (CV = 87%). No association was found between nivolumab levels (Cmax, Cmin) and adverse events. Regarding efficacy, in patients treated with the nivolumab + ipilimumab combination, there was no statistical difference in Cmax levels between clinical benefit and PD patients (37.9 µg/mL vs. 33.9 µg/mL p>0.05) and in Cmin (25 µg/mL vs. 15.5 µg/mL p>0.05, t-test) despite a numerical difference in trough levels of +61%. Similarly, there was no statistical difference in Cmax between clinical benefit and PD patients treated with nivolumab monotherapy (203.1 µg/mL vs . 149.6 µg/mL, p>0.05) despite a numerical difference of +35%. Conversely, a statistical difference was found in Cmin between patients with clinical benefit and PD (58.5 µg/mL vs. 33.9 µg/mL p=0.04). ROC analysis showed that a trough value of ≤40.6 µg/mL was significantly associated with Progressive Disease (p=0.038). Conclusions: This real-world study suggests that with single-agent nivolumab, trough levels after the first cycle may predict clinical outcome, as patients with plasma concentrations ≤40.6 µg/mL are at significantly higher risk of experiencing PD. The marked interpatient variability observed in the pharmacokinetics of nivolumab warrants the use of Therapeutic Drug Monitoring to check that exposure levels are within the expected range and to identify patients with low exposure after the first cycle who may be at risk of treatment failure.