Exposure-response relationship of nivolumab and ipilimumab in patients with metastatic renal cell carcinoma from the randomised phase 2 BIONIKK study.

[BACKGROUND] We aimed to investigate the exposure-response (E/R) relationship for ipilimumab and nivolumab in metastatic clear cell renal cell carcinoma (m-ccRCC) patients from the randomised phase 2 BIONIKK trial (EudraCT 2016-003099-28).

[METHODS] This study included patients treated with either single-agent nivolumab (Nivo monotherapy group, n = 39) or nivolumab plus ipilimumab (Ipi/Nivo group, n = 71). Trough plasma concentrations (C) were assayed at week 6 after treatment start. Cox proportional hazard and logistic regression models were used to investigate the E/R relationship between C and clinical outcomes.

[RESULTS] Low nivolumab C (<median) was not identified as an independent risk factor for progression in either the Nivo monotherapy group (HR 2.03, 95% CI [0.93-4.44]; p = 0.076) or the Ipi/Nivo group (HR 1.06, 95% CI [0.63-1.79]; p = 0.83). Interestingly, low ipilimumab C (<4.9 µg/mL) was independently associated with worse PFS in the Ipi/Nivo group (HR 1.77, 95% CI [1.03-3.05]; p = 0.040). In both groups, neither nivolumab C nor ipilimumab C was associated with the risk of death or grade ≥ 3 TRAEs occurrence.

[CONCLUSIONS] This study suggests an E-R relationship for the efficacy of ipilimumab in m-ccRCC patients treated in combination with nivolumab. Prospective validation of our efficacy threshold in larger cohorts or phase 3 trials is essential prior to the implementation of a pharmacokinetically guided strategy.