Low ipilimumab trough concentration linked to worse progression-free survival in metastatic clear cell renal cell carcinoma

This randomized phase 2 trial included 110 patients with metastatic clear cell renal cell carcinoma. The cohort consisted of 39 patients in the nivolumab monotherapy group and 71 patients in the nivolumab plus ipilimumab group. Follow-up duration was week 6 after treatment start.

Investigators analyzed nivolumab trough plasma concentrations and ipilimumab trough plasma concentrations. In the nivolumab monotherapy group, low nivolumab concentrations below the median were not identified as an independent risk factor for progression (HR 2.03, 95% CI [0.93-4.44]; p=0.076). Similarly, in the nivolumab plus ipilimumab group, low nivolumab concentrations were not identified as an independent risk factor (HR 1.06, 95% CI [0.63-1.79]; p=0.83).

However, low ipilimumab concentrations below 4.9 µg/mL were independently associated with worse progression-free survival in the combination group (HR 1.77, 95% CI [1.03-3.05]; p=0.040). Neither nivolumab trough plasma concentrations nor ipilimumab trough plasma concentrations were associated with risk of death. Additionally, neither drug concentration was associated with grade ≥ 3 TRAEs occurrence. Adverse events, serious adverse events, discontinuations, and tolerability were not reported.

Prospective validation of efficacy threshold in larger cohorts or phase 3 trials is essential prior to implementation. Practice relevance indicates prospective validation essential prior to implementation of pharmacokinetically guided strategy. The study suggests an exposure-response relationship for efficacy of ipilimumab, though association versus causation was not explicitly distinguished.