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The role of checkpoint inhibition in renal cell carcinoma (RCC) is less clear than in other tumor types. A multitude of targeted therapies are approved for RCC, with extensive detail paid to sequencing these treatments for optimal results. At this point, it is unclear where a checkpoint inhibitor could fit into this treatment landscape, Robert Dreicer, MD, suggests.
In a phase II dose-finding study, patients with RCC who received the PD-1 inhibitor nivolumab experienced a median progression-free survival (PFS) of approximately 4 months. The objective response rate was near 20%, with a stable disease rate between 37% and 44% at the time of the analysis. A phase III trial is currently comparing nivolumab with the mTOR inhibitor everolimus in 822 patients with advanced or metastatic clear cell RCC who have received 2 prior antiangiogenic. The primary endpoint of this study is overall survival (OS), with PFS as a secondary outcome measure.
Many of the approvals in RCC were based on PFS as an endpoint, since OS can be a difficult endpoint to measure, notes Dreicer. Moreover, early trials have suggested that the level of single-agent activity with nivolumab may not be sufficient for regulatory approval, warranting the exploration of combination approaches.
Nivolumab was explored in combination with the CTLA-4 inhibitor ipilimumab in a phase Ib study. With the combination, the ORR was 43% to 48% based on dose size. The median PFS was not reached, with a 24-week rate of approximately 65%. A phase II study is currently recruiting that will examine single-agent nivolumab versus either nivolumab with bevacizumab or ipilimumab as a treatment for patients with metastatic RCC (NCT02210117).
The issue with combination strategies will be toxicity, which could result in shorter treatment duration. Ideally, as a single-agent, a checkpoint inhibitor could be used to replace a more toxic agent. A potential strategy could be to replace IL-2 with a checkpoint inhibitor, suggests Omid Hamid, MD.