Early clinical trials looking at the PD-1 inhibitor nivolumab demonstrated promising findings, sparking the initiation of several clinical trials, explains Brian I. Rini, MD. In the initial 34 patients with renal cell carcinoma (RCC) who were treated with nivolumab, the ORR was 29% and the overall survival (OS) rate was 50% at 2 years.

In a phase II dose-finding study, patients with RCC who received 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.

Based on a promising signal seen in melanoma, the combination of nivolumab and the CTLA-4 inhibitor ipilimumab was explored in a phase Ib study, notes Rini. In this trial, 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 III trial is currently comparing nivolumab with the mTOR inhibitor everolimus in 822 patients with advanced or metastatic clear cell RCC who received 2 prior antiangiogenic therapies. The primary endpoint of the study is OS, with PFS as a secondary outcome measure.

Toxicity management with these agents differs significantly from what is commonly seen with TKIs, notes Rini. The immunotherapies activate the immune system against the tumor but also against healthy cells. This can cause liver function abnormalities and other unique side effects, cautions Rini.

Managing the unique adverse events associated with immunotherapy will likely be an initial barrier to the broader use of these therapies in clinical trials and the clinic, Rini believes. Side effect management education will be needed, in order to fully understand how to balance the risks and benefits of treatment with the novel therapies.