Immune checkpoint inhibitors have shown clinical activity in patients with advanced renal cell carcinoma (RCC). The distinct mechanism of action of these therapies represents the potential for combination strategies, suggests Thomas Hutson, DO, PharmD. In early studies assessing the combination of VEGF inhibitors with anti–PD-1 or –PD-L1 antibodies, adverse events (AE) were a challenge, particularly hepatotoxicity, although promising activity was also observed, Hutson notes. 

The AE profile with immune checkpoint inhibition is different than experienced with therapies against VEGF and mTOR, Hutson notes. Immune checkpoint inhibition causes the activation of T-cells against normal host cells along with tumor cells. This activation can cause flu-like symptoms, along with damage to the skin, gastrointestinal tract, adrenal glands, and pituitary gland.

As a single-agent, the PD-1 inhibitor nivolumab demonstrated activity in patients with metastatic clear-cell RCC. At a 2.0 mg/kg dose, the treatment showed a progression-free survival of 4 months, an objective response rate of 22%, and a median overall survival (OS) of 25.5 months in patients with previously treated mRCC. Interestingly, since these therapies are immune-based, histology should not significantly impact efficacy, suggesting that there should be activity in both clear cell and non-clear cell histologies, Hutson notes.
 
Top-line findings from the pivotal phase III CheckMate-025 study revealed that second-line nivolumab improved OS compared with everolimus for patients with metastatic RCC, although full data were not yet released. Results from this study are eagerly anticipated, particularly since profound and prolonged responses have been observed in a subset of patients, Eric Jonasch, MD comments. There are very limited data in untreated patients, which is the setting that is ideal for immunotherapy, notes David F. McDermott, MD.
 

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