Immune Checkpoint Inhibition in RCC

Mechanistically, inhibition of PD-1 and PD-L1 augments antitumor immune response in renal cell carcinoma (RCC), Sumanta Kumar Pal, MD, states. Several immunotherapy agents are being investigated in RCC, including nivolumab, MPDL3280A, and ipilimumab.

Nivolumab, a PD-1 inhibitor, is currently in the later stages of development. It is being investigated as monotherapy compared with everolimus in the second-line and in combination with ipilimumab compared with sunitinib in the first-line setting. However, the combination of nivolumab and ipilimumab can cause serious gastrointestinal and hepatic toxicities that require immediate management, says Pal. Nivolumab as a second-line monotherapy may be better tolerated, adds Pal.

Although combining a VEGF inhibitor with immunotherapy seems intuitive, the risk of toxicities may prove to be prohibitive to further development of those combination regimens, notes Pal. Another approach, is the sequencing of agents. Some studies have noted immune-based markers emerging as tumors develop resistant to TKIs, including some that may predispose a response to immunotherapy. These findings suggest that sequencing of a TKI followed by immunotherapy may be a feasible approach.

Ideally, biomarker development should coincide with drug development, notes Saby George, MD, FACP. At this point, PD-L1 expression is the frontrunner for selecting patients for PD-1 and PD-L1 therapies, but its role as a predictive marker must continue to be validated. There is still a need for a better biomarker.