Immune checkpoint inhibitors have shown significant clinical benefits in many tumor types, including renal cell carcinoma (RCC).1

The complexity of these pathways’ mechanism of action allows them to be interrupted by multiple drugs at different stages, and a number of recent and ongoing studies are investigating the potential for the inclusion of combination therapies.2

These strategies were discussed in July 2015 by a panel that was moderated by Robert A. Figlin, MD, FACP, of Cedars-Sinai Samuel Oschin Comprehensive Cancer Center in Los Angeles, CA, and included Thomas Hutson, DO, PharmD, of Texas Oncology–Baylor in Dallas, TX, Eric Jonasch, MD, The University of Texas MD Anderson Cancer Center in Houston, TX, and David F. McDermott, MD, of Dana Farber/Harvard Cancer Center in Cambridge, MA.3

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Dr. Hutson discussed the difficulties surrounding combining active drugs, which currently fall into two classes: vascular endothelial growth factor receptor (VEGF)-related drugs and mammalian target of rapamycin (mTOR)-related drugs.

He noted that there is a tendency for overlapping toxicities that lower the effective dose of drugs to the point that they do not work in combination, but also acknowledged that new research developments in the arena offer possibilities for clinical application. 

He said that newly discovered potential mechanisms of action, different side-effect profiles, and different dose-limiting toxicities allow for the potentially successful combination, although there are still difficulties in combining certain VEGF inhibitors with anti-PD-1 and anti-PDL-1 drugs due to toxicity concerns. But he said he remains  hopeful about the possibilities offered by immunotherapies in treating RCC.

Immune-based Therapies Can Be Independent of Histology

Used alone, the PD-1 inhibitor nivolumab, a fully human IgG4 programmed cell death-1 immune checkpoint inhibitor antibody, showed clinical activity in patients with metastatic clear-cell RCC.

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At a dose of 2.0 mg/kg, the therapy demonstrated 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 previously treated for metastatic RCC.

“What’s nice about immune-based therapies is that they’re not histology-dependent,” said Dr. Hutson. “There’s no reason to think that a histologic sub-type of kidney cancer would respond less than clear-cell, and what we’ve seen in VEGF inhibitors  aimed at clear-cell histologies, which have a HIF-dependent mechanism, [suggests that] these PD-1 and PDL-1 drugs should be potentially active in all histologies.”