Dr Galsky on the Need for Novel Drug Classes and Non–Cross-Resistant Options in mRCC

Matthew Galsky, MD, professor of medicine, hematology and medical oncology, professor of urology, director of Genitourinary Medical Oncology, codirector, the Center of Excellence for Bladder Cancer, and associate director, Translational Research at the Tisch Cancer Institute, Mount Sinai, explains how the development of novel drug classes and therapeutic combinations could address unmet needs in patients with metastatic renal cell carcinoma (mRCC).

In the past few years, several phase 3 trials within RCC have reported positive data and introduced new agents into the treatment armamentarium, Galsky begins. However, these agents often belong to the same therapeutic classes, and many patients can develop cross-resistance. Accordingly, the development of non–cross-resistant therapies and expansion of effective therapeutic classes is of great interest within RCC, Galsky explains.

Patients with RCC are commonly treated with surgery, targeted therapy, or immunotherapy, either alone or in combination with another therapy. VEGF TKIs are a highly effective treatment option in this space but can be limited in the types of kinases they target, Galsky says. Although different VEGF TKIs can display variable efficacy and toxicity profiles, they still encompass a single class of therapies and can confer general TKI resistance, Galsky explains.

In terms of immunotherapy, PD-1, PD-L1, and CTLA-4 inhibitors are commonly utilized in RCC, Galsky continues. PI3K/mTOR inhibition is another viable option and can be combined with immune checkpoint inhibitor therapy, he adds. With the designation of HIF-2α as a novel actionable target for drug development in RCC, several HIF inhibitors like tivozanib (Fotivda) and belzutifan (Welireg) are also being investigated in the metastatic space, Galsky notes.

Research has shown that combination therapy is an effective approach in the frontline metastatic setting, Galsky reports. Ultimately, the introduction of additional non–cross-resistant agents with different mechanisms of action and different safety profiles could further improve the efficacy of these combination approaches, he concludes.

Disclosures: Dr Galsky reported serving as a consultant or in an advisory role for Aileron Therapeutics, Astellas Pharma, AstraZeneca, Basilea, BioMotiv, Bristol Myers Squibb, Dendreon, Dracen, Dragonfly Therapeutics, EMD Serono, Genentech, Gilead Sciences, GlaxoSmithKline, Incyte, Infinity Pharmaceuticals, Inovio Pharmaceuticals, Janssen, Lilly, Merck, Novartis, NuMab, Pfizer, Seattle Genetics, Silverback Therapeutics, Urogen pharma; he reports receiving research funding from AstraZeneca, Bristol Myers Squibb, Dendreon, Genentech/Roche, Janssen Oncology, Merck, and Novartis; he has ownership interests in Rappta Therapeutics.