Exploring a Triplet Approach to Kidney Cancer Treatment

Pavlos Msaouel, MD, PhD, assistant professor at MD Anderson Cancer Center, delves into a phase 1 study investigating a novel triplet immunotherapy for patients with advanced clear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer. While current immunotherapy approaches have shown promise, offering responses in 40% to 60% of patients, a significant challenge remains: many individuals eventually develop resistance. This leads to a crucial question driving Msaouel's research: can we do better?

As he explains, current standard immunotherapy strategies for ccRCC typically involve a doublet, meaning 2 drugs working in combination. A prime example is the FDA-approved pairing of the anti-PD-1 agent nivolumab (Opdivo) with the anti-CTLA4 agent ipilimumab (Yervoy). While effective, these doublets typically result in 5% to 10% of patients achieving a disease-free state. The core objective of this new study is to elevate these numbers, to increase the proportion of patients who become disease-free and ultimately improve their survival by introducing a third therapeutic agent.

The innovative component of this triplet regimen is sitravatinib (MGCD516), an anti-VEGF tyrosine kinase inhibitor. Msaouel highlights that their previous work has shown sitravatinib's ability to target not only VEGF but also other critical pathways such as cMET, Axel, Tyro3, and MerTK. Importantly, Axel, Tyro3, and MerTK have demonstrated the potential to invigorate immune responses by clearing away immunosuppressive myeloid cells and activating T cells to fight the cancer. Early data, combining sitravatinib with just nivolumab in metastatic ccRCC, hinted at this synergistic potential.

This prior evidence, coupled with the understanding that the CTLA4 pathway plays a significant role in overall immune interaction, provided the strong rationale for combining all three drugs: nivolumab, ipilimumab, and sitravatinib. The ongoing phase 1 trial aims to thoroughly evaluate what happens when these three agents are brought together, with the ultimate goal of finding a more effective and durable treatment strategy for patients battling advanced clear cell renal cell carcinoma.

“The immediate next step was to see what happens when we combine all 3 drugs. The previous data had also suggested that the CTLA4 pathway may play a role in this whole interaction, so that generated additional rationale for testing those 3 drugs,” he says.

REFERENCE

Msaouel P, Yu K, Yuan Y, et al. Sitravatinib in combination with nivolumab plus ipilimumab in patients with advanced clear cell renal cell carcinoma: a phase 1 trial. Nat Commun. 2025;16(1):578. Published 2025 Jan 10. doi:10.1038/s41467-024-55642-8