The Rationale for JAK Inhibition/PD-1 Blockade in Immune-Resistant RCC

Addressing disease progression following frontline immunotherapy remains one of the most critical challenges in renal cell carcinoma (RCC). In an interview with CancerNetwork®, Yu-Wei Chen, MD, MS, an assistant professor of medicine specializing in genitourinary oncology at the University of California San Diego, discussed the rationale behind the investigator-initiated phase 1b PRISM trial (NCT07219576), led by Rana McKay, MD, which is evaluating the combination of the JAK inhibitor ruxolitinib (Jakafi) and the PD-1 inhibitor retifanlimab-dlwr (Zynyz) in patients with RCC whose disease has progressed on initial checkpoint inhibitor regimens. McKay presented on the PRISM trial at the 2026 Kidney Cancer Research Summit (KCRS).

Building on preclinical evidence and translational success in other malignancies, the study aims to overcome secondary resistance by reinvigorating the tumor microenvironment and reactivating exhausted T cells. By reversing immune dysfunction in heavily pretreated tumors, investigators hope to observe meaningful clinical responses, sustained tumor shrinkage, and restored treatment durability. If early readouts show a clear signal of efficacy, Chen suggested this combination could establish a vital strategy for restoring immunotherapy sensitivity in advanced renal malignancies.

Transcript:

CancerNetwork: Based on your co-authorship of the PRISM trial, what is the mechanistic rationale behind combining a JAK inhibitor with PD-1 blockade to overcome immune checkpoint inhibitor resistance in renal cell carcinoma, and what signal are you hoping to see in early trial readouts?

Chen: This is an investigator-initiated study led by Dr. Rana McKay in our group. The rationale behind it is that there is an unmet need once [patients with kidney cancer] progress after frontline immunotherapy-based combinations. We know that with immunotherapy combinations as first-line treatment, [a small subset of] patients can achieve long-term durable responses and even cures. The main question is how we can reinvigorate the tumor microenvironment once a patient progresses on frontline therapy.

There has been translational and preclinical work investigating ruxolitinib in this setting, and we have seen early success in lymphoma, though not yet in RCC. The reasoning behind this study is that we hope to reinvigorate the tumor microenvironment and reactivate T cells after progression on frontline immunotherapy, and that is the rationale for combining ruxolitinib with a PD-1 inhibitor in this trial. We hope to see clinical responses in this patient subgroup, continued tumor control and shrinkage, and hopefully translate that into long-term durable responses. That is the goal of this study.

Reference

McKay RR, Wei LJ, Chen YW, et al. PRISM: phase 1b of retifanlimab and ruxolitinib in solid malignancies progressing on prior checkpoint inhibition (NCT07219576). Presented at: 2026 Kidney Cancer Research Summit (KCRS26); July 23-24, 2026; Boston, MA.