23 PRISM: Phase 1b of Retifanlimab and Ruxolitinib in Solid Malignancies Progressing on Prior Checkpoint Inhibition (NCT07219576)

Abstract

Abstract Background Despite improved outcomes with programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) immune checkpoint inhibitors (ICI) in renal cell carcinoma (RCC) and non-small cell lung cancer (NSCLC), most patients develop resistance. Preclinical data demonstrate that Janus kinase inhibition (JAKi) restores T cell cytokine production and proliferation, potentiating ICI activity, with ruxolitinib plus ICI demonstrating superior tumor control across multiple murine models. Ruxolitinib may also reprogram immunosuppressive myeloid populations within the tumor microenvironment. In an investigator-initiated trial (NCT03681561), 53% of patients with relapsed/refractory Hodgkin’s Lymphoma previously failing anti-PD-1 therapy responded to ruxolitinib plus nivolumab, including 6 complete responses. High response rates were also observed with JAKi plus anti-PD-1 in NSCLC (NCT03425006). We aim to investigate whether combining ruxolitinib with anti-PD-1 therapy can overcome resistance in solid tumors. Methods This prospective, open-label, single-arm phase 1b study evaluates ruxolitinib plus retifanlimab in patients with advanced clear cell RCC or NSCLC progressing on prior PD-1/PD-L1 therapy. Patients must have measurable disease (Response Evaluation Criteria in Solid Tumors [RECIST] 1.1), Eastern Cooperative Oncology Group (ECOG) performance status 0-1, and adequate organ function. Key exclusions: prior JAKi, >1 prior line of PD-1/PD-L1 therapy, primary progression on prior ICI, or unresolved immune-related adverse event (>grade 1). A 3 + 3 dose escalation design evaluates ruxolitinib 15 mg and 20 mg twice daily with fixed retifanlimab 500mg intravenously (IV) every 4 weeks, followed by dose expansion. Treatment continues until progression, toxicity, or withdrawal. The primary objective is determining the recommended phase 2 dose (RP2D). Secondary objectives include objective response rate, duration of response, radiographic progression-free survival, overall survival, and safety. To further interrogate mechanisms of response and resistance, correlative studies evaluating tumor microenvironment, immune cell composition, and molecular profiling are ongoing. A Simon’s two-stage design is utilized for testing the null hypothesis (true response rate 10%) against an alternative of 30%, rejecting null if ≥ 6 responses occur in 25 participants (α = 0.05, power 80%). Assuming a dropout rate of 5%, we will target a minimum enrollment of 36 and maximum enrollment of 42 participants to ensure a maximum of 40 evaluable participants on the trial. The standard survival analysis will be conducted for the time-to-event endpoints. The study is activated at the University of California San Diego and is currently open to accrual. Clinical Trial Information: NCT07219576. Results Resistance to PD-1/PD-L1 blockade is a major unmet need in RCC and NSCLC, with few effective options after progression on frontline immunotherapy. PRISM tests a mechanistically rational combination, ruxolitinib to reverse chronic interferon-driven T cell dysfunction and immunosuppressive myeloid skewing, paired with retifanlimab to sustain antitumor T cell activity. Integrated correlative studies aim to identify biomarkers of response to guide patient selection. Our vision is to establish JAK inhibition as a tractable strategy for restoring checkpoint sensitivity across solid tumors, providing the foundation for a biomarker-driven randomized phase 2 trial in checkpoint-refractory disease. Conclusions NA23 Figure