86 SPARCC: A Single Arm Phase 2 Study of Sasanlimab, Palbociclib and Axitinib in Metastatic Renal Cell Carcinoma (NCT07123090)

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Abstract Background Clear cell renal cell carcinoma (ccRCC) is characterized by loss of VHL through mutational inactivation or hypermethylation. In addition, mutation, deletion or hypermethylation of CDKN2A, a negative regulator of CDK4/6, has been observed in 15% of ccRCC which is associated with worse survival. Synthetic lethality between decreased CDK4/6 activity and VHL loss has been described in diverse human ccRCC cell lines and xenografts. Moreover, in translocation renal cell carcinoma (tRCC), a rare and aggressive variant histology, CDK4/6 have been shown to be activated downstream of TFE3 translocation. In preclinical studies, CDK4/6 inhibitors have shown in vitro activity against ccRCC and tRCC while combination with a VEGFR-TKI (abemaciclib with sunitinib) led to tumor reduction in murine xenografts. Moreover, CDK4/6 inhibition has demonstrated immunomodulatory properties with potential synergism with anti-PD(L)-1 therapies. Current study evaluates the efficacy of combining palbociclib, a CDK4/6 inhibitor; with axitinib, a VEGFR-TKI; and sasanlimab, a PD-1 inhibitor. Methods This multi-center, single-arm, phase II study evaluates the safety and efficacy of combination treatment with palbociclib, axitinib, and sasanlimab in patients with metastatic renal cell carcinoma. Patients with unresectable advanced or ccRCC or tRCC are eligible. Patients will receive sasanlimab 300 mg s.c. every 4 weeks (1 cycle length), with palbociclib 75 mg daily week 2-4 every cycle, and axitinib 5 mg twice daily. The primary objective is to determine the overall response rate of the combination treatment. Secondary objectives include estimating the rate of complete or deep partial response (>80% tumor shrinkage per RECIST1.1), progression free survival and overall survival and evaluating safety of the combination treatment. The study will employ a single-arm one stage design with planned sample size of 25 patients. If 17 or more responses out of 25 patients are observed, we would declare this treatment effective in this cohort. The probability of concluding that treatment is effective is 0.85 if the underlying true ORR rate is 75% or higher and is 0.054 if the true rate is 50% or less. The study began enrollment in multiple sites across the United States beginning December 2025. Results This trial tests a combination treatment with strong preclinical synergistic activity, and includes patients with two different RCC histologies: ccRCC and tRCC. The study will inform the use of CDK4/6 inhibitors and expand therapeutic strategies in first line treatment of RCC beyond PD-1/ VEGF-TKI combination treatments. Conclusions N/A DOD CDMRP Funding yes

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