CDK4/6 Inhibition With Abemaciclib in Patients With Previously Treated Advanced Renal Cell Carcinoma

This single arm phase 1b study exploring safety and efficacy of abemaciclib in pretreated RCC with a clear cell component to our knowledge is the first to report activity of CDK4/6 inhibition monotherapy in advanced RCC. No responses were seen in 11 patients with no new toxicity signals. While no activity as a monotherapy, ongoing trials exploring CDK4/6 inhibitors in combination with active therapeutic agents must continue, before we rule out this class of agents in this disease setting a. Background: Preclincal data provide a rationale for cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors alone and in combination with HIF-2 alpha inhibitors in treatment of clear cell renal cell carcinoma (ccRCC), with randomized phase 2 clinical trials currently open exploring the combination of palbociclib with belzutifan vs belzutifan in treatment resistant ccRCC (NCT05468697). However, single agent activity for CDK4/6 inhibitors in ccRCC has not been reported. In this multi-center phase 1b clinical trial ( NCT04627064 ), we investigated the safety and efficacy of monotherapy with abemaciclib, an oral CDK4/6 inhibitor in patients with advanced pretreated RCC. Methods: Adult patients with advanced RCC with a clear cell component and ECOG status of <= 2 progressing after at least 1 prior regimen including immunotherapy and a VEGFR TKI received abemaciclib 200 mg twice daily in 4-week cycles until progression or unacceptable toxicity. The primary objective was to evaluate the objective response rate (ORR) of abemaciclib with a secondary endpoint of safety. First imaging was performed after 8 weeks or 2 cycles. Response was assessed per RECIST 1.1 and toxicity graded per CTCAE v5.0. Results: Eleven patients were enrolled between December 31, 2020 and October 03, 2023. Median age was 62 years (range 54-68); 73% ( n = 8) had IMDC intermediate risk disease and 1 patient had translocation RCC with a clear cell component. Median number of prior therapies was 4 (range 1-9). ORR was 0% (0/11; 8 progressive disease, 1 stable disease stopping for clinical progression, 2 not evaluable with clinical progression). About 27% ( n = 3) experienced grade >= 3 treatment-related adverse events (diarrhea n = 1, nausea n = 1, neutropenia n = 1). Conclusion: In patients with heavily pretreated metastatic RCC, abemaciclib monotherapy had no clinically meaningful activity without new toxicity signals. This data will offer important insight into interpretation of results for ongoing trials exploring CDK4/6 inhibition in combination with HIF-2 alpha inhibitors and immunotherapy.