24 A Phase 1b/2 Study of Abemaciclib Plus Cabozantinib in Immune Checkpoint Blockade-Pretreated Metastatic Clear Cell Renal Cell Carcinoma and Translocation-Associated Renal Cell Carcinoma (NCT06835972)

Abstract

Abstract Background There is a need for novel systemic therapies in patients with metastatic renal cell carcinoma (RCC) who progress on standard agents. A hallmark of clear cell RCC (ccRCC) is von Hippel Lindau (VHL) inactivation which affects downstream targets including vascular endothelial growth factor (VEGF). It also increases cellular proliferation via activation of the CCND1 gene which encodes cyclin D1, a key partner to cyclin-dependent kinases 4 and 6 (CDK4 and CDK6) in driving cancer cells through the cell cycle. Translocation-associated renal cell cancers (tRCC) are rare variants that constitutes <5% of RCCs; they lack consistently effective treatment, highlighting the need for novel strategies. A recent report demonstrated downstream effects of the tRCC fusion transcripts include CDKs. Indeed, preclinical models of human tRCC confirmed CDK4 dependency and demonstrated antitumor effect with CDK4/6 inhibition in vitro and in vivo (Gupta S, 2025). We hypothesize that targeting these pathways will provide benefit in treatment refractory patients with metastatic ccRCC and tRCC. Methods This study is an investigator-initiated, two-center (Memorial Sloan Kettering Cancer Center and Johns Hopkins University), single-arm, phase 1b/2 trial to evaluate the combination of MET/VEGFR/AXL-directed multireceptor tyrosine kinase inhibitor (TKI) cabozantinib with the CDK 4/6 inhibitor abemaciclib in patients with ccRCC or tRCC. Patients must have received both immune checkpoint blockade and TKI. The phase 1b dose escalation will require between 4 and 24 patients in a 3 + 3 dose escalation design across 4 dose levels. Treatment is once daily cabozantinib plus twice daily abemaciclib (see table) and is continued until disease progression, intolerance, or discontinuation for other reasons. Restaging imaging is performed every 8 weeks for the first 3 assessments and then every 12 weeks thereafter. Pharmacokinetic assessments will be integrated for both agents during phase 1b. The maximal tolerated dose (MTD) will be defined as the dose level at which a dose limiting toxicity occurs in at most 1 out of 6 patients. The recommended phase 2 dose (RP2D) will integrate this information with longer-term tolerance, pharmacokinetics, and efficacy signal. In phase 2, patients will be treated at the RP2D following a Simon minimax two-stage design with the primary endpoint being objective response rate at 24 weeks. In stage 1, if 4 or more of the first 12 patients achieve an objective response, enrollment will be extended to 13 additional patients for a total of 25. We are currently accruing patients to the phase 1b portion. Results Metastatic RCC remains a clinical challenge, particularly for patients who have exhausted standard lines of therapy including immune checkpoint blockade and tyrosine kinase inhibition. This study addresses a critical unmet need by rationally targeting convergent oncogenic dependencies, VHL-driven VEGF signaling and CDK4/6-mediated cell cycle dysregulation, in both clear cell and translocation-associated RCC. The inclusion of tRCC is especially meaningful given its rarity, poor prognosis, and near-total absence of evidence-based systemic options. By combining cabozantinib’s broad receptor tyrosine kinase inhibition with abemaciclib’s CDK4/6 blockade, this trial is among the first to clinically exploit the CDK4 dependency recently identified in tRCC preclinical models, translating compelling laboratory findings into a therapeutic strategy for patients with no established next-line standard of care. Beyond establishing safety and tolerability, this investigator-initiated trial is designed to generate meaningful early efficacy signals through a rigorous phase 1b/2 framework with integrated pharmacokinetic analysis. If successful, this combination could define a novel treatment paradigm for a refractory RCC population and lay the groundwork for broader exploration of CDK4/6 inhibition across molecularly defined RCC subtypes. Conclusions N/A24 Table Dose level Cabozantinib (once daily) Abemaciclib (twice a day) -1 40mg 50mg 1*(Starting Dose) 40mg 100mg 2 40mg 150mg 3 60mg 150mg24 Figure RCC = renal cell carcinoma. ICB = Immune checkpoint blockade. TKI = tyrosine kinase inhibitor. MTD = maximal tolerated dose. RP2D = Recommended phase 2 dose.