LITESPARK-024: A randomized phase 1/2 study of belzutifan with or without palbociclib for previously treated advanced renal cell carcinoma

Abstract Background Immunotherapy is a standard-of-care first-line treatment for advanced clear cell renal carcinoma (ccRCC). However, many patients will develop resistance to therapy, and effective second- later-line options are therefore needed. The von Hippel-Lindau (VHL) gene inactivated in approximately 90% of with RCC results the constitutive activation hypoxia-inducible factor 2α (HIF-2α), key oncogenic driver RCC. Belzutifan, first-in-class HIF-2α inhibitor, has demonstrated antitumor activity manageable safety previously treated ccRCC. cyclin-dependent kinase (CDK) pathway also associated poor clinical outcomes In lines, CDK 4/6 inhibitor palbociclib inhibited growth. inhibition shown synergistic antiproliferative effects HIF-2α–dependent VHL -/- lines. Palbociclib could potentially enhance efficacy belzutifan as combination therapy pts Methods LITESPARK-024 2-part, open-label, multicenter, phase 1/2 randomized study (NCT05468697). Part 1 intended establish recommended 2 dose (RP2D) plus using modified toxicity probability interval design. After RP2D established, part directly compare monotherapy + both parts, measurable disease per RECIST v1.1, Karnofsky Performance Status score ≥70%, histologically confirmed unresectable stage IV component progressing on or after receiving at least systemic treatments (both an anti–PD-1/L1 monoclonal antibody VEGF receptor–targeted tyrosine sequence combination) be enrolled. Up 30 enrolled into 3 groups receive 120 mg once daily (75, 100, 125 mg) 21 consecutive days followed by 7 off. 2, 150 randomly assigned 2:1 (21 days/7 off) daily. Patients stratified International metastatic Database Consortium risk (0 vs 1-2 3-6) sarcomatoid histology (yes no) randomization 2. primary end point assess dose-limiting toxicities adverse events determine palbociclib. objective response rate v1.1 investigator assessment. Secondary points benefit rate, duration response, progression-free survival assessment; overall survival, tolerability. Enrollment began July 2022. ©2023 American Society Clinical Oncology, Inc. Reused permission. This abstract was accepted presented 2023 ASCO Genitourinary Cancers Symposium. All rights reserved. CDMRP DOD Funding: no