Abstract CT221: Belzutifan, a hypoxia-inducible factor-2α (HIF-2α) inhibitor, for von Hippel-Lindau (VHL) disease-associated neoplasms: Long-term results of the phase 2 LITESPARK-004 study

Abstract Introduction: Belzutifan is a first-in-class HIF-2α inhibitor approved for patients (pts) with VHL disease-associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas (HB), or pancreatic neuroendocrine tumors (pNET) not requiring immediate surgery based on initial results from the phase 2 LITESPARK-004 study (NCT03401788). We present results from pts with more than 4 years of follow-up from LITESPARK-004. Methods: Adults with germline VHL alteration, ≥1 measurable nonmetastatic RCC tumor, no RCC tumor >3 cm requiring immediate surgery, and no prior systemic anticancer therapy received oral belzutifan 120 mg once daily until disease progression, unacceptable toxicity, or withdrawal. The primary end point was objective response rate (ORR) in VHL-associated RCC per RECIST v1.1 by independent review. Secondary end points included ORR in CNS HB and pNET; duration of response (DOR), time to response (TTR), progression-free survival (PFS), and time to surgery (TTS) in RCC, CNS HB, and pNET; and safety. Results: As of April 3, 2023, 36 of 61 pts (59%) were continuing treatment. Median follow-up was 49.9 mo (range, 48.2-58.1). Efficacy data are shown in the table. In the 4 years preceding belzutifan treatment, 46 pts (75%) underwent a total of 86 VHL-related tumor reduction procedures (surgery or radiation therapy). Since starting belzutifan, 16 pts (26%) underwent 18 tumor reduction procedures (RCC, n = 13; CNS HB, n = 3; retinal HB, n = 2). Safety profile remained unchanged with long-term follow-up. Conclusions: With a median follow-up of more than 4 years, belzutifan continues to demonstrate clinically meaningful ORR and durable responses in VHL-associated RCC, CNS HBs, and pNET. Fewer tumor reduction procedures were observed after pts started belzutifan treatment. These results support belzutifan as a standard of care for this pt population. Citation Format: Ramaprasad Srinivasan, Othon Iliopoulos, Kathryn E. Beckermann, Vivek Narayan, Benjamin L. Maughan, Stephane Oudard, Tobias Else, Jodi K. Maranchie, Ane B. Iversen, Jerry Cornell, Rodolfo F. Perini, Yanfang Liu, W. Marston Linehan, Eric Jonasch. Belzutifan, a hypoxia-inducible factor-2α (HIF-2α) inhibitor, for von Hippel-Lindau (VHL) disease-associated neoplasms: Long-term results of the phase 2 LITESPARK-004 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT221.