Belzutifan treatment for von Hippel-Lindau (VHL) disease–associated central nervous system (CNS) hemangioblastomas (HBs) in the phase 2 LITESPARK-004 study.
Authors: Iliopoulos Othon , Bundsbæk Bøndergaard Iversen Ane , Beckermann Katy , Narayan Vivek , Maughan Benjamin L. , Oudard Stephane , Else Tobias , Maranchie Jodi K. , Fu Wei , Perini Rodolfo F. , Liu Yanfang , Linehan W. Marston , Srinivasan Ramaprasad , Jonasch Eric 
Published: June 2023

2008 Background: Patients (pts) with VHL disease are at risk for developing multiorgan tumors and cysts, including CNS HBs. The first-in-class hypoxia-inducible factor 2α (HIF-2α) inhibitor belzutifan showed clinically meaningful antitumor activity in VHL disease–associated renal cell carcinoma (RCC) and other neoplasms in the ongoing, single-arm, phase 2 LITESPARK-004 study (NCT03401788). We present updated results for the subgroup of pts with CNS HBs. Methods: Adults with a VHL disease diagnosis based on germline VHL alteration, ≥1 measurable RCC tumor, no RCC tumor > 3 cm or other VHL tumor requiring immediate surgical intervention, no evidence of metastatic disease, no prior systemic anticancer treatment, and an ECOG PS score of 0 or 1 received belzutifan 120 mg orally once daily. End points evaluated in pts with CNS HBs included objective response rate (ORR), duration of response (DOR), time to response (TTR), and progression-free survival (PFS) per RECIST v1.1 by an independent review committee; linear growth rate (LGR); and safety. CNS HBs were assessed using 2 methodologies: 1) with measurable (≥1 cm) and/or nonmeasurable disease at baseline and with associated cysts, if present; and 2) with measurable disease at baseline, excluding associated cysts, if present, from the lesion measurement. Results: Of 61 enrolled pts, 50 (82%) had ≥1 CNS HB evaluable at baseline, and 22 (59%) pts had undergone ≥1 CNS-related surgery within 4 years prior to starting belzutifan treatment. As of the April 1, 2022 data cutoff date, median study follow-up for pts with CNS HBs was 38.0 mo (range, 36.1-46.1). ORR was 44% (n = 22; 95% CI, 30-59; 4 CRs, 18 PRs), and DCR was 90% (n = 45; 95% CI, 78-97). Median TTR was 5.4 mo (range, 2.3-33.1), and median DOR was not reached (NR; range, 3.7+ to 38.7+ mo). Median PFS was NR (95% CI, 38 mo to NR). After initiating belzutifan, median LGR for all evaluable pts was –1.6 mm/year (range, –7.0 to 3.1). Of all pts, 25/50 (50%) had ≥1 measurable CNS HBs, excluding any associated cysts. For these pts, ORR was 76% (95% CI, 55-91; 1 CR, 18 PRs), and DCR was 96% (n = 24; 95% CI, 80-100). Median TTR was 3.1 mo (range, 2.5-27.8), and median DOR was NR (range, 3.7+ to 38.7+ mo). Median PFS was NR (95% CI, 36 mo to NR). After initiating belzutifan, median LGR was –1.1 mm/year (range, –3.9 to –0.1). Of all pts, 1/50 (2%) underwent a CNS-related surgery after starting belzutifan. Two (3%) pts discontinued treatment due to treatment-related adverse events. Conclusions: With more than 3 years of treatment with belzutifan, consistent and durable antitumor activity was observed in pts with CNS HBs, which is consistent with findings in other VHL disease–associated neoplasms. Using different methodologies of assessing tumors, our data demonstrated that belzutifan induced the shrinkage of VHL disease–related CNS HBs with or without the presence of associated cysts. Clinical trial information: NCT03401788 .