ESMO 2022: Belzutifan, a HIF-2α Inhibitor, for von Hippel-Lindau (VHL) Disease–Associated Neoplasms: 36 Months of Follow-Up of the Phase 2 LITESPARK-004 Study

( In the second Mini Oral session of the European Society for Medical Oncology (ESMO) Annual Congress focusing on non-prostate genitourinary cancers, Dr. Srinivasan presented results of the LITESPARK-004 trial of Belzutifan for von Hippel-Lindau (VHL) Disease–Associated Neoplasms, after additional follow-up.

It has been recognized for years that the transcription factor HIF-2α is an established oncogenic driver, and its activation in VHL disease is caused by germline alterations in the VHL gene. Recently, belzutifan has been identified as a first-in-class HIF-2α inhibitor which has been approved for patients with VHL disease who require therapy for associated renal cell carcinoma (RCC), CNS hemangioblastomas, or pancreatic neuroendocrine tumors (pNET) not requiring immediate surgery.

The phase 2 LITESPARK-004 study (NCT03401788) enrolled adults patients with germline VHL alteration, at least one measurable nonmetastatic RCC tumor, no RCC tumor >3 cm requiring immediate surgery, no prior systemic anticancer therapy, and ECOG PS 0-1.


Once enrolled, patients received oral belzutifan 120 mg once daily until disease progression, unacceptable toxicity, or withdrawal. The primary endpoint was ORR in VHL disease–associated RCC per RECIST v1.1. Secondary endpoints were ORR in other VHL disease–associated neoplasms, TTR, DOR, and safety. In this presentation, Dr. Srinivasan provided results with more than 3 years of follow-up.

As of April 1, 2022, 38 of 61 patients initially treated (62%) remain on treatment. Among those who have ceased treatment, primary reasons for treatment discontinuation were patient decision (n = 11; 18%) and disease progression (n = 6; 10%).

Over a median follow-up of 37.8 months (range, 36.1-46.1 months), among the 61 patients with RCC, the ORR was 64% (95% CI 50.6-75.8; 4 CRs, 35 PRs).


The median TTR was 11.1 months (range, 2.7-30.5 months), and median DOR was not reached (range, 5.4+ to 35.8+ months). Among 61 patients enrolled, 38 remain on treatment as of the data cut-off.

Among the 22 patients with pNET, the ORR was 91% (95% CI 70.8-98.9; 7 CRs, 13 PRs); median DOR was not reached (range, 11.0+ to 37.3+ months). Among the 50 patients with CNS hemangioblastomas, ORR was 44% (95% CI 30.0-58.7; 4 CRs, 18 PRs); median DOR was not reached (range, 3.7+ to 38.7+ months). Finally, of 16 evaluable eyes in 12 patients with retinal hemangioblastomas, 100% showed improvement.

He noted that the frequency of VHL disease-related surgeries dramatically decreased after starting belzutifan therapy in this population.


Grade 3 treatment-related AEs (TRAEs) occurred in 18% of patients (n = 11) with anemia being the most common (n = 7; 11%).


No grade 4 or 5 TRAEs occurred. No new safety findings were observed with additional follow-up.

Thus, Dr. Srinivasan highlighted that this longer follow-up of the LITESPARK-004 trial (37.8 months) demonstrates that belzutifan continues to have clinically meaningful antitumor activity and durable responses in VHL disease–associated RCC, pNET, and CNS and retinal hemangioblastomas, with a manageable safety profile.

Presented by: Ramaprasad Srinivasan, MD, PhD, Center for Cancer Research National Cancer Institute, Bethesda, MD

Written by: Christopher J.D. Wallis, University of Toronto Twitter: @WallisCJD during the 2022 European Society for Medical Oncology (ESMO) Annual Congress, 9-13 September 2022.