LBA69 - Belzutifan, a HIF-2α Inhibitor, for von Hippel-Lindau (VHL) disease-associated neoplasms: 36 months of follow-up of the phase II LITESPARK-004 study

Background

Transcription factor HIF-2α is an established oncogenic driver, and its activation in VHL disease is caused by germline alterations in the VHL gene. Belzutifan is a first-in-class HIF-2α inhibitor approved for patients (pts) with VHL disease who require therapy for associated renal cell carcinoma (RCC), CNS hemangioblastomas, or pancreatic neuroendocrine tumors (pNET) not requiring immediate surgery. Results with more than 3 years of follow-up from the phase 2 LITESPARK-004 study (NCT03401788) are presented.

Methods

Adults with germline VHL alteration, ≥1 measurable nonmetastatic RCC tumor, no RCC tumor >3 cm requiring immediate surgery, no prior systemic anticancer therapy, and ECOG PS 0-1 were eligible to receive 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.

Results

As of April 1, 2022, 38 of 61 pts (62%) remain on treatment; primary reasons for treatment discontinuation were pt decision (n = 11; 18%) and disease progression (n = 6; 10%). Median follow-up was 37.8 mo (range, 36.1-46.1 mo). Of 61 pts with RCC, ORR was 64% (95% CI 50.6-75.8; 4 CRs, 35 PRs). Median TTR was 11.1 mo (range, 2.7-30.5 mo), and median DOR was not reached (range, 5.4+ to 35.8+ mo). Of 22 pts with pNET, ORR was 91% (95% CI 70.8-98.9; 7 CRs, 13 PRs); median DOR was not reached (range, 11.0+ to 37.3+ mo). Of 50 pts 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+ mo). Of 16 evaluable eyes in 12 pts with retinal hemangioblastomas, 100% showed improvement. Grade 3 treatment-related AEs (TRAEs) occurred in 18% of pts (n = 11); anemia was most common (n = 7; 11%). No grade 4 or 5 TRAEs occurred. No new safety findings were observed with additional follow-up.

Conclusions

With a median follow-up of 37.8 mo, belzutifan continues to demonstrate clinically meaningful antitumor activity and durable responses in VHL disease–associated RCC, pNET, and CNS and retinal hemangioblastomas, with a manageable safety profile.

Clinical trial identification

NCT03401788; Release date: January 17, 2018.

Editorial acknowledgement

Medical writing and/or editorial assistance was provided by Mallory Campbell, PhD, and Matthew Grzywacz, PhD, of ApotheCom (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Legal entity responsible for the study

Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Funding

Merck Sharp & Dohme LLC., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Disclosure

R. Srinivasan: Financial Interests, Institutional, Funding: Merck/Peloton. O. Iliopoulos: Financial Interests, Personal, Full or part-time Employment: Chiesi Inc; Financial Interests, Personal, Advisory Role: Merck Inc.. W..K. Rathmell: Financial Interests, Personal, Stocks/Shares, Spouse activation of stock options in company: Caribou; Financial Interests, Personal, Stocks/Shares, stock options: sitryx; Financial Interests, Institutional, Invited Speaker, Clinical trial: Merck; Financial Interests, Institutional, Invited Speaker, Clinical Trial: Pfizer, BMS; Financial Interests, Institutional, Research Grant, Lab research - pilot funds: Incyte; Non-Financial Interests, Advisory Role, Scientific Advisory Committee: Bayer. V. Narayan: Financial Interests, Personal and Institutional, Advisory Board: Merck, Janssen, Pfizer; Financial Interests, Personal, Advisory Board: Exilixis, Myovant; Financial Interests, Personal and Institutional, Research Grant: Merck, Janssen, Pfizer. B.L. Maughan: Financial Interests, Personal, Advisory Role: AbbVie, Pfizer, AVEO oncology, Janssen, Astellas, Bristol-Myers Squibb, Clovis, Tempus, Merck, Exelixis, Bayer Oncology, Peloton Therapeutics;; Financial Interests, Institutional, Funding: Exelixis, Bavarian-Nordic, Clovis, Bristol-Myers Squibb. S. Oudard: Financial Interests, Personal, Advisory Board, consultancy, advisory role: Sanofi; Financial Interests, Personal, Invited Speaker, public speaking and advisory role: Janssen; Financial Interests, Personal, Advisory Board, advisory role and public speaking: AstraZeneca, MSD, Merck, Astellas, Ipsen, Pfizer, Roche, Genetech; Financial Interests, Personal, Advisory Board, Advirory board and public speaking: BMS, bayer, Novartis. T. Else: Financial Interests, Personal, Advisory Role: Merck, HRA Pharma, Corcept, Progenics; Financial Interests, Institutional, Research Grant: Merck, Strongbridge, Corcept. J.K. Maranchie: Financial Interests, Institutional, Principal Investigator: Merck, Janssen, Coimmune; Financial Interests, Institutional, Sponsor/Funding: Merck, Janssen, Coimmune. K. Chen: Non-Financial Interests, Institutional, Full or part-time Employment: Merck Research Laboratories, Biostatistics and Research Decision Sciences Department. R.F. Perini: Financial Interests, Personal and Institutional, Stocks/Shares: MSD; Financial Interests, Personal and Institutional, Full or part-time Employment: MSD; Financial Interests, Personal and Institutional, Advisory Role: MSD. Y. Liu: Financial Interests, Personal, Full or part-time Employment: Merck. E. Jonasch: Financial Interests, Personal, Advisory Board: Aveo, Aravive, Eisai; Financial Interests, Institutional, Research Grant: Arrowhead; Financial Interests, Personal, Invited Speaker: DAVA, Takeda; Financial Interests, Personal and Institutional, Advisory Board: Exelixis, Merck, NiKang, Novartis; Financial Interests, Personal and Institutional, Invited Speaker: Ipsen; Financial Interests, Personal and Institutional, Principal Investigator: Merck. All other authors have declared no conflicts of interest.