Belzutifan for patients with von Hippel-Lindau disease-associated CNS haemangioblastomas (LITESPARK-004): a multicentre, single-arm, phase 2 study.

Background: The first-in-class hypoxia-inducible factor-2α inhibitor, belzutifan, showed clinically meaningful antitumour activity in von Hippel-Lindau (VHL) disease-associated neoplasms in the ongoing, single-arm, phase 2 LITESPARK-004 study. We aimed to investigate antitumour activity with an additional 16 months of follow-up and present updated results for the subgroup of patients with CNS haemangioblastomas.
Methods: In the multicentre, single-arm, phase 2 LITESPARK-004 study, adults (aged ≥18 years) from 11 cancer centres or hospitals in the USA, Denmark, France, and the UK, with germline VHL alterations, at least one measurable renal cell carcinoma tumour, no renal cell carcinoma tumour greater than 3 cm requiring immediate surgical intervention, an Eastern Cooperative Oncology Group performance status 0 or 1, and no previous systemic therapy received oral belzutifan 120 mg once daily until unacceptable toxicity, disease progression, or patient decision to withdraw. The primary endpoint, evaluated in patients with CNS haemangioblastomas, was the proportion of patients with an objective response per RECIST version 1.1 by an independent review committee. We assessed response using two approaches. In approach 1, we evaluated all measurable (≥1 cm maximum diameter) or non-measurable lesions at baseline, including both the solid lesion and the associated cystic component if present. In approach 2, we evaluated only baseline lesions with a measurable (≥1 cm maximum diameter) solid lesion. Antitumour activity was assessed in all patients who received at least one dose of belzutifan. This study is no longer recruiting but is ongoing, and is registered with Clinicaltrials.gov, NCT03401788.
Findings: Between May 31, 2018, and March 29, 2019, of 67 patients screened, 61 (32 [52%] male and 29 [48%] female) were enrolled; 50 (82%) had at least one CNS haemangioblastoma evaluable at baseline (184 total lesions). Median follow-up for the 50 patients with CNS haemangioblastomas was 38·0 months (IQR 36·7-40·1). In approach 1, 22 of 50 patients (44% [95% CI 30-59]) had an objective response. In approach 2, 19 of 25 patients (76% [55-91] had an objective response. 23 (46%) of 50 patients had a grade 3-5 all-cause adverse event. 19 (38%) patients reported grade 3 adverse events, the most common of which was anaemia (in 6 [12%] patients). Two of 50 patients (4%) reported grade 4 events (retinal vein occlusion and embolism). Two patients died owing to adverse events not considered treatment-related (suicide and toxicity to various agents).
Interpretation: Belzutifan showed meaningful antitumour activity in VHL disease-associated CNS haemangioblastomas that was sustained for more than 3 years of treatment. These results continue to support belzutifan as a systemic treatment option for patients with VHL disease-related CNS haemangioblastomas.
Funding: Merck Sharp & Dohme, National Institutes of Health, and National Cancer Institute.
Competing Interests: Declaration of interests VN has received support (to his institution) for the present manuscript from Merck; consulting fees from Bristol Myers Squibb, Exelixis, Janssen, Regeneron, and Eisai; honoraria from Pfizer; has participated on advisory boards for Myovant; and has received research support (to his institution) from Bristol Myers Squibb, Janssen, Merck, Rahway, NJ, USA, Pfizer, and Regeneron. BLM has received research funding (to his institution) from Exelixis, Bavarian-Nordic, Clovis, and Bristol Myers Squibb; and consulting fees from AbbVie, Pfizer, AVEO Oncology, Janssen, Astellas, Bristol Myers Squibb, Clovis, Tempus, Merck, Exelixis, Bayer Oncology, Lilly, Sanofi, Telix, and Peloton Therapeutics. KEB has received support for the present manuscript from Merck for provision of study drug and funding to her institution; has received the Young Investigator Award for correlative science from same clinical trial (to her institution), from BMS-IASLC-LCFA; has received funding for translational research (to her institution) from Aravive, Pionyr, and ArsenalBio; and has received consulting fees from Aravive, Alpine Bioscience, Aveo, AstraZeneca, Eisai, Exelixis, Bristol Myers Squibb, Merck, Nimbus, Sanofi, and Seagen. SO has received research funding (to his institution) from Bristol Myers Squibb, Sanofi, and AstraZeneca; consulting fees from Bristol Myers Squibb, Sanofi, Pfizer, Novartis, Janssen, Astellas, Bayer, and Ipsen; honoraria from Bristol Myers Squibb, Sanofi, Novartis, Janssen, Astellas, Bayer, and Ipsen; travel support from Janssen, Ipsen, and Bayer; and has participated on advisory boards for Roche, Ipsen, Pfizer, Bayer, and Janssen. TE has received support (to his institution) for the present manuscript from Merck; and consulting fees for advisory boards from Merck and Lanthaeus. JKM has received contracts for editorial services from Elsevier; honoraria from the Large Urology Group Practice Association; and travel support from the Kidney Cancer Association and Kidney Cancer Research Symposium. CMG is an employee of Merck Sharp & Dohme, a subsidiary of Merck (Rahway, NJ, USA), and has stock ownership in Merck. WF is an employee of Merck Sharp & Dohme, a subsidiary of Merck, and has stock ownership in Merck. RFP is an employee of Merck Sharp & Dohme, a subsidiary of Merck, and has stock ownership in Merck. YL is an employee of Merck Sharp & Dohme, a subsidiary of Merck, and has stock ownership in Merck. RS has received support for the present manuscript from Merck and Peloton; received drugs to do the studies and funds from the National Cancer Institute to partially cover the costs of doing the study at the National Institutes of Health from NiKang; received investigational agents for an investigator-initiated study under a CRADA with the National Cancer Institute from Pfizer; was primary investigator for an investigator-initiated trial where trial agents were provided by Genentech, and on an investigator-initiated trial where investigational agents were provided by Novartis. EJ has received research funding (to his institution) from Arrowhead, Merck, NiKang, andNovartis; consulting fees from Aveo, Eisai, Exelixis, Ipsen, Merck, and NiKang; honoraria from DAVA; participated on an advisory board for Novartis; and has a leadership role at the National Comprehensive Cancer Network. OI, ABI, and WML declare no competing interests.
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