LITESPARK-004 (MK-6482-004) phase 2 study of belzutifan, an oral hypoxia-inducible factor 2α inhibitor (HIF-2α), for von Hippel-Lindau (VHL) disease: Update with more than two years of follow-up data.
Authors: Jonasch Eric , Iliopoulos Othon , Rathmell Wendy Kimryn , Narayan Vivek , Maughan Benjamin L. , Oudard Stephane , Else Tobias , Maranchie Jodi K. , Welsh Sarah Joanne , Bundsbæk Bøndergaard Iversen Ane , Roy Ananya , Liu Yanfang , Perini Rodolfo F. , Linehan W. Marston , Srinivasan Ramaprasad 
Published: June 2022

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Background: VHL disease is associated with malignant or benign tumors, including renal cell carcinoma (RCC), pancreatic neuroendocrine tumors (pNETs), and hemangioblastomas. Alterations in the VHL gene cause aberrant stabilization and accumulation of HIF-2α, leading to activation of genes associated with tumor growth. Antitumor activity observed in the ongoing open-label phase 2 study, LITESPARK-004 (NCT03401788), led to the approval of belzutifan for the treatment of patients (pts) with VHL disease who require therapy for associated RCC, CNS hemangioblastomas, or pNETs not requiring immediate surgery. Updated results are presented after > 2 years of follow-up. Methods: Pts (≥18 years) with germline VHL alterations, ≥1 measurable nonmetastatic RCC tumor, no tumor of > 3 cm that necessitated immediate surgery, no prior anticancer systemic treatment, and an ECOG PS score of 0 or 1 received oral belzutifan 120 mg once daily until disease progression, unacceptable toxicity, or pt withdrawal. The primary end point was objective response rate (ORR) in VHL disease–associated RCC per RECIST v1.1 by independent central review (ICR). Secondary end points were safety, ORR in non-RCC neoplasms, and duration of response (DOR) in renal and nonrenal neoplasms, per RECIST v1.1 by ICR. Results: Of 61 pts, 50 were on treatment as of July 15, 2021; the primary reasons for discontinuation were disease progression in RCC neoplasms (n = 4) and pt decision to withdraw (n = 4). Twenty pts (33%) had ≥1 pNET and 50 (82%) had ≥1 CNS hemangioblastoma evaluable by ICR at baseline. At baseline, 97% of pts (n = 59) had prior VHL-related surgery; 38 pts had ≥1 VHL-related surgery within 3 years before starting belzutifan. Median time from first dose to database cutoff date was 29.3 mo (range, 27.6-37.5). ORR in RCC was 59% (n = 36), with 2 CRs (3%) and 34 PRs (56%). Median DOR was not reached (range, 8.3+ to 27.6+ mo). ORR in CNS hemangioblastomas was 38% (n = 19; 3 CRs; 16 PRs); median DOR was not reached (range, 3.7+ to 28.0+ mo). ORR in pNETS was 90% (n = 18; 3 CRs; 15 PRs); median DOR was not reached (range, 11.0+ to 31.0+ mo). Three pts (5%) underwent VHL-related surgeries after starting belzutifan. Grade 3 treatment-related adverse events (TRAEs) were reported in 10 pts (16%); the most common was anemia (n = 6 [10%]). No pt had a grade 4 or 5 TRAE. Two pts (3%) stopped treatment because of TRAEs (grade 1 dizziness and grade 2 intracranial hemorrhage). Conclusions: After a median follow-up of 29.3 mo, belzutifan continued to show antitumor activity in VHL disease–related neoplasms, including RCC, pNETs, and CNS hemangioblastomas, whereas the safety profile remained consistent with that of previous reports. These results support the use of belzutifan as a systemic treatment for VHL disease. Clinical trial information: NCT03401788.