ASCO 2022: LITESPARK-004 (MK-6482-004) Phase 2 Study of Belzutifan, an Oral HIF-2α Inhibitor, for Von Hippel-Lindau Disease: Update With More Than Two Years of Follow-Up Data

( The 2022 ASCO annual meeting featured a session on kidney and bladder cancer, including a presentation by Dr. Eric Jonasch discussing updated results of the LITESPARK-004 phase 2 study of belzutifan, an oral hypoxia-inducible factor 2α inhibitor (HIF-2α), for von Hippel-Lindau (VHL) disease. 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 the 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 with VHL disease who require therapy for associated RCC, CNS hemangioblastomas, or pNETs not requiring immediate surgery.1 At ASCO 2022, Dr. Jonasch presented updated results of this trial after > 2 years of follow-up.

 Patients (≥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 performance status score of 0 or 1 received oral belzutifan 120 mg once daily until disease progression, unacceptable toxicity, or patient withdrawal. The primary endpoint was objective response rate (ORR) in VHL disease–associated RCC per RECIST v1.1 by independent central review. Secondary endpoints were safety, ORR in non-RCC neoplasms, and duration of response (DOR) in renal and nonrenal neoplasms, per RECIST v1.1 by independent central review.

 Among 61 patients enrolled in this trial, 50 were on treatment as of July 15, 2021, with the primary reasons for discontinuation being disease progression in RCC neoplasms (n = 4) and patient decision to withdraw (n = 4). Twenty patients (33%) had ≥1 pNET and 50 (82%) had ≥1 CNS hemangioblastoma evaluable by independent central review at baseline. At baseline, 97% of patients (n = 59) had prior VHL-related surgery, and 38 patients had ≥1 VHL-related surgery within 3 years before starting belzutifan. The median time from the first dose to the database cutoff date was 29.3 months (range, 27.6-37.5). The ORR among RCC neoplasms was 59% (n = 36), with 2 complete responses (3%) and 34 partial responses (56%). The best percentage change from baseline in target lesion size is as follows:


ASCO 22_Jonasch_0 


Median DOR was not reached (range, 8.3+ to 27.6+ months) among RCC neoplasms:


ASCO 22_Jonasch_1 


The ORR in CNS hemangioblastomas was 38% (n = 19; 3 complete responses; 16 partial responses) and median DOR was not reached (range, 3.7+ to 28.0+ months). The ORR in pNETS was 90% (n = 18; 3 complete responses; 15 partial responses) and median DOR was not reached (range, 11.0+ to 31.0+ months). Three patients (5%) underwent VHL-related surgeries after starting belzutifan. Grade 3 treatment-related adverse events were reported in 10 patients (16%), and the most common was anemia (n = 6 [10%]). No patient had a grade 4 or 5 treatment-related adverse event. Two patients (3%) stopped treatment because of treatment-related adverse events (grade 1 dizziness and grade 2 intracranial hemorrhage).


Dr. Jonasch concluded his presentation by discussing updated results of the LITESPARK-004 phase 2 study of belzutifan for VHL disease with the following take-home messages:

  • After a median follow-up of 29.3 months, belzutifan continued to show antitumor activity in VHL disease–related neoplasms, including RCC, pNETs, and CNS hemangioblastomas
  • As of the data cutoff date, 3 patients had undergone VHL-related surgery since starting belzutifan
  • No new safety signals emerged with additional follow-up
  • These results support the use of belzutifan as a systemic treatment for VHL disease

Presented by: Eric Jonasch, MD, The University of Texas MD Anderson Cancer Center, Houston, TX

Co-Authors: Othon Iliopoulos, Wendy Kimryn Rathmell, Vivek Narayan, Benjamin L. Maughan, Stephane Oudard, Tobias Else, Jodi K. Maranchie, Sarah Joanne Welsh, Ane Bundsbæk Bøndergaard Iversen, Ananya Roy, Yanfang Liu, Rodolfo F. Perini, W. Marston Linehan, Ramaprasad Srinivasan

Affiliations: Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, Vanderbilt University Medical Center, Nashville, TN, University of Pennsylvania, Philadelphia, PA, University of Utah, Salt Lake City, UT, Georges Pompidou Hospital, University of Paris, Paris, France, University of Michigan, Ann Arbor, MI, University of Pittsburgh, Pittsburgh, PA, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom, Aarhus University Hospital, Aarhus, Denmark, Merck & Co., Inc., Kenilworth, NJ, Center for Cancer Research, National Cancer Institute, Bethesda, MD


Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, Fri, June 3 – Mon, June 7, 2022.


  1. Jonasch E, Donskov F, Iliopoulos O, et al. Belzutifan for Renal Cell Carcinoma in von Hippel-Lindau Disease. N Engl J Med. 2021;385:2036-2046.