Effect of erythropoietin-stimulating agent use on belzutifan antitumor activity in patients with VHL disease–associated renal cell carcinoma: Post hoc analysis of the LITESPARK-004 study.
Authors: Maughan Benjamin L. , Srinivasan Ramaprasad , Iliopoulos Othon , Bundsbæk Bøndergaard Iversen Ane , Narayan Vivek , Oudard Stephane , Else Tobias , Maranchie Jodi K. , Beckermann Katy , Fu Wei , Perini Rodolfo F. , Liu Yanfang , Linehan W. Marston , Jonasch Eric 
Published: January 2024

3 Background: The ongoing, open-label, phase 2 LITESPARK-004 study (NCT03401788) showed that belzutifan, a HIF-2α inhibitor, exhibited antitumor activity in patients (pts) with VHL disease associated renal cell carcinoma (RCC), pancreatic neuroendocrine tumors (pNETs), and CNS hemangioblastomas. The most common adverse event (AE) of any grade was anemia and pts could have received erythropoietin-stimulating agents (ESA) and/or blood transfusions for management. This exploratory post-hoc analysis described pattern of ESA use and whether use of ESA impacted antitumor activity to belzutifan in pts with VHL disease. Methods: Pts (≥18 years) with germline VHL alterations, ≥1 measurable nonmetastatic RCC tumor, no tumor of >3 cm requiring immediate surgery, and no prior anticancer systemic treatment received oral belzutifan 120 mg once daily until disease progression, unacceptable toxicity, or pt withdrawal. End points included objective response rate (ORR) and duration of response (DOR) in VHL disease–associated RCC and non-RCC neoplasms per RECIST v1.1 by independent central review, and safety. Efficacy and safety outcomes among pts who received and did not receive ESA were evaluated. Data cutoff was April 1, 2022. Results: Of 61 treated pts, 14 (23%) received ESA and 47 (77%) did not. Median (range) time to onset of ESA use was 151 days (59-886) and median dose per pt was 5 injections (range 1-35). Duration of belzutifan exposure for ≥12 months was achieved in 100% of pts who received ESA vs 92% in pts who did not receive ESA. Median (range) relative dose intensity was 97.4 (51.4-100) and 98.8 (26.4-100) for pts who received and did not receive ESA, respectively. ORR for VHL-associated RCC was 71% (10/14, 95% CI, 42-92) for pts who received ESA and 62% (29/47, 46-76) for those who did not. Median DOR was not reached (NR) for pts who received and who did not receive ESA (NR, range 5.5+ to 33.5+ months and NR, range 5.4+ to 35.8+ months). All pts in both groups had a response for ≥12 months. In pts with CNS hemangioblastomas, ORR was 46% (5/11, 17-77) for pts who received ESA and 44% (17/39, 28-60) for those who did not. In pts with pNETs, ORR was 100% (4/4, 40-100) for pts who received ESA and 89% (16/18, 65-99) for those who did not. Median DOR was not reached for both groups in pts with CNS hemangioblastomas and pNETs. Among pts who received and did not receive ESA, 5 (36%) and 6 (13%) pts had at least 1 dose reduction, respectively. All pts reported at least 1 AE but a larger percentage of pts who received ESA had AEs of grade 3 or higher than those who did not receive ESA (57% and 40%). Conclusions: In this exploratory, post-hoc analysis of LITESPARK-004, data suggests that administration of ESA did not adversely impact overall drug exposure or efficacy of belzutifan in pts with VHL disease associated RCC, CNS hemangioblastomas, and pNETs. Clinical trial information: NCT03401788 .