Belzutifan

A preliminary interim analysis from a late-stage study of Merck & Co.'s Welireg (belzutifan) in earlier-stage clear cell renal cell carcinoma (RCC) showed that the oral HIF-2α inhibitor significantly boosting disease-free survival (DFS) when combined with the PD-1 inhibitor Keytruda (pembrolizumab) as adjuvant therapy following nephrectomy. The latest readout — building on findings highlighted last October — prompted a priority review by the FDA, with a target action date of June 19. The LITESPARK-022 trial randomised 1841 patients to receive either Welireg plus Keytruda for approximately one year, or Keytruda plus placebo, with the primary endpoint being DFS. Results presented Saturday at the American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU) showed that Welireg plus Keytruda lowered the risk of disease recurrence or death by 28% compared with Keytruda plus placebo at a median follow-up of 28.4 months. While the estimated 24-month DFS rate was 80.7% for the combination arm versus 73.7% for the control arm, median DFS was not reached in either group. The trial's key secondary endpoint of overall survival (OS) continues to be evaluated. "These findings represent the first positive Phase III data for Welireg in earlier stages of disease, as well as the first positive Phase III results for a HIF‑2α inhibitor and immunotherapy combination," said M Catherine Pietanza, VP of global clinical development at Merck Research Laboratories. Welireg is approved in multiple regions for advanced RCC following prior PD-(L)1 and VEGF-targeted therapies, whereas Keytruda is authorised across the US, EU, Canada and Japan in the adjuvant RCC setting. Merck's pivotal LITESPARK programme in RCC also includes LITESPARK-011, wherein Welireg plus Eisai's oral tyrosine kinase inhibitor Lenvima (lenvatinib) improved progression-free survival (PFS) versus Exelixis' Cabometyx (cabozantinib) in the post-immunotherapy setting. Having been top-lined as positive last year, data presented at ASCO GU showed that with a median follow-up of 29 months, Welireg in combination with Lenvima reduced the risk of disease progression or death by 30% compared to Cabometyx, with median PFS in the two groups of 14.8 months and 10.7 months, respectively. The trial also demonstrated a trend toward improvement in survival, with median OS of 34.9 months for Welireg plus Lenvima, versus 27.6 months for Cabometyx. Based on the findings, submissions to expand the use of Welireg in combination with Lenvima have been accepted by the FDA, with a target review data of October 4. Meanwhile, the ongoing LITESPARK-012 trial, due to read out later this year, is evaluating the addition of Welireg to Keytruda plus Lenvima in first-line advanced RCC. For more, see – Spotlight On: Evolving treatment trends in RCC and Spotlight On: Rising use of adjuvant Keytruda among major RCC treatment trends. The content above comes from the network. if any infringement, please contact us to modify.

Merck released results from the Phase III LITESPARK-022 trial showing that Keytruda (pembrolizumab) plus Welireg (belzutifan) given as adjuvant therapy reduced the risk of disease recurrence or death by 28% compared to pembrolizumab alone in patients with clear cell renal cell carcinoma (RCC) following nephrectomy. The data, presented at the 2026 ASCO Genitourinary Cancers Symposium, represent the first Phase III readout for a HIF-2α inhibitor and immunotherapy combination in earlier-stage disease and the first trial in any tumor type to demonstrate a disease-free survival benefit over pembrolizumab monotherapy in the adjuvant setting. Trial specifics LITESPARK-022 is a multicenter, randomized, double-blind Phase III trial that enrolled 1,841 adult patients with clear cell RCC at increased risk of recurrence following nephrectomy. Patients were randomized to receive either belzutifan 120 mg orally once daily plus pembrolizumab 400 mg intravenously every six weeks, both for approximately one year, or pembrolizumab plus placebo on the same schedule. At the first pre-specified interim analysis, with a median follow-up of 28.4 months, the combination met the primary endpoint of disease-free survival. The hazard ratio was 0.72 (95% CI, 0.59–0.87; p=0.0003). Median DFS was not reached in either arm. The estimated 24-month DFS rate was 80.7% in the belzutifan-pembrolizumab arm versus 73.7% in the pembrolizumab-placebo arm. Overall survival, a key secondary endpoint, remains immature and the trial will continue follow-up. The safety profile was consistent with known profiles of both agents. Grade 3 or higher treatment-emergent adverse events occurred in 52.1% of patients receiving the combination versus 30.2% in the control arm. Approximately 69.5% of patients in the combination arm and 71.1% in the control arm completed assigned treatment. Based on these data, the US FDA has accepted for priority review supplemental applications for belzutifan in combination with pembrolizumab or Keytruda Qlex (pembrolizumab and berahyaluronidase alfa-pmph) for adjuvant treatment of adult patients with RCC with a clear cell component at increased risk of recurrence following nephrectomy. The PDUFA target action date is June 19, 2026. Filings for global markets are also expected. Keytruda already holds adjuvant RCC approvals in the US, Canada, the EU, and Japan based on the KEYNOTE-564 trial. Welireg was first approved by the US FDA in 2021 for von Hippel-Lindau disease-associated tumors, received a second approval in 2024 for advanced RCC after prior PD-1/PD-L1 and VEGF-TKI therapy based on the LITESPARK-005 trial, and gained a third in January 2025 in combination with pembrolizumab and lenvatinib for first-line advanced RCC based on LITESPARK-012. Research context Belzutifan is an oral small-molecule inhibitor of hypoxia-inducible factor-2 alpha (HIF-2α), a transcription factor that drives expression of genes governing angiogenesis, cellular proliferation, and tumor metabolism. In clear cell RCC, loss of the VHL tumor suppressor gene — present in the majority of cases — leads to constitutive HIF-2α activity, making it a central node in disease biology. By blocking this transcription factor, belzutifan suppresses downstream oncogenic signaling. The rationale for combining HIF-2α inhibition with PD-1 blockade rests on evidence that hypoxia-driven signaling can upregulate PD-L1 and promote immunosuppressive tumor microenvironments; inhibiting HIF-2α may therefore complement checkpoint inhibitor activity. The adjuvant kidney cancer treatment landscape has been shaped by pembrolizumab’s approval based on KEYNOTE-564, which established PD-1 blockade as the standard of care after nephrectomy in high-risk patients. However, recurrence rates remain substantial — approximately 40% of patients experience disease return after initial treatment, as noted by trial investigator Dr. Toni K. Choueiri. Other adjuvant approaches, including combinations of checkpoint inhibitors with VEGF-TKIs, have not demonstrated DFS improvements over pembrolizumab alone, making the LITESPARK-022 result a first in this setting. The competitive landscape for HIF-2α inhibitors in RCC is narrow but evolving. Key competitors include Arcus Biosciences’ casdatifan, a HIF-2α inhibitor that the California-based company has positioned as a potential best-in-class molecule. Arcus has outlined plans for Phase III development in RCC and is also exploring the compound in inflammation-related indications.