Casdatifan

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.

Merck is seeking approval for two new combination regimens using its drug Welireg to treat kidney cancer, even though it doesn’t yet have data confirming it extends patients’ lives. On Saturday, it shared results from the studies at the ASCO Genitourinary Cancers Symposium. One tested Welireg in combination with Eisai’s Lenvima to treat certain advanced renal cell carcinoma patients, and another used it in combination with Merck’s Keytruda as an adjuvant therapy in earlier-stage patients. In the first, called LITESPARK-011, Welireg and Lenvima reduced patients’ risk of disease progression or death by 30% compared with Exelixis’ Cabometyx, a standard of care in advanced kidney cancer. However, the combination didn’t hit the co-primary endpoint of overall survival. Merck said there was a “trend toward improvement” at a median follow-up of 29 months, but the data weren’t statistically significant. Catherine Pietanza, Merck Research Laboratories’ vice president of global clinical development, told Endpoints News that the data weren’t yet mature at that interim analysis, and there will be a follow-up survival analysis. “Hopefully once we get to the final analysis, we’ll see more encouraging data for overall survival,” she said in an interview. Merck said that it has submitted the data to the FDA and expects a decision by Oct. 4. The trial enrolled patients with advanced renal cell carcinoma who had previously been treated with a first- or second-line PD-1 or PD-L1 therapy. The data could make Welireg available to a broader group of patients, since Welireg is currently approved for patients who’ve already received a PD-1/PD-L1 therapy and a VEGF-TKI. Side effects led to treatment discontinuations at similar rates in both the Welireg and Cabometyx arms, according to Merck. There were two treatment-related deaths in the Welireg arm (from thrombotic microangiopathy and pneumonitis) and one in the Cabometyx arm (from hemoptysis). In a separate Phase 3 study, LITESPARK-022, Merck said Welireg and Keytruda reduced patients’ risk of disease recurrence or death by 28% compared with Keytruda alone, when given as an adjuvant therapy after surgery to remove all or part of the kidney. Data for overall survival, the trial’s secondary endpoint, again weren’t mature. The drug “is proving to be a very powerful agent in the armamentarium for” renal cell carcinoma, Pietanza said. The company said the safety data were “consistent with that observed in previously reported studies for both agents.” Grade 3 or higher treatment-emergent adverse events occurred in 52.1% of patients in the Keytruda plus Welireg arm, compared with 30.2% of patients who only received Keytruda, the most common of which were anemia (12.1% versus 0.5%), increased alanine aminotransferase (a sign of liver irritation or damage) and hypoxia. The FDA has also accepted applications for Welireg plus intravenous or subcutaneous Keytruda in the adjuvant setting, and set a goal date of June 19 for a decision. Welireg was the focus of Merck’s $2.2 billion Peloton Therapeutics buyout in 2019, and is the first drug in its class for advanced renal cell carcinoma patients. It works by inhibiting HIF-2α, a protein that can accumulate and lead to tumor growth. Another company shared HIF-2α data at ASCO GU this week. Arcus Biosciences shared a new analysis from a Phase 1/1b study of its candidate casdatifan, showing that at a median follow-up of 17.9 months, median progression-free survival was 15.1 months among a cohort of patients who received a 100 mg tablet dose. That same dose and formulation are being used in an ongoing Phase 3 study. Editor’s note: This article was updated to correct Pietanza’s job title.