The treatment landscape for clear cell renal cell carcinoma (ccRCC) could be due for a shake-up following dual breakthroughs from Merck’s Litespark clinical trial program for Welireg. Data being presented at the 2026 American Society for Clinical Oncology (ASCO) Genitourinary Cancers Symposium suggest that adding Welireg to other existing drugs significantly improves outcomes for patients at two distinct stages of their cancer journeys.
For advanced ccRCC patients whose cancer has recurred following previous immunotherapy, a combination of Welireg (belzutifan) and Merck’s Eisai-partnered Lenvima (lenvatinib) significantly reduced patients’ risk of disease progression or death by 30% compared with Exelixis’ Cabometyx (cabozantinib), according to results from the Litespark-011 trial.
Separately, in patients with resected ccRCC at an increased risk of recurrence following surgery, by adding Welireg to Merck’s standard Keytruda, investigators achieved a 28% reduction in the risk of the patients’ cancer returning, according to data from the Litespark-022 study.
CcRCC is the most common form of kidney cancer, accounting for about 4 in 5 cases.
Data from both trials are “very compelling,” showing statistically significant and clinically meaningful improvements on their primary endpoints, Cathy Pietanza, M.D., vice president of global clinical development at Merck Research Laboratories, said in an interview with Fierce Pharma.
The Welireg-Lenvima regimen “could represent a potential new treatment option for patients with RCC that have progressed on” an immune checkpoint inhibitor, as Litespark-011 is the first phase 3 trial in a post-immunotherapy setting in kidney cancer to improve outcomes versus a contemporary anti-VEGFR tyrosine kinase inhibitor, lead study author Robert Motzer, M.D., from the Memorial Sloan Kettering Cancer Center, said during a press call.
For its part, Litespark-022 is the first adjuvant trial in kidney cancer to show a benefit for a combo versus a PD-1 agent alone, supporting it as a new standard of care in patients at increased risk of recurrence, lead study author Toni Choueiri, M.D., from the Dana-Farber Cancer Institute said during the press call. Benefits were shared across prespecified subgroups, including in PD-L1-high and -low patients, according to Choueiri.
However, one critical uncertainty remains that could hinder these Welireg regimens from shifting from potential treatment options to the universal standard of care in their respective settings—neither has mature gold-standard overall survival (OS) data to back their case.
For now, without a definitive OS showing, Welireg may be a tougher sell in the second-line metastatic setting than in the adjuvant setting. As early-stage patients may be exposed to many additional therapies down the line, the OS effect of their earlier treatment is naturally more difficult to tease out.
In the second-line metastatic setting, OS, a dual primary endpoint of Litespark-011, did not reach statistical significance at the time of the second interim analysis. Data so far favor the Welireg regimen with a preliminary 15% reduction in the risk of death, as the combo started to show signs of a survival advantage beginning at around 15 months. The trial is continuing toward its final analysis, Motzer said.
In an ASCO perspective, Sumanta Kumar Pal, M.D., of City of Hope characterized the Welireg-Lenvima combo as a potential new option for advanced ccRCC, though he noted a “trade-off” in certain side effects compared with traditional monotherapy.
Notably, the rates of anemia, proteinuria, vomiting, hypoxia and cardiac dysfunction were higher for the combo, whereas such adverse events as diarrhea, a skin condition called hand-foot syndrome, stomatitis and elevated liver enzymes were more common in the Cabometyx arm.
Still, the overall adverse event rates were similar between the two arms, and patient-reported quality-of-life outcomes so far didn’t show a decline for the combo, Motzer pointed out. Grade 3 or above treatment-emergent adverse events (TEAEs) occurred in 84% of patients with the Welireg combo and 83% with Cabometyx.
As for the adjuvant setting, early OS data also favored Welireg-Keytruda with a 22% death risk reduction, but this did not cross statistical significance. In the large Litespark-022 trial of more than 1,800 patients, only 87 patients—4.1% in the experimental arm and 5.3% in control—have passed away. The final OS analysis will occur after about 300 deaths.
The disease-free survival data for the new adjuvant regimen are “encouraging,” Brian Rini, M.D., from Vanderbilt University Medical Center, said in an ASCO-facilitated statement. But “the combination treatment was associated with increased toxicity, and we are still awaiting long-term data to determine if this regimen translates into a definitive overall survival benefit,” he added.
Grade 3 or higher TEAEs occurred in 52% of patients who got the Welireg combo, versus 30% who got Keytruda alone. Choueiri noted that on the more clinically relevant metric—treatment-related discontinuations—the rate was 10% for the combo versus 7% for the comparator.
Citing her experience as a practicing oncologist before coming to Merck, Pietanza argued that delaying progression in the metastatic setting and preventing recurrence in the adjuvant setting are meaningful for patients because it keeps them from having to worry about the next line of treatment. And for doctors, a positive OS trend is also reassuring to suggest there’s at least no detriment to patient survival, she said.
Still, the current Litespark data are enough to get Merck inside the FDA’s door. The agency has accepted the company’s filings for both Welireg regimens, and additional submissions to other global regulatory agencies are underway, Pietanza said.
Welireg is the first medicine to target a protein called hypoxia inducible factor-2 alpha (HIF-2 alpha). It could help Merck cope with the upcoming Keytruda loss of exclusivity, even though it’s not the biggest project in Merck’s oncology pipeline.