Merck & Co.’s first-in-class HIF-2 alpha inhibitor Welireg is touching down in the clear cell renal cell carcinoma (ccRCC) treatment space, notching a Keytruda combination nod that stands to pad the landing for the company’s post-Keytruda outlook.
The June 12 FDA approval is the first for a PD-1 and HIF-2a inhibitor combo, stipulating the regimen’s use as an adjuvant treatment for adults with ccRCC who are at intermediate-high or high risk of recurrence following kidney removal surgery. Welireg can be used in the disease setting with standard Keytruda or subcutaneous Keytruda Qlex.
With that, Welireg can reach earlier-stage ccRCC for the first time following its 2023 clearance in advanced RCC, marking an “important step in addressing the needs of patients with earlier-stage renal cell carcinoma,” kidney cancer advocacy group KidneyCan’s CEO and co-founder Bryan Lewis noted in a Merck press release.
Welireg flexed its muscles in the ccRCC treatment space with its pivotal Litespark-022 study, the first adjuvant trial in kidney cancer that showed a benefit for a combo over a PD-1 agent alone. In the 1,841-patient trial, Welireg and Keytruda significantly reduced the risk of disease recurrence, metastasis or death by 28% compared to a Keytruda and placebo regimen. The estimated disease-free survival rate came out to 81% for the treatment over 74% in the Keytruda-placebo arm.
At the time, Merck Research Laboratories’ VP of global clinical development Cathy Pietanza, M.D., called the data “very compelling” in a February interview around the 2026 American Society for Clinical Oncology (ASCO) Genitourinary Cancers Symposium. Lead study author Toni Choueiri, M.D., from the Dana-Farber Cancer Institute further commented in a press call that the trial could support the combo as a new standard of care in patients at increased risk of recurrence.
However, overall survival results are not yet mature for Litespark-022. Still, Pietanza pointed out that preventing recurrence in the adjuvant setting is meaningful for patients because it keeps them from having to worry about the next line of treatment.
“Reflecting on my own experience as a clinical oncologist, I know the significant impact that improved disease-free survival can have on the lives of patients,” Pietanza explained in Merck’s release. “These approvals demonstrate Merck’s commitment to pursuing innovative treatment options that may help these patients experience longer periods without disease.”
The initial Litespark-022 readout, together with a separate phase 3 win for Welireg and Eisai-partnered Lenvima in second-line kidney cancer, drew predictions that Welireg could become a “substantial revenue contributor” for Merck, Leerink Partners analysts wrote in a note to clients in October, adding that the positive results should “inspire investor confidence” in “post-Keytruda” Merck.
After seeing detailed trial results, the Leerink analysts said in a March note that they expect the Welireg regimen's adjuvant use “will build more slowly given immature OS outcomes and ongoing debate about over-treatment in the setting.” In the second-line setting, the team projected rapid uptake “based on compelling survival and durability outcomes that showed little detriment in toxicity and quality of life” compared with Exelixis' Cabometyx.
The Leerink team therefore raised its Welireg sales estimates by 36% to $3.4 billion in 2028.
Welireg is one of a handful of growth drivers Merck is banking on for its post-Keytruda future. The drug came to Merck from its 2019 Peloton acquisition and earned its initial FDA approval in 2021 to treat certain tumors in patients with von Hippel-Lindau disease. Later on, the therapy nabbed its first kidney cancer indication in 2023 and added on an expansion in 2025 to treat rare pheochromocytoma and paraganglioma tumors.
Welireg saw 41% sales growth in 2025, garnering revenues of $716 million that year. Keytruda, meanwhile, made up nearly half of Merck’s total sales last year with a $31.7 billion haul across Keytruda and Keytruda Qlex.
Earlier this year, a piece of Welireg’s emerging kidney cancer leadership was thrown into question when it failed to move the needle in progression-free survival or overall survival when combined with Keytruda and Merck’s Eisai-partnered Lenvima as a first-line treatment for ccRCC. The prespecified interim analysis from the phase 3 Litespark-012 trial came as a surprise on the tail of those two positive phase 3 readouts in the disease.
Nonetheless, the company emphasized that the flop wouldn’t affect other ongoing trials in the Litespark program. The Welireg-Lenvima combo is still up for an Oct. 4, FDA decision in second-line kidney cancer.