As reported on FiercePharma, Merck & Co.’s Welireg has secured an expanded FDA approval that moves the drug earlier in the treatment of advanced kidney cancer, adding a new option for patients whose disease has progressed following immunotherapy.
The agency cleared Welireg (belzutifan) in combination with Lenvima (lenvatinib), which Merck develops with Eisai, for second-line treatment of renal cell carcinoma with a clear cell component following prior PD-1 or PD-L1 therapy. Welireg had previously been available in a later-line setting.
The decision was supported by results from the phase 3 Litespark-011 trial, which compared Welireg plus Lenvima with Exelixis’ Cabometyx (cabozantinib).
In the study, the Welireg-Lenvima regimen lowered the risk of disease progression or death by 26% relative to Cabometyx. Median progression-free survival reached 14.6 months with the combination, representing an improvement of approximately four months over the comparator.
The overall survival analysis did not meet the threshold for statistical significance, although the numerical results favored Welireg plus Lenvima. Median overall survival was 33.7 months with the combination compared with 28.6 months among patients receiving Cabometyx.
Tumor responses also favored the Merck-Eisai regimen. The objective response rate was 53% with Welireg and Lenvima versus 40% with Cabometyx. Additionally, responses proved substantially more durable, lasting a median of 23 months with the combination compared with 12 months in the control arm.
The findings have generated enthusiasm among kidney cancer specialists and analysts. Katy Beckermann, M.D., Ph.D., director of genitourinary cancer research at Tennessee Oncology, previously characterized the Litespark-011 findings as potentially practice-changing in comments reported by William Blair analysts.
Leerink Partners analysts have likewise forecast strong adoption in the second-line setting, pointing to the regimen’s efficacy and durability as well as its toxicity and quality-of-life profile relative to Cabometyx.
Welireg could also change the competitive landscape of kidney cancer treatment because it uses a different mechanism from established tyrosine kinase inhibitors. Belzutifan is a first-in-class inhibitor of hypoxia-inducible factor 2 alpha, or HIF-2α, while Lenvima and Cabometyx are multitargeted TKIs.
Welireg initially entered the renal cell carcinoma market as an option for patients previously treated with both a PD-1/PD-L1 inhibitor and a VEGF-targeted TKI. The latest approval therefore provides Merck with an opportunity to introduce the drug at an earlier stage of treatment.
Prospects in other kidney cancer settings have been less straightforward. Welireg’s attempt to advance into first-line treatment suffered a setback after the phase 3 Litespark-012 trial failed earlier this year. Analysts have also anticipated more gradual adoption in the adjuvant setting, where questions remain about the balance between additional toxicity and clinical benefit despite positive disease-free survival findings from Litespark-022, which evaluated Welireg with Keytruda.
Merck is continuing to study additional Welireg-based combinations. Through a collaboration established with Exelixis in 2024, the company is evaluating Welireg alongside the next-generation TKI zanzalintinib. The phase 3 Litespark-033 study is investigating that combination in recurrent clear cell renal cell carcinoma occurring during or after adjuvant PD-1/PD-L1 therapy.
For Merck, the second-line approval represents an important expansion of Welireg’s role in kidney cancer. With Litespark-011 demonstrating improvements in disease control, response rates and response durability over Cabometyx, the Welireg-Lenvima combination now has an opportunity to reshape treatment decisions following frontline immunotherapy.
