Per Endpoints, Merck's Welireg-Lenvima wins FDA approval in advanced ccRCC

Endpoints News reported on 25 September 2026 that the FDA approved Merck's Welireg (belzutifan) in combination with Eisai's Lenvima (lenvatinib) for certain patients with advanced renal cell carcinoma carrying a clear-cell component ^[1]. Belzutifan is a HIF-2α inhibitor ^[5]. This is the second Welireg indication Merck has landed in kidney cancer inside four months: the FDA approved Welireg plus Keytruda as adjuvant treatment after surgery to remove all or part of the kidney around 12 June 2026 ^[2], on a priority review built on pivotal disease-free survival data ^[6], after belzutifan combinations met disease-free and progression-free survival endpoints in RCC ^[7].

The read for a competitor is that Merck is converting belzutifan from a niche agent into a kidney-cancer franchise across settings. The drug was first approved for von Hippel-Lindau disease-associated tumors and later for advanced clear-cell RCC after prior IO/TKI therapy ^[13]; the EU cleared it for VHL-associated tumors and advanced ccRCC around December 2024 to February 2025 ^[8][9]. With an adjuvant Keytruda combination ^[2] and now an advanced-setting Lenvima combination ^[1], Merck is stacking belzutifan on top of its own PD-1 backbone and Eisai's TKI rather than defending a single line.

Why it matters

Advanced clear-cell RCC is fought with IO/TKI doublets, and Exelixis' cabozantinib is described in Exelixis' own filings as the market-leading TKI monotherapy and most-prescribed TKI in combination with immunotherapy in RCC as of Q3 2025 ^[10]. A belzutifan-plus-lenvatinib option adds a mechanistically distinct HIF-2α layer to that mix. For a development or BD team, the question shifts from whether HIF-2α inhibition works in kidney cancer to where in the treatment sequence it now sits relative to established doublets.

The most exposed challenger is Arcus Biosciences. In an 5 August 2026 filing, Arcus positions its own HIF-2α inhibitor casdatifan as a backbone therapy across every line of ccRCC, explicitly against the HIF-2 class that includes belzutifan ^[11]. Arcus reports $775M cash and runway to at least the second half of 2028, with multiple ARC-20 casdatifan readouts expected in the second half of 2026, including progression-free survival data for casdatifan plus cabozantinib in second line; separately, a new ARC-20 cohort will test casdatifan with tivozanib in patients previously treated with belzutifan ^[11]. Merck's second kidney-cancer approval raises the incumbent bar those readouts must clear.

What belzutifan has shown, and what remains unconfirmed

Merck's own dose-comparison study in advanced RCC (MK-6482-013), which tested belzutifan monotherapy rather than the approved Lenvima combination, reported objective response rates of 23.1% and 23.7%, progression-free survival of 9.1 and 7.3 months, and clinical benefit rates of 41.0% and 47.4% across its two dose arms ^[3]. That frames single-agent activity; it is not the efficacy dataset behind the combination approval. That dataset is LITESPARK-011 (NCT04586231), named in the FDA's approval notice: 747 patients whose disease had progressed on a PD-1 or PD-L1 inhibitor were randomized to belzutifan plus lenvatinib or cabozantinib; median progression-free survival was 14.6 versus 10.6 months (hazard ratio 0.74), and overall survival was not statistically significant (hazard ratio 0.85) ^[14]. The FDA's approval notice, dated 24 September 2026, confirms the approval for adults whose disease progressed after a PD-1 or PD-L1 inhibitor ^[14].

What to watch next

Merck is not standing still on belzutifan combinations. LITESPARK-034, a Phase 3 trial of belzutifan plus Exelixis-partnered zanzalintinib in advanced RCC, is recruiting toward a planned 758 patients ^[4], and Exelixis confirms Merck initiated it as the second pivotal trial under their collaboration ^[12]. Arcus' ARC-20 casdatifan readouts in the second half of 2026 (first line with zimberelimab, second line with cabozantinib, late-line monotherapy) are the near-term catalyst that will test whether a second HIF-2α inhibitor can carve room against an entrenched Welireg ^[11].

The now-what

Three moves are on the table for a competing RCC program. First, re-baseline any HIF-2α or IO/TKI positioning against a belzutifan that now spans adjuvant and advanced settings, not just VHL disease. Second, pressure-test differentiation on sequencing and belzutifan-experienced patients, the population Arcus has only now opened a new cohort to study. Third, watch the LITESPARK-034 zanzalintinib combination as the signal for where Merck takes belzutifan next.

Threat level: elevated for HIF-2α challengers and IO/TKI doublet holders in advanced ccRCC. Window to act: the second half of 2026, when Arcus' casdatifan readouts arrive.