Development

Merck and Eisai's triplet and MK-1308A regimens fall short against Keytruda combo in RCC Phase III

Edited by Robert McTiernan··4 min read

Merck (NYSE: MRK) and Eisai reported that neither experimental combination regimen tested in the Phase III LITESPARK-012 trial met the dual primary endpoints of progression-free survival and overall survival in first-line advanced clear cell renal cell carcinoma. That left pembrolizumab plus lenvatinib intact as the standard against which further escalation strategies will need to be measured.

Trial specifics

The randomized, open-label study enrolled 1,688 patients and evaluated two escalation strategies: a triplet of pembrolizumab (Keytruda, Merck) plus lenvatinib (Lenvima, Eisai) and belzutifan (Welireg, Merck), and a doublet of MK-1308A — a coformulation of pembrolizumab and the investigational anti-CTLA-4 antibody quavonlimab (both Merck) — plus lenvatinib (Eisai). Both regimens were compared against the approved pembrolizumab-lenvatinib combination.

At a pre-specified interim analysis, neither the triplet pembrolizumab-lenvatinib-belzutifan arm nor the MK-1308A-lenvatinib arm demonstrated improvement over the pembrolizumab-lenvatinib control on PFS or OS. The companies did not disclose specific numerical data at this stage, stating that a full evaluation is ongoing and that results will be shared with the scientific community. Safety profiles for both combination regimens were described as consistent with those previously observed for the individual agents and the pembrolizumab-lenvatinib doublet.

Development rationale and implications

The outcome carries weight beyond a single trial. The pembrolizumab-lenvatinib combination, approved in the US, EU, and Japan for first-line advanced RCC, has become one of the most widely used regimens in this setting following its approval on the basis of the KEYNOTE-581/CLEAR trial. The LITESPARK-012 results suggest that layering additional agents — whether a HIF-2α inhibitor or a dual checkpoint blockade strategy — onto that backbone does not translate into measurable survival benefit at interim, at least in an unselected clear cell RCC population.

The triplet arm was grounded in a biologically coherent rationale. Belzutifan (Welireg) inhibits hypoxia-inducible factor-2 alpha, a transcription factor that drives angiogenesis and tumor proliferation in clear cell RCC, where VHL loss-of-function mutations are nearly universal. Adding HIF-2α blockade to VEGF-TKI and PD-1 inhibition was intended to suppress a complementary oncogenic pathway. The LITESPARK-005 trial previously demonstrated that belzutifan outperformed everolimus in previously treated clear cell RCC, supporting its activity as a single agent in this histology. Whether the failure in LITESPARK-012 reflects a ceiling effect of the pembrolizumab-lenvatinib doublet, schedule or dose interactions among three agents, or patient selection factors will require analysis of the full dataset.

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The MK-1308A arm pursued a different logic: adding CTLA-4 blockade to PD-1 inhibition and VEGF-TKI therapy, a strategy that has shown benefit in other tumor types. Ipilimumab plus nivolumab is approved in first-line RCC based on CheckMate 214 data, and the combination of PD-1 and CTLA-4 blockade with a TKI has been explored in other settings. In RCC specifically, the COSMIC-313 trial previously showed that adding cabozantinib to nivolumab-ipilimumab improved PFS over nivolumab-ipilimumab alone in intermediate- and poor-risk patients, though OS data were immature and toxicity was substantial. The failure of MK-1308A plus lenvatinib to improve on pembrolizumab plus lenvatinib adds to a growing body of evidence that triplet intensification in first-line RCC does not reliably convert mechanistic rationale into clinical benefit. Cross-trial comparisons are limited by differences in patient populations, risk stratification, and trial design.

For Merck, the LITESPARK-012 results do not alter the regulatory trajectory of belzutifan in RCC more broadly. The FDA has accepted two supplemental new drug applications for belzutifan in combination with lenvatinib for previously treated advanced RCC, based on data from the LITESPARK-011 trial, with a PDUFA target action date of October 4, 2026. That program addresses a distinct, later-line population and remains on track. The companies stated that LITESPARK-012 results do not affect other ongoing LITESPARK program trials.

For the first-line advanced clear cell RCC treatment landscape, the practical implications are limited in the near term. Pembrolizumab plus lenvatinib, pembrolizumab plus axitinib, and nivolumab plus ipilimumab remain the dominant regimens, with cabozantinib-based combinations also in use. No approved first-line option has demonstrated a clear OS advantage over the field in a head-to-head comparison, and the field has been searching for strategies that can improve on current benchmarks. LITESPARK-012 narrows the list of combinations that appeared plausible for doing so.

The quavonlimab program also faces a setback. MK-1308A had been under investigation across multiple tumor types as Merck sought to develop a next-generation CTLA-4 antibody with a differentiated profile. The failure to improve on pembrolizumab-lenvatinib in first-line RCC will inform how that asset is prioritized going forward, though data from other indications remain pending.

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