Merck's Welireg Fails in First-Line Kidney Cancer Trial

Merck & Co.'s investigational drug Welireg, a first-in-class HIF-2 alpha inhibitor, has failed to demonstrate significant benefits as a first-line treatment for advanced clear cell renal cell carcinoma (ccRCC) in the Phase 3 Litespark-012 trial. The trial assessed the combination of Welireg with Merck’s PD-1 inhibitor Keytruda and Eisai’s tyrosine kinase inhibitor Lenvima. The interim analysis revealed that the triplet therapy did not improve either progression-free survival (PFS) or overall survival (OS) compared to the Keytruda and Lenvima combination alone.

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Welireg was previously approved by the FDA in 2021 for von Hippel-Lindau disease and became a treatment option for kidney cancer by the end of 2023. Prior to the Litespark-012 trial, Welireg had shown promise in two earlier Phase 3 trials, Litespark-011 and Litespark-022, leading to high expectations for its performance in the first-line setting. Analysts had predicted a positive outcome based on these earlier successes, with consensus peak sales estimates reaching approximately $2.6 billion.

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Despite the disappointing results, experts have expressed that the data from the Litespark-012 trial will contribute to a deeper understanding of advanced renal cell carcinoma. Catherine Pietanza, M.D., VP of global clinical development at Merck Research Laboratories, stated, “While these regimens did not demonstrate the results we hoped, the data deepen our understanding of advanced renal cell carcinoma and will help shape the next generation of treatment approaches.” However, concerns remain regarding the use of Lenvima in combination therapies, with some experts preferring to reserve it for salvage options in later treatment lines.

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The failure of the Litespark-012 trial could potentially open avenues for competitors, particularly Exelixis, which is developing zanzalintinib, another oral kinase blocker for RCC. Merck and Eisai's collaboration, which dates back to 2015, has had both successes and setbacks, including the previous FDA approval of the Keytruda-Lenvima combination for advanced RCC in 2021. The companies have indicated that the results from Litespark-012 will not impact other ongoing trials within the Litespark program.

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While the Litespark-012 trial results were disappointing, the broader implications for Merck's ongoing research and development efforts remain unclear. The FDA is currently reviewing Merck’s application based on the Litespark-011 trial, with a target action date set for October 4, 2026. Additionally, the maturity of the data from the Litespark-022 trial has been questioned, as experts caution against over-treatment in settings where surgical outcomes are typically favorable.

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• “While these regimens did not demonstrate the results we hoped, the data deepen our understanding of advanced renal cell carcinoma and will help shape the next generation of treatment approaches,” — Catherine Pietanza, M.D., VP of Global Clinical Development, Merck Research Laboratories.

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• “could theoretically open a path” — Analysts at William Blair.

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• “Results from the Litespark-012 trial do not affect other ongoing trials from the Litespark program for Welireg, Merck said.” — Merck and Eisai's news release.

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