Merck's Welireg falls short in overall survival despite positive trial

Merck's kidney cancer drug, Welireg, continues to show mixed results from its phase 3 trial, LITESPARK-005. While it has demonstrated significant benefits in progression-free survival (PFS), it falls short on overall survival (OS) improvement when compared to Novartis' chemotherapy drug, Afinitor. The dual primary endpoint trial presents a nuanced picture: Welireg has excelled in PFS, yet has not achieved statistically significant gains in OS.

Welireg, also known as belzutifan, outperformed Afinitor in OS at 18 and 24 months but failed to reach statistical significance. The most recent data indicates a slight narrowing of the survival gap. At 18 months, patients on Welireg survived a median of 21 months compared to 17.2 months for those on Afinitor. At the 24-month mark, Welireg's median survival was 21.4 months versus 18.2 months for Afinitor. Merck shared these findings during the European Society of Medical Oncology Congress in Barcelona, noting that the majority of patients in the trial (87.4%) received Welireg as their third or fourth-line treatment following PD-1/L1 inhibitors and a vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TK1).

Despite the lack of statistical significance in OS, Merck underscores that this phase 3 trial is the first to show positive results for this heavily pre-treated patient group based on the PFS endpoint. Measuring OS can be particularly challenging, requiring large patient populations, extended follow-up periods, and substantial costs to demonstrate significant improvements, as highlighted by the National Cancer Institute.

Welireg is a hypoxia-inducible factor-2 alpha (HIF-2a) inhibitor, a novel class of treatment approved in 2021 for von Hippel-Lindau disease, a rare hereditary condition that can lead to tumor growth in various organs, notably the kidneys. In December of the previous year, the FDA approved Welireg for advanced renal cell carcinoma (RCC) in patients who did not respond to PD-1 or PD-L1 inhibitors and had been treated with a VEGF-TK1. This approval expanded Welireg's patient base significantly, reflected in Merck’s financial reports, which showed an increase in sales to $126 million in the second quarter compared to $50 million in the same quarter of the previous year. To reach its projected blockbuster potential, Welireg must secure its place in earlier treatment lines.

The latest 24-month analysis of the 746-patient LITESPARK-005 trial highlighted several positive outcomes for Welireg. The PFS rates for Welireg were 17.5% compared to Afinitor's 4%. At 18 months, these rates were 22% for Welireg and 9% for Afinitor. Merck emphasized the clinical significance of achieving a positive PFS benefit against everolimus, pointing out that this approval marks the first time in nearly a decade that a new treatment in a novel therapeutic class has been approved for these patients, providing a crucial option in later-line settings.

Welireg's overall response rate has remained stable at 23%, compared to 3.5% for Afinitor. The duration of response was 19.3 months for Welireg versus 13.7 months for Afinitor. Treatment discontinuation due to adverse events was reported in 6% of Welireg patients, compared to 15% in the Afinitor group.

The LITESPARK-005 trial is part of Merck’s comprehensive development program for Welireg, which includes four phase 3 trials in RCC. These trials aim to evaluate Welireg in combination with other medicines across various stages and settings of the disease.

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