One year after reporting a split result on Merck’s Welireg in a key phase 3 trial, the song remains the same for the kidney cancer drug as it continues to show benefits in progression-free survival (PFS) but no significant improvement in overall survival (OS) when compared to Novartis’ chemotherapy Afinitor.

The results from the dual primary endpoint LITESPARK-005 trial have been generally positive, but OS remains a tough nut to crack. While Welireg (belzutifan) has outperformed Afinitor (everolimus) in OS at 12 months and 24 months, the results have not achieved statistical significance. 

The OS gap between Welireg and Afinitor actually narrowed in the most recent readout. At 18 months, patients on Welireg had survived a median of 21 months versus 17.2 months for Afinitor. After a median follow-up of 35.8 months, patients on Welireg had survived a median of 21.4 months versus 18.2 months for Afinitor. 

At 12 months, the OS rate for Welireg was 68% compared to 66% for Afinitor. At 24 months, Welireg came in at 45% against 41% for Afinitor.

Merck broke down the results Friday at the European Society of Medical Oncology Congress in Barcelona.

In an email, the company pointed out that the majority of patients in LITESPARK-005 received Welireg as their third or fourth-line treatment (87.4%) after being treated with PD-1/L1 inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TK1).

"Although the results for the dual primary endpoint of OS did not reach statistical significance, it is still the first positive phase 3 trial in this heavily pre-treated patient population, based on the other dual primary endpoint of PFS," a Merck spokesperson wrote. 

Measuring OS can be challenging, especially if a new treatment only marginally improves survival. Large patient populations, several years of follow-up and higher costs may be required to demonstrate increased OS, according to the National Cancer Institute.

Welireg, which is a first-in-class hypoxia-inducible factor-2 alpha (HIF-2a) inhibitor, was approved in 2021 for a rare hereditary condition, von Hippel-Lindau disease, which can cause tumor growth in various organs, especially the kidney.

In December of last year, based on the results from LITESPARK-005, the FDA signed off on Welireg to treat advanced renal cell carcinoma (RCC) for those who have not responded to PD-1 or PD-L1 inhibitors and who have been treated with a VEGF-TK1.

The RCC nod opened Welireg to a much larger patient population; this was reflected in the company’s second-quarter financial report, which showed a sales bump to $126 million compared to $50 million in the second quarter of 2023. For Welireg to reach the blockbuster potential projected by Bernstein analysts upon its initial approval, it will have to work its way into earlier lines of use.

As for the most recent analysis of the 746-patient LITESPARK-005 trial at 24 months, there were several positive results. Welireg still excels in PFS, coming in at 17.5% compared to 4.1% for Afinitor. At 12 months, the figures were 33.7% and 17.6%.

"Achieving a positive PFS benefit versus everolimus is still a clinically meaningful result. The 2023 approval of Welireg represents the first time a new treatment has been approved in a novel therapeutic class for these patients in nearly a decade and is a critical treatment option in this later-line setting," Merck said.

Welireg’s overall response rate remained virtually unchanged from previously reported results, at 22.7% compared to 3.5% for Afinitor. Duration of response was 19.3 months for Welireg versus 13.7 months for Afinitor. Discontinuation of treatment for adverse events happened to 6% of the Welireg patients compared to 15% of the patients in the Afinitor group.  

LITESPARK-005 is part of Merck’s development program for Welireg comprised of four phase 3 trials in RCC, in which the company is evaluating Welireg in new combinations with other medicines across different setting stages and settings of the disease.