Two months ago, when Merck revealed its phase 3 trial in renal cell carcinoma achieved its primary endpoint, as Welireg (belzutifan) racked up a decisive win over Novartis’ chemotherapy Afinitor in progression-free survival (PFS), there was disquieting side note.
In the gold-standard measure of efficacy against cancer—overall survival (OS)—Welireg outperformed the comparator, but not enough to achieve statistical significance. While Welireg patients lived a median of 21 months, the result for Afinitor came in at 17.2 months.
At the European Society of Medical Oncology Congress in Madrid, Merck reveled data from the LITESPARK-005 trial and on Saturday investigators discussed the results.
Is Merck disappointed in the OS performance? Not at all. Just give Welireg more time, the company says.
“The overall survival is immature still,” Marjorie Green, M.D., Merck’s late-stage oncology chief, said in an interview. “This data to me is somewhat reminiscent of what we saw with checkpoint inhibitors when they first came out.”
Welireg, which Merck obtained in a $1.1 billion acquisition of Peloton Therapeutics in 2019, is a first-in-class oral hypoxia-inducible factor-2 alpha (HIF-2a) inhibitor. It was approved by the FDA two years ago for the rare von Hippel-Lindau (VHL) disease. Merck is hoping to add indications for Welireg and turn it into a blockbuster.
The LITESPARK-005 study examined Welireg in patients with pretreated advanced clear cell renal cell carcinoma (ccRCC), a common type of kidney cancer in which the survival rate is particularly low.
In the trial, PFS at 12 months was 33.7% for Welireg patients compared to 17.6% for those on Afinitor. At 18 months, the figures were 22.5% versus 9.0%.
The objective response rate (ORR) advantage for Welireg was even more decisive—21.9% for Welireg versus 3.5% for Afinitor. While 13 Welireg patients experienced complete responses, none achieved that goal from the comparator arm.
“That response rate, the duration of response, usually those things translate into good, prolonged benefit for people,” Green said.
As for OS, Green pointed out that its hazard ratio (.87) is trending in the right direction.
“The time to response with belzutifan is about three months,” Green said. “You think about chemotherapies, some are super fast—usually you see response at the first imaging. (Welireg) is slower onset. Once it gets rolling, patients really have very durable responses.”
The study is one of four LITESPARK phase 3 trials assessing Welireg’s potential in ccRCC.
At ESMO, an updated analysis of LITESPARK-003, a phase 2 study that is assessing the efficacy of Welireg plus the chemotherapy cabozantinib as a first-line and subsequent-line treatment, showed durable antitumor activity. The results further support the combination of an HiF-2a inhibitor and VEGFR-TKI as a potential option for ccRCC in both first-line and subsequent-line treatment, according to the company.
Also at ESMO, results from LITESPARK-013 showed that testing Welireg at a 200 mg dose—as opposed to its 120 mg formulation—achieved no greater efficacy and did not alter the safety profile.
“There are limited treatment options for patients with advanced RCC whose cancer progresses after both immune checkpoint and anti-angiogenic therapies,” Laurence Albiges, LITESPARK-005 investigator and chairman of the Gustave Roussy Cancer Medicine Department, said in a release. “It is an important step forward to see that in this study, belzutifan demonstrated a statistically significant reduction in the risk of disease progression or death, and an improvement in overall response rate."