Zanzalintinib

Neither Welireg nor Merck's anti-CTLA-4 agent quavonlimab added benefits on top of Keytruda and Lenvima in first-line kidney cancer. After prevailing in two kidney cancer trials in the refractory and early-stage settings, Merck & Co.’s blockbuster prospect Welireg surprisingly failed to ignite hope as a first-line treatment.Welireg did not improve progression-free survival or overall survival when added to a combination of Merck’s Keytruda and Lenvima as first-line treatment for advanced clear cell renal cell carcinoma (ccRCC), the company said Tuesday.The negative result, from a prespecified interim analysis of the phase 3 Litespark-012 trial, comes as a major surprise. After two positive phase 3 readouts, the first-in-class HIF-2 alpha inhibitor is in the running to set new treatment standards for patients with advanced ccRCC who have failed on previous immunotherapy and for early-stage patients with resected ccRCC who’re at an increased risk of recurrence following surgery.Following the Litespark-011 and -022 wins, a genitourinary cancer expert predicted to Leerink Partners that the first-line Litespark-012 trial would be “wildly positive” on PFS since it is “hard to believe an adjuvant and two refractory studies are positive and somehow the first-line will be negative,” according to a March 3 Leerink note. The other positive refractory study for Welireg is Litespark-005, in which the Merck drug outperformed Novartis’ Afinitor on PFS but not OS.With the prior phase 3 wins, Leerink analysts previously suggested that Welireg’s consensus peak sales expectations of around $2.6 billion “underestimate the drug’s role in ccRCC.” First approved by the FDA in 2021 for von Hippel-Lindau disease, Welireg became a kidney cancer treatment at the end of 2023. Last year, the drug’s $716 million in global sales marked a 41% jump year-over-year.   Meanwhile, certain aspects of the Litespark-011 and -022 readouts could prevent Welireg from becoming the unchallenged standard of care in the second-line and adjuvant settings. While the Welireg-Lenvima combo’s PFS win could drive some adoption in the second line, OS has not met statistical significance. Two genitourinary cancer experts that Leerink spoke with both shared reservations about the regimen because of its Lenvima component—but for different reasons. One expert primarily uses Lenvima for first-line treatment and was not interested in changing that practice just to accommodate a second-line option. The other one wanted to save Lenvima as a valuable salvage option and would be reluctant to use it in the second line.The FDA is reviewing Merck’s application based on Litespark-011, with a target action date of Oct. 4, 2026.As for the adjuvant setting, the two experts agreed that despite a disease-free survival triumph, the Litespark-022 data are still too immature to justify broad usage given the widespread understanding within the medical community that it’s best to avoid over-treating patients in a setting where most are cured by surgery, according to Leerink.Besides Merck, Arcus Biosciences is developing a rival HIF-2α inhibitor called casdatifan. Despite promising data, Gilead Sciences passed on its chance to license the drug last year.Merck’s April 21 announcement actually included a second flop. A third arm of Litespark-012, which evaluated MK-1308A, a coformulation of Keytruda and Merck’s CTLA-4 antibody quavonlimab, plus Lenvima, also failed to beat Keytruda and Lenvima on the trial’s dual primary endpoints of PFS and OS in first-line ccRCC. This combination appeared to be a wild card for Merck anyway. Before the readout, Leerink analysts said they were “highly pessimistic” on this comparison after Exelixis’ Cosmic-313 trial of a pairing of its Cabometyx and Bristol Myers Squibb’s Opdivo and Yervoy showed that the addition of a CTLA-4 agent may backfire. “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 at Merck Research Laboratories, said in a statement Tuesday. Results from the Litespark-012 trial do not affect other ongoing trials from the Litespark program for Welireg, Merck said. Through a collaboration with Exelixis, Merck is running the phase 3 Litespark-033 trial testing Welireg alongside the biotech’s investigational tyrosine kinase inhibitor zanzalintinib in frontline kidney cancer patients who had been treated with Keytruda in the adjuvant setting.

iStock, Alberto Barros A triplet regimen comprising Merck’s Welireg and PD-1 blockbuster Keytruda and Eisai’s Lenvima flopped in a Phase 3 renal cell carcinoma trial. Merck and Eisai are looking at an investigational regimen of three FDA-approved therapies for the treatment of renal cell carcinoma. Tuesday, however, a late-stage readout found that the three-drug combo showed no significant survival benefit. In the Phase 3 LITESPARK-012 study, the partners combined Merck’s mega-blockbuster PD-1 inhibitor Keytruda with the pharma’s oral HIF-2α inhibitor Welireg and Eisai’s tyrosine kinase inhibitor Lenvima. All three drugs have previously been cleared by the FDA for various cancers. Merck and Eisai did not provide specific data from LITESPARK-012 in their news release on Tuesday, disclosing only that the triplet therapy “did not meet the dual primary endpoints” of overall survival and progression-free survival. The companies were testing the combo regimen as a first-line therapy for renal cell carcinoma (RCC). Controls were given Keytruda plus Lenvima. These data represent a “triplet trip-up” for Merck and Eisai, according to analysts at William Blair, who wrote in a Monday note that the miss “could theoretically open a path” for competitors. In particular, William Blair pointed to Exelixis and its oral kinase blocker zanzalintinib. Merck is currently testing zanzalintinib with Welireg in the Phase 3 LITESPARK-033 trial in RCC. The study is set to complete in 2032. Exelixis is up just over 2% to $44.56 in premarket trading on Tuesday. LITESPARK-012’s failure on Tuesday does not affect the other ongoing trials under the LITESPARK program, according to Merck and Eisai’s news release. The companies are “disappointed” with the survival miss, but such study failures “play an important role in shaping health care providers’ perspectives as the treatment paradigm” for RCC evolves, Corina Ductus, Oncology Global Clinical Development Lead at Eisai, said in a prepared statement. Merck and Eisai have a long history of working together to advance cancer treatment. Their partnership stretches as far back as 2015, when the companies inked a clinical trial collaboration to test Keytruda with Lenvima and Eisai’s breast cancer drug Halaven. In 2018, the partners reaffirmed their commitment to each other when Merck bet up to $5.76 billion to develop and commercialize a combo regimen of Keytruda and Lenvima. Over the years, the collaboration has had its fair share of successes and stumbles. In August 2021, for instance, the FDA cleared the Keytruda-Lenvima combo as a first-line therapy for advanced RCC. In October last year, however, the doublet, when used alongside transarterial chemoembolization, failed to significantly boost overall survival in a Phase 3 hepatocellular carcinoma study.