After winning two clinical trials for intractable and early-stage kidney cancer, Merck & Co.’s blockbuster candidate Wellireg surprisingly failed to inspire hope as a first-line treatment.
Wellireg did not improve progression-free survival or overall survival when given in addition to Merck’s Keytruda and Lenvima combination therapy as a first-line treatment for advanced clear cell renal cell carcinoma (ccRCC), the company announced Tuesday.
The negative results from the pre-specified interim analysis of the Phase 3 Litespark-012 trial were a major surprise. After two positive Phase 3 results, first-in-class HIF-2 alpha inhibitor We are preparing for Setting new standards of care Patients with advanced ccRCC who have not responded to previous immunotherapy and patients with early-stage resected ccRCC who are at high risk of recurrence after surgery are targeted.
Following the wins for WrightsPark-011 and -022, genitourinary cancer experts predicted to Leerink Partners that the first-line WrightsPark-012 trial would be “very positive” for PFS because “it is hard to believe that the adjuvant and two refractory tests would be positive, but somehow the first-line test would be negative,” according to a March 3 Leerink memo.
Another positive refractory study for Wellireg was Litespark-005, in which Merck’s drug outperformed Novartis’ Afinitor in PFS but not OS.
With its previous Phase 3 win, Leerink analysts previously suggested that Wellreg’s consensus peak sales estimate of approximately $2.6 billion “underestimates the drug’s role in ccRCC.” Wellreg was first approved by the FDA to treat von Hippel-Lindau disease in 2021, and became a treatment for kidney cancer in late 2023. Last year, global sales of the drug were $716 million, an increase of 41% from the previous year.
On the other hand, certain aspects of the Litespark-011 and -022 measurements may prevent Wellileg from becoming the undisputed standard of care in second-line and adjuvant therapy.
A PFS win for the Welireg-Lenvima combo could drive adoption on the second line, but the OS does not meet statistical significance.
Two genitourinary cancer experts Leerink spoke to both shared concerns about the therapy because it contains Lenvima ingredients, but for different reasons. One specialist used Lenvima primarily as a first-line treatment and was not interested in changing that practice just to accommodate a second-line option. The other wanted to preserve Lenvima as a valuable salvage option and was reluctant to use it in a second line.
FDA is reviewing Merck’s application under Litespark-011 with a target action date of October 4, 2026.
When it comes to the adjuvant setting, two experts agreed that despite the disease-free survival victory, the data on Litespark-022 is still too immature to justify widespread use, given the widespread understanding in the medical community that it is best to avoid overtreatment of patients in settings where the majority are cured by surgery, Leerink said.
In addition to Merck, Arcus Biosciences is also developing a rival HIF-2α inhibitor called Kasdatifan. Despite promising data, Gilead Sciences abandoned its chance to get the drug approved last year.
Merck’s April 21 announcement actually included a second flop. The third arm of Litespark-012, which evaluated MK-1308A, a co-formulation of Keytruda and Merck’s CTLA-4 antibody quavonlimab, and Lenvima, also failed to outperform Keytruda and Lenvima in the dual primary endpoints of PFS and OS in first-line ccRCC.
In any case, this combination appeared to be a wild card for Merck. Before the announcement, Leerink analysts said they were “very pessimistic” about the comparison after the Cosmic-313 trial of Exelixis’ Cabometyx and Bristol-Myers Squibb’s Opdivo and Yervoy showed that adding a CTLA-4 agent could backfire.
“Although these regimens did not show the results we had hoped for, this data will deepen our understanding of advanced renal cell carcinoma and help shape the next generation of treatment approaches,” Katherine Pietanza, M.D., vice president of global clinical development at Merck Research Laboratories, said in a statement Tuesday.
Merck said the results of the Litespark-012 trial do not impact other ongoing trials under the Litespark program for Welireg.
