Since 2017, Pfizer’s kinase inhibitor Sutent has been approved to help prevent tumors from returning in high-risk kidney cancer patients after surgery. But its efficacy and safety are far from ideal.
Now, Merck & Co. hopes to set a new standard of care with its PD-1 inhibitor Keytruda.
In patients with clear-cell renal cell carcinoma, Keytruda treatment after surgery slashed the risk of disease returning or death by 32% compared with placebo, according to data presented at the virtual American Society of Clinical Oncology meeting.
At the two-year mark, 77.3% of patients who got Keytruda in the phase 3 Keynote-564 trial remained alive and disease-free, while 68.1% of patients in the placebo group could say that.
It marks the first time a PD-1/L1 inhibitor improved so-called disease-free survival for patients with high-risk kidney cancer. If approved, Keyturda could become a new standard of care for clear-cell renal cell carcinoma, ASCO Chief Medical Officer Julie Gralow, M.D., said in a statement. About 70% of renal cell carcinomas are the clear-cell variety.
That magnitude of improvement in disease-free survival has fueled FDA approvals in the past and is considered clinically meaningful, Scot Ebbinghaus, M.D., vice president of clinical research at Merck Research Laboratories, said in an interview ahead of the presentation.
Two experts specializing in genitourinary cancers recently interviewed by SVB Leerink said a disease-free survival improvement of at least eight months would be compelling to support Keytruda adoption in high-risk kidney cancer, even before key data on patient survival are ready, according to an investor’s note.
While median disease-free survival data were immature at this point, Keytruda will likely cross the eight-month threshold given historical clinical data from Sutent.
Sutent previously earned its adjuvant kidney cancer green light based on data from the S-Trac trial. There, the Pfizer small-molecule drug pared down the risk of disease returning or death by 24% over placebo as patients on Sutent lived a median 6.8 years without recurrence, a 1.2-year improvement over placebo.
But that win didn’t exactly make Sutent the standard of care; it’s only approved for adjuvant kidney cancer in the U.S., and its use there has been “sporadic,” Ebbinghaus noted.
Indeed, during an FDA advisory committee meeting in 2017, external experts cast a tie vote of 6-6 on Sutent’s use in adjuvant kidney cancer. Panelists struggled with the significance of the disease-free survival advantage and pointed to Sutent's 60% rate of side effects of grade 3 or above. About 28% of patients discontinued treatment while on Sutent. The FDA doled out an approval later anyway.
The magnitude of disease-free survival is greater for Keytruda in its own trial, and the side effect profile for single-agent anti-PD-1 is favorable compared with long-term use of a kinase inhibitor, Ebbinghaus said. Side effects of grade 3 or above happened in 32.4% of Keytruda patients in Keynote-564. On those two parameters, Keytruda “will have an important role to play” in adjuvant kidney cancer, he added.
Other PD-1/L1 inhibitors are also targeting the adjuvant kidney cancer field. These include Roche’s IMmotion010 trial for Tecentriq, AstraZeneca’s Rampart study for Imfinzi with or without CTLA-4 inhibitor tremelimumab, and Bristol Myers Squibb’s CheckMate-914 trial that’s comparing Opdivo with or without Yervoy against placebo.