In kidney cancer, a regimen of Bristol Myers Squibb’s Opdivo and Yervoy—and an Opdivo combination with Exelixis’ Cabometyx have both been approved in newly diagnosed patients. Now, Exelixis suggests the three drugs should be paired together.
Adding Cabometyx to the Opdivo-Yervoy combo cut the risk of disease progression or death by 27% among patients with previously untreated advanced intermediate- or poor-risk renal cell carcinoma, Exelixis said Monday.
The phase 3 COSMIC-313 trial has therefore met its primary goal, and Exelixis said it plans to talk to the FDA about a potential application. But the combination has yet to show it can extend patients’ lives, an improvement that all other FDA-approved frontline immuno-oncology treatments for kidney cancer have already demonstrated.
After failing to show a significant benefit on patient survival during a prespecified interim analysis, the trial will continue to see if the three-drug regimen can eventually hit the key overall survival endpoint. Meanwhile, Exelixis appears hopeful.
“COSMIC-313 is the first trial to show that a tyrosine kinase inhibitor added to dual checkpoint inhibition can improve progression-free survival in patients with advanced kidney cancer,” Exelixis’ chief medical officer, Vicki L. Goodman, M.D., noted in a statement.
Back in 2018, Bristol’s Opdivo-Yervoy combo won its frontline kidney cancer go-ahead for intermediate or poor-risk patients after showing it can cut the risk of death by 37% over Pfizer’s old standard of care, Sutent. It’s worth noting that the dual-I-O regimen didn’t stall tumor progression any better than Sutent did in the CheckMate-214 study. But adding Cabometyx in the current COSMIC-313 trial apparently moved the needle on that trial marker.
Last January, the Cabometyx-Opdivo cocktail got its own frontline OK based on a death risk reduction of 40% against Sutent in a broader patient population, including those with favorable risk prognostic risks.
Then last August, Merck & Co.’s Keytruda snagged a green light alongside Eisai-partnered Lenvima in the same setting thanks to its ability to pare down the risk of death by 34% compared with Sutent. And Keytruda’s pairing with Pfizer’s Inlyta also carries a frontline kidney cancer label with a life extension win.
“As the treatment landscape continues to evolve, resulting in more options for advanced kidney cancer, there is still a need for additional effective first-line treatment options for patients with intermediate- or poor-risk disease,” Toni Choueiri, M.D., from the at Dana-Farber Cancer Institute, and an investigator of COSMIC-313, said in a statement.
Back in 2020, interviews by SVB Securities analysts showed that experts preferred the Opdivo-Yervoy pure I-O regimen for their intermediate- and poor-risk patients because the combo’s “strong, stable survival tail with immune-related adverse events that are often more tolerable than [adverse events] with [tyrosine kinase inhibitors],” SVB analyst Daina Graybosch wrote in a February 2021 note after Merck detailed Keytruda-Lenvima’s phase 3 data.
Now, Exelixis has shown that Cabometyx can improve upon Opdivo and Yervoy in this more vulnerable patient population—at least in terms of disease progression. But adding a tyrosine kinase inhibitor that’s known to have various toxicities might erase the tolerability benefits doctors see in a pure I-O regimen. The side effects observed in the COSMIC-313 trial were reflective of the known safety profiles for each single agent, Exelixis said.
The question now is, will the FDA accept a progression-free survival win without an overall survival showing? With an increased emphasis on overall survival lately at the agency and all other regimens having shown a life extension benefit, Exelixis will have to make a strong case.