Exelixis trots out combo win for Cabometyx and BMS meds in kidney cancer. Will the FDA get on board?

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.