After trial flop, Exelixis drops plan to pair Cabometyx with Roche's Tecentriq in early-stage liver cancer

After last year’s surprise flop in previously untreated hepatocellular carcinoma (HCC)—the most common type of liver cancer—Exelixis’ hopes dimmed around the combination of its tyrosine kinase inhibitor Cabometyx with Roche’s immuno-oncology agent Tecentriq. Now, the other shoe has dropped. 

Faced with disappointing data from a phase 3 study pitting the Exelixis-Roche combo against Bayer’s Nexavar in newly-diagnosed liver cancer, Exelixis is calling it quits on plans for a Cabometyx label expansion. 

The final analysis of overall survival (OS) data from the combo therapy’s phase 3 COSMIC-312 study showed “neither improvement nor detriment in OS for cabozantinib in combination with atezolizumab versus sorafenib,” Exelixis said Tuesday, using the generic names for Cabometyx, Tecentriq and Nexavar, respectively. 

Based on that overall survival flop and “the rapidly evolving treatment landscape for previously untreated advanced HCC,” Exelixis has decided not to submit the combo for FDA approval. 

Exelixis’ COSMIC-312 study enrolled 837 patients who received either Cabometyx and Tecentriq, Cabometyx solo or Nexavar. The company didn’t offer any firm data points in Tuesday’s release, instead saying full results would be presented at an upcoming medical meeting.

In interim results from COSMIC-312 unveiled last year, the Cabometyx-Tecentriq combo failed to prolong the lives of patients with previously untreated HCC. In announcing the results, Exelixis admitted in June that the “probability of reaching statistical significance at the time of the final analysis [was] low.”

At the time, the combo did cut the risk of cancer progression or death by 37% over Bayer’s Nexavar, however.

Last year’s trial failure came as something of a shock, given Cabometyx and Tecentriq’s previous liver cancer wins. Cabometyx has been approved in previously-treated liver cancer since early 2019, while Tecentriq plus Roche’s Avastin in 2020 became the first immuno-oncology therapy approved for newly diagnosed patients.

Cabometyx won its liver cancer nod thanks to an overall survival advantage versus placebo. The Tecentriq-Avastin combo, meanwhile, showed a death risk reduction of 42% over Nexavar in a phase 3 study dubbed IMbrave150. 

Despite the latest combo therapy setback, Exelixis’ Cabometyx franchise continues to grow in its established kidney, liver and thyroid cancer indications. The drug generated $302.7 million in 2021’s fourth quarter, with full-year U.S. sales clocking in at $1.08 billion, Exelixis said in its full-year earnings report published last month.