In a surprising setback, the combination of two drugs—both with proven track records in liver cancer—didn't significantly extend life for newly diagnosed patients.
Pitted against Bayer’s old standard Nexavar, the combo of Exelixis’ tyrosine kinase inhibitor Cabometyx and Roche’s immuno-oncology agent Tecentriq failed to prolong patients’ lives in previously untreated hepatocellular carcinoma (HCC), the most common type of liver cancer, Exelixis said Monday.
The miss came from an interim analysis of a phase 3 trial dubbed COSMIC-312. While investigators noted a trend in favor of the combo, Exelixis said that its “probability of reaching statistical significance at the time of the final analysis is low.” The trial will continue to read out that data in early 2022, it added.
Exelixis isn’t throwing in the towel just yet. The company will dig deeper into the final data to identify factors that might explain the unfavorable results, including patient demographics, subsequent anti-cancer treatment and the impact of COVID-19 on the trial, Exelixis CEO Michael Morrissey said in a statement.
Failing in front-line liver cancer is a big blow to Exelixis; about 90% of the over 900,000 new cases of liver cancer diagnosed worldwide each year are HCC, according to the company.
During an investors call in May, Morrissey compared the HCC market opportunity to that of Cabometyx’s recent FDA nod alongside Bristol Myers Squibb’s I-O drug Opdivo in front-line kidney cancer, which Bank of America analyst Jason Gerberry said was “so important” to Exelixis’ business. The company expects Cabometyx’s annualized revenues from kidney cancer—including from previously treated patients—to reach $1.5 billion by the end of 2022, Morrissey said on the call.
Monday’s trial setback came as a surprise, given both Cabometyx and Tecentriq have posted wins in treating liver cancer before. Cabometyx has been approved in previously treated liver cancer since early 2019 on the back of an overall survival advantage against placebo. And Tecentriq, used in tandem with Roche’s own Avastin, last year became the first immuno-oncology therapy approved for newly diagnosed patients after demonstrating a death risk reduction of 42% over Nexavar in the phase 3 IMbrave150 trial.
On the positive side for Exelixis, Cabometyx and Tecentriq met the other co-primary endpoint in the COSMIC-312 trial, progression free survival, by cutting the risk of cancer progression or death by 37% over Nexavar. Exelixis said it plans to take the data to the FDA and discuss next steps for a potential regulatory filing.
Exelixis isn’t the only drugmaker exploring a TKI/I-O approach for liver cancer. Merck & Co. and partner Eisai are testing the mixture of Keytruda and Lenvima. But the FDA recently slapped a complete response letter on an application for that regimen in front-line liver cancer, suggesting its early tumor response data weren’t enough to prove a benefit.
Beyond liver cancer, Exelixis recently unveiled that the Cabometyx-Tecentriq combo triggered a 27% response rate in previously treated patients with metastatic castration-resistant prostate cancer. The company hopes the data, from cohort 6 of the phase 1b COSMIC-021 study, could support a filing—and accelerated approval—in the disease.