Exelixis and Roche's Cabometyx + Tecentriq Combination Fails to Improve Overall Survival in First-Line Hepatocellular Carcinoma Despite PFS Benefit

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Recently, Exelixis announced clinical trial data for the tyrosine kinase inhibitor (TKI) Cabometyx in combination with Roche’s immuno-oncology (I-O) therapy Tecentriq as a first-line treatment for hepatocellular carcinoma (HCC). Surprisingly, this combination therapy did not extend the survival of newly diagnosed HCC patients.

This result is derived from the interim analysis data of the Phase 3 COSMIC-312 clinical trial. Although investigators observed a trend favoring the combination therapy, Exelixis stated that "the probability of achieving statistical significance at the final analysis is low." The trial will continue as planned, with final data to be reported earlier in 2022.

However, Exelixis has not conceded defeat. In a statement, the company’s Chief Executive Officer, Michael Morrissey, said that the company will conduct a thorough analysis of the final data to identify factors that may explain the unfavorable outcomes, including patient demographics, subsequent anticancer therapy, and the impact of COVID-19 on the trial.

The failure in first-line liver cancer treatment represents a major blow to Exelixis. According to the company, of the more than 900,000 liver cancer cases diagnosed globally each year, approximately 90% are HCC. During an investor conference call in May, Michael Morrissey compared the market opportunity for HCC with that of the recent FDA approval of Cabometyx in combination with Bristol Myers Squibb’s I-O drug Opdivo for the first-line treatment of renal cell carcinoma. Bank of America analyst Jason Gerberry stated that this approval is "highly significant" for Exelixis’s business. The company projected that by the end of 2022, annual revenue from Cabometyx for renal cell carcinoma (including in previously treated patients) would reach $1.5 billion.

The failure of the COSMIC-312 trial indeed came as a surprise to everyone, as both Cabometyx and Tecentriq had previously achieved success in the treatment of hepatocellular carcinoma. Since early 2019, Cabometyx has been approved for patients with previously treated HCC based on an overall survival benefit relative to placebo. Tecentriq, in combination with Roche’s own Avastin, received regulatory approval last year (including in the United States, the European Union, China, and Japan) after demonstrating a 42% reduction in the risk of death compared with Nexavar in the Phase 3 IMbrave150 trial, becoming the first immuno-oncology (I-O) therapy approved for patients with newly diagnosed HCC.

However, on a positive note for Exelixis, the combination therapy of Cabometyx and Tecentriq met another co-primary endpoint of the COSMIC-312 trial—progression-free survival (PFS): compared with Nexavar, it reduced the risk of cancer progression or death by 37%. Exelixis stated that it plans to submit these data to the FDA and discuss potential next regulatory filings.

Exelixis is not the only pharmaceutical company exploring the TKI/I-O approach for the treatment of liver cancer. Merck, in collaboration with its partner Eisai, is testing the combination of Keytruda and Lenvima. However, in July 2020, the FDA issued a Complete Response Letter regarding the application for this combination as a first-line treatment for HCC, indicating that the early tumor response data were insufficient to demonstrate a clinically meaningful advantage over currently available therapies.

Currently, Exelixis is also conducting clinical trials to evaluate Cabometyx in combination with Keytruda, or in combination with Opdivo and Bristol-Myers Squibb’s CTLA-4 inhibitor Yervoy, as a first-line treatment for HCC. Additionally, Exelixis is evaluating Cabometyx as a monotherapy and in combination with chemotherapy, targeted therapies, or immuno-oncology (I-O) agents for various tumor types across multiple clinical trials. According to its website, the clinical development program for Cabometyx currently includes 19 Phase 1, 51 Phase 2, and 8 Phase 3 clinical trials.

In addition to liver cancer, Exelixis recently announced data from Cohort 6 of the Phase 1b COSMIC-021 study, demonstrating that the combination therapy of Cabometyx and Tecentriq achieved an overall response rate of 27% in patients with previously treated metastatic castration-resistant prostate cancer. The company hopes that these data will support the regulatory submission and accelerated approval of this combination for this indication.

Source: In surprising flop, Exelixis' Cabometyx combo with Roche's Tecentriq fails to extend life in liver cancer