Roche's Tecentriq Plus Cotellic Fails to Outperform Keytruda in Phase III Melanoma Trial

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Biopharmaceutical company Exelixis stated in a recent filing with the U.S. Securities and Exchange Commission that its partner, Genentech (a member of the Roche Group), has informed it that the Phase III clinical trial IMspire170, evaluating the targeted anticancer drug Cotellic in combination with the tumor immunotherapy Tecentriq as first-line treatment for melanoma, did not meet its primary endpoint.

This study was conducted in patients with previously untreated, BRAF V600 wild-type advanced melanoma, comparing the combination of Cotellic plus Tecentriq with Keytruda. The results showed that the Cotellic plus Tecentriq combination failed to reduce the risk of disease progression or death and did not significantly improve progression-free survival (PFS). The safety profile observed in this study was consistent with the known safety profiles of the individual agents, and no new safety signals were identified with the combination therapy.

Cotellic is an oral, selective small-molecule MEK inhibitor that was discovered and advanced to the investigational new drug stage by Exelixis, which subsequently entered into a collaboration with Genentech for joint development. In 2015, the U.S. FDA approved Cotellic in combination with Zelboraf for the treatment of patients with unresectable or metastatic melanoma harboring BRAF V600E or V600K mutations.

Tecentriq and Keytruda are both PD-(L)1 cancer immunotherapies. Tecentriq is designed to target PD-L1 on the surface of tumor cells and tumor-infiltrating immune cells, blocking its binding to the PD-1 and B7.1 receptors. By inhibiting PD-L1, Tecentriq enables the reactivation of T cells.

This Phase III clinical failure was not the first setback for the Cotellic plus Tecentriq combination. Last May, the Phase III IMblaze370 study evaluating this combination in colorectal cancer (CRC) also failed to meet its primary endpoint. Conducted in patients with refractory locally advanced or metastatic CRC, the study showed that neither the Cotellic plus Tecentriq combination nor Tecentriq monotherapy significantly improved overall survival compared with the standard-of-care drug Stivarga.

Just one month before the failure of the IMblaze370 study, another Phase II trial investigating the combination of Cotellic and Tecentriq for the treatment of metastatic colorectal cancer (CRC) was halted due to four patient deaths. According to reports at the time, one death was attributed to treatment-related cardiogenic shock, two were due to disease progression, and one was unrelated to the treatment.

Cotellic has never been a blockbuster product for either Roche or Exelixis. In the first quarter of this year, Roche reported global sales of CHF 15 million, while Exelixis reported sales and licensing revenue of $2.6 million. Nevertheless, both parties are eager to protect their revenue streams. Two years ago, they resolved a dispute over revenue sharing for Cotellic and renegotiated new terms for revenue and cost allocation covering all commercialized applications of the drug.

In addition to IMspire170, Exelixis and Roche are also conducting another Phase III study evaluating the triple-drug combination of Tecentriq, Cotellic, and Zelboraf for the treatment of melanoma, with results expected by the end of 2019.

Currently, multiple pharmaceutical companies are evaluating "immunotherapy + targeted therapy" combination treatments for melanoma, including Merck & Co. and Novartis, both of whom are assessing a triple-drug regimen combining Keytruda with Tafinlar and Mekinist.

Some analysts have pointed out that, compared to competitors' combination therapies, the positioning of Roche and Exelixis's three-drug regimen is to protect market share rather than expand it. Therefore, this ongoing Phase III clinical trial is more important for both parties.

References: 1. Exelixis' Late-Stage Melanoma Combination Falls Short in Phase III Trial 2. Beating Keytruda a Big Task, Exelixis and Roche Find