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

Compiled by Fan Dongdong

Combining Roche’s Tecentriq with Exelixis’ drug Cotellic as a combination therapy for melanoma is a promising approach. Cotellic, initially discovered by Exelixis as an oral selective small-molecule MEK inhibitor, was subsequently co-developed in partnership with Roche. 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.

Unfortunately, this may remain merely a concept, as the Tecentriq plus Cotellic combination failed to outperform Keytruda in head-to-head melanoma trials. In the Phase 3 IMspire170 study, the Tecentriq plus Cotellic regimen failed to inhibit melanoma progression across nearly all endpoints and did not demonstrate superior efficacy compared with Keytruda; metrics such as overall response rate, progression-free survival, and adverse events also fell short of those achieved with Keytruda.

Specific data showed that the response rate was 26% in the Tecentriq + Cotellic group and 32% in the Keytruda group; median progression-free survival was 5.5 months in the Tecentriq + Cotellic group and 5.7 months in the Keytruda group. In terms of safety, 67% of patients in the Tecentriq + Cotellic group experienced severe adverse events (Grade 3 or higher), compared with 33% in the Keytruda group. Due to these adverse effects, 12% of patients in the Tecentriq + Cotellic group discontinued the trial, versus 6% in the Keytruda group.

This is not the first major setback for the Cotellic plus Tecentriq combination. In May 2018, the Phase III IMblaze370 study evaluating Cotellic plus Tecentriq for the treatment of colorectal cancer also failed to yield positive results. The study primarily compared the efficacy of this combination therapy with Stivarga, the current standard-of-care drug, in patients with refractory locally advanced or metastatic colorectal cancer. The results showed that neither Cotellic plus Tecentriq nor Tecentriq monotherapy met the primary endpoint of significantly prolonging overall survival. One month before the failure of the IMblaze370 study, a Phase II clinical trial of Cotellic plus Tecentriq for metastatic colorectal cancer was forced to terminate due to four patient deaths.

Although the IMspire170 study failed to yield positive results, there remains room for future collaboration between Exelixis and Roche. The two companies are currently conducting another Phase III trial in melanoma, evaluating the efficacy of the triple-drug combination of Tecentriq, Cotellic, and Zelboraf for the treatment of melanoma. The trial results are expected to be released by the end of 2019.

Although Roche’s Tecentriq encountered setbacks in the melanoma field, the drug has achieved certain progress in other oncology indications. On September 12, Roche announced positive results from the Phase III IMpower110 clinical trial evaluating Tecentriq as a first-line monotherapy for non-small cell lung cancer (NSCLC). The results demonstrated that Tecentriq met the primary endpoint of the trial in patients with advanced non-squamous and squamous NSCLC lacking ALK or EGFR mutations, showing a statistically significant overall survival benefit compared to platinum-based chemotherapy (cisplatin or carboplatin) combined with either pemetrexed or gemcitabine. Furthermore, Roche is actively advancing multiple late-stage trials of Tecentriq, both as monotherapy and in combination regimens, covering indications such as gynecologic cancers, skin cancer, breast cancer, genitourinary tumors, lung cancer, gastrointestinal tumors, and head and neck cancer.

Reference Source: Roche's Tecentriq-Cotellic Duo Tried—and Failed—to Beat Merck's Keytruda in Melanoma