Anti–PD-L1 Immunotherapy, MEK Inhibition Active in Metastatic CRC

Results of a phase I study have shown combination treatment with the MEK inhibitor cobimetinib and the anti–programmed death ligand 1 (PD-L1) drug atezolizumab was active in patients with microsatellite-stable metastatic colorectal cancer.

Results from the study were presented by Johanna Bendell, MD, of Sarah Cannon Research Institute and Tennessee Oncology in Nashville, at the 18th European Society for Medical Oncology (ESMO) World Congress on Gastrointestinal Cancer in Barcelona (abstract LBA-01).

“So far, immunotherapy has only shown activity in patients with microsatellite instability–high colorectal cancer, which is only 5% of the population,” Bendell said in a press release. Patients with microsatellite instability–high disease have more mutations and are, therefore, more responsive to immunotherapy with PD-L1/PD-1 blockade.

In this study, Bendell and colleagues combined immunotherapy with a MEK inhibitor because previous studies have suggested that MEK inhibition could make a tumor more responsive to immunotherapy.

The phase I study included 23 patients with previously treated metastatic colorectal cancer. During the dose escalation portion of the study, patients were given 20-mg, 40-mg, or 60-mg cobimetinib in combination with 800-mg atezolizumab; the expansion dose was 60-mg cobimetinib and 800-mg atezolizumab. Patients were not selected for PD-L1 expression or microsatellite instability status.

Of the 23 patients enrolled, 4 patients (17%) had confirmed partial responses to the drug combination, with at least a 30% decrease in tumor size. Three of these patients had microsatellite-stable or microsatellite instability–low disease. One patient had an unknown status.

Five patients (22%) had stable disease. Response duration ranged from 4 months to longer than 15 months. Two of the four patients with partial responses had ongoing responses at data cutoff.

“What we saw is consistent with the hypothesized mechanism of action of this combination, which shows promise in giving the other 95% of colon cancer patients a chance to respond to immunotherapy,” Bendell said. 

With a median safety follow-up of 3.78 months, no dose-limiting toxicities occurred, and no one experienced any treatment-related grade 4 or grade 5 adverse events. Thirty-five percent of patients experienced a treatment-related grade 3 adverse event. The most common events of any grade were rash, diarrhea, and fatigue.

Florian Lordick, MD, director of the University Cancer Centre Leipzig, Germany, commented on these results in a press release: “This important phase 1b study now shows for the first time that metastatic colorectal cancer can be sensitized for immune therapy by inhibition of MEK-dependent intracellular signaling. This is the first step for immunotherapy to reach patient populations who previously were not identified as good candidates for immune checkpoint inhibition.”

Researchers have now launched a randomized phase III study to compare the combination with standard treatment for patients with refractory metastatic colorectal cancer.