Combining anti-PD-L1 immunotherapy with an MEK inhibitor significantly increases treatment response in patients with microsatellite-stable metastatic colorectal cancer, according to results from a Phase 1b trial presented at the recent European Society for Medical Oncology (ESMO) 18th World Congress of Gastrointestinal Cancer in Barcelona.
Lead study lead author Dr. Johanna Bendell, of Sarah Cannon Research Institute and Tennessee Oncology, in Nashville, said in a press release that only 5 percent of patients with microsatellite instability-high colorectal cancer typically respond to immunotherapy.
But preclinical studies suggested that stopping mitogen-activated protein kinase (MEK) enzymes with a MEK inhibitor made tumors more responsive to immunotherapy. The response was attributed to increased numbers of active immune cells such as CD8+T cells in the tumor microenvironment, and the increase of higher expressions of factors that spur the immune system.
Florian Lordick, director of the University Cancer Centre Leipzig, in Germany, said the study 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,” Lordick said.
For the study, 23 previously treated patients were administered escalating doses of the MEK inhibitor cobimetinib for 21 days on, 7 days off. An 800mg dose of intravenous PD-L1 inhibitor atezolizumab was given every two weeks.
The combination therapy showed at least 30% decrease in tumor size for four patients, and stable disease in five patients. The length of response ranged from 4 months to more than 15 months. In two out of four patients, the responses were still ongoing. Three had microsatellite-stable or microsatellite instability-low disease and one had unknown microsatellite status.
No adverse side effects were reported; the baseline PD-L1 status did not appear to affect response.
Bendell summarized the findings: “What we saw is consistent with the hypothesized mechanism of action of this combination, which shows promise in giving the other 95 percent of colon cancer patients a chance to respond to immunotherapy.”
Researchers will later investigate the response of the combined therapy in patients with refractory (resistant) metastatic colorectal cancer.
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