Anti–PD-L1 Immunotherapy Shows Response in Microsatellite-Stable Metastatic Colorectal Cancer in Combination With MEK Inhibition

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Anti–PD-L1 (programmed death ligand 1) immunotherapy may achieve a response in patients with microsatellite-stable metastatic colorectal cancer if combined with a MEK inhibitor, according to phase I data presented at the European Society for Medical Oncology (ESMO) 18th World Congress on Gastrointestinal Cancer in Barcelona.1

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.
— Johanna Bendell, MD

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“So far, immunotherapy has only shown activity in patients with microsatellite instability–high colorectal cancer, which is only 5% of the population,” says the study’s principal investigator Johanna Bendell, MD, of the Sarah Cannon Research Institute and Tennessee Oncology.

Microsatellite instability–high colorectal cancers are associated with a greater number of mutations and are therefore more responsive to immunotherapy with PD-L1/PD-1 (programmed cell death protein 1) blockade. However, the majority of patients with metastatic colorectal cancer—around 95%—have microsatellite-stable disease, which so far has shown almost no response to immunotherapy.

Preclinical studies have suggested that a MEK inhibitor can make a tumor more responsive to immunotherapy by increasing the number of active immune cells—such as CD8+ cells—in the tumor and increasing the expression of factors that cause the immune system to be more active.

Study Findings

In this phase Ib study, 23 previously treated patients with metastatic colorectal cancer were treated with escalating doses of the MEK inhibitor cobimetinib (Cotellic; 20 mg, 40 mg, and 60 mg daily; 21 days on, 7 days off), with an expansion of patients at the highest dose level, and an 800-mg dose of intravenous PD-L1 inhibitor atezolizumab (Tecentriq) every 2 weeks.

Following treatment, researchers saw a decrease of at least 30% in the tumor size in four patients (17%) and stable disease in five patients (22%). The duration of responses ranged from 4 months to over 15 months and were still ongoing in 2 of 4 patients who were partial responders at the time of the data cut.

Three of the partial responders had microsatellite-stable or microsatellite instability–low disease, and one had unknown microsatellite status. None of the patients in the study had known microsatellite instability–high disease.

The baseline PD-L1 status did not appear to affect responses, and the combination was well tolerated with no serious treatment-related adverse events reported.

In summary, Dr. Bendell said, “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.”

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


1. Bendell J, Kim TW, Chee CE, et al: Safety and efficacy of cobimetinib and atezolizumab in a phase 1b study of metastatic colorectal cancer. ESMO World Congress on Gastrointestinal Cancer. Abstract LBA-01. Presented June 29, 2016.




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