Immunotherapy Combination Achieves Response in Colorectal Cancer

An anti-PD-L1 immunotherapy combined with an MEK inhibitor may improve treatment for microsatellite-stable metastatic colorectal cancer, a recent study found.

The data was presented at the ESMO World Congress of Gastrointestinal Cancer in Barcelona, Spain. Microsatellite instability-high colorectal cancers are associated with increased mutations that results in a greater response to immunotherapy with PD-L1/PD-1 blockade.

However, this form of cancer accounts for only a small portion of patients, while 95% of patients with this disease have microsatellite-sable metastatic colorectal cancer, which has almost no response to immunotherapy.

“So far, immunotherapy has only shown activity in patients with microsatellite instability-high colorectal cancer, which is only 5% of the population,” said principal study investigator Johanna Bendell.

There have been preclinical studies that suggest an MEK inhibitor has the ability to increase a tumor response to immunotherapy by increasing the number of active immune cells in the tumor, such as CD8+ cells, and increasing the expression of factors that cause the immune system to become more active.

With this knowledge, researchers conducted a phase 1b study involving 23 previously treated patients with metastatic colorectal cancer. Patients were administered escalating doses of the MEK inhibitor cobimetinib (20-mg, 40-mg, and 60-mg daily) for 21 days on and 7 days off.

There was an expansion of patients at the highest dosage, and an 800-mg dose of intravenous PD-L1 inhibitor atezolizumab every 2 weeks. The results of the study showed that after treatment, there was a decrease of at least 30% in the tumor size of 4 patients (17%) and stable disease in 5 patients (22%).

The duration of responses ranged from 4 months to more than 15 months, and were still ongoing in 2 of 4 patients who were initially partial responders. Three of the partial responders had microsatellite-stable or microsatellite instability-low disease, and 1 patient had an unknown microsatellite status.

None of the participants had known microsatellite high disease. Researchers also found that baseline PD-L1 status did not seem to affect responses, and the combination therapy did not result in any serious treatment-related adverse events.

“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.

The findings provided researchers with more information on the treatment of metastatic colorectal cancer.

“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,” said researcher Florian Lordick. “This is the first step for immunotherapy to reach patient populations who previously were not identified as good candidates for immune checkpoint inhibition.”

The authors are currently in the process of conducting a randomized phase 3 study to compare the combination therapy with standard treatments in refractory metastatic colorectal cancer patients.