Chris Lieu, MD

If colon cancer is caught in its early stages, patients typically have a good chance of living five years past diagnosis, and beyond. However, for patients with late-stage, metastatic colon cancer, the chance drops dramatically, to a five-year survival rate of only about 12 percent. Now an innovative new clinical trial offered at the University of Colorado Cancer Center and partner institutions will look at a new combination therapy that may be effective in treating this advanced form of the disease.  This study is being supported by a National Cancer Institute/National Institutes of Health (NCI/NIH) R01 grant.

“Put very simply, we are investigating a combination of immune therapy and targeted therapies in hopes that we can help to extend patients’ lives,” explains Chris Lieu, MD, CU Cancer Center’s deputy associate director for clinical research, and principal investigator on the study.

While the 5 percent of patients with “microsatellite-instable” disease (MSI-H) are already treated with a combination immunotherapy targeted therapy, the current trial takes aim at approximately 95 percent of metastatic colorectal cancer patients with “microsatellite stable” (MSS) disease.

“Our thought is that if we use a more robust combination of two targeted therapies and one immune therapy, we may get a better response rate,” says Lieu.

The trial’s two targeted therapies include the VEGF inhibitor, bevacizumab, and the MEK inhibitor, binimetinib. The immunotherapy is the PD-1 inhibitor, pembrolizumab.

VEGF stimulates cell growth and survival, and improper activation of VEGF can help new tumors establish a vascular system that feeds its growth. MEK is a protein that is often improperly activated in many types of cancer, allowing mutations in other genes important to tumor growth. And PD-1 is like a “white flag” that tumor cells can wave to deactivate the immune system. Researchers hope that the combination of bevacizumab, binimetinib, and pembrolizumab will turn off VEGF, MEK and PD-1, respectively, delivering a potent, three-part attack against metastatic microsatellite stable colorectal cancer.

The NCI/NIH R01 grant will also support the investigation of tumor tissue to look for biomarkers that may explain why the combination of drugs work or don’t work.  “By determining why our treatments are effective or not, we may be able to select the patients that are most likely to respond to this combination. We can also investigate why tumors are resistant to these treatments in order to propose a more effective combination in the future.”

This collaborative effort includes multiple scientists and laboratory teams, including Dr. Todd Pitts, Dr. Kimberly Jordan, Julie Lang, and the Human Immunology and Immunotherapy Initiative (HI3).

“We are hopeful that this study will be effective in treating patients that, unfortunately, are limited in treatment options for metastatic disease,” says Lieu. “We are expanding a strategy that has been utilized to treat a smaller population of MSI-H to include the more prominent MSS population.”