Metastatic colorectal cancer patients with a certain genetic mutation respond well to immunotherapy
A practice-changing clinical trial conceived and led by MD Anderson investigators showed that metastatic colorectal cancer patients with a specific genetic defect respond well to a common cancer immunotherapy drug.
About 5% of patients with colorectal cancer that has spread to other organs have a genetic mutation known as DNA mismatch repair deficiency, or dMMR, in their tumors. These tumors’ inability to repair a certain type of damage leaves them harboring more DNA mutations, which attract the attention of immune system T cells.
This finding suggested that an immunotherapy that frees the immune system to attack by blocking PD1, a protein on T cells that shuts down immune response, could help these patients, says Michael Overman, M.D., an associate professor of Gastrointestinal Medical Oncology.
Overman and Scott Kopetz, M.D., associate professor of Gastrointestinal Medical Oncology, recommended a targeted clinical trial for these patients to Bristol-Myers Squibb, the company that makes nivolumab, a PD1 checkpoint inhibitor known commercially as Opdivo.
International clinical trial results reported online by Lancet Oncology showed that 23 of 74 patients (31%) had their tumors shrink, and the other 51 had disease progression halted for at least 12 weeks.
“That level of response and disease control is unheard of in these heavily pretreated patients, outside of frontline therapy,” Overman says. “Because the benefit was so dramatic and the responses durable, this therapy was approved by the FDA based on a single-arm study and is now indicated for microsatellite instability-high metastatic colorectal cancer patients in second or third line therapy.”
Traditional chemotherapy and targeted therapies have little effect for patients with tumors defective in mismatch repair with microsatellite instability-high status, a reflection of their heavy mutational load.
All responders were alive after 12 months of follow-up, and while eight cases of grade 3 and grade 4 side effects were noted, no patients died during the treatment.
Clinical trials are under way to test anti-PD1 therapy as frontline therapy for these patients.
Based on early results, the National Cancer Center Network recommended in November the testing of all metastatic colorectal cancer patients for mismatch repair defects with microsatellite instability-high status. The U.S. Food and Drug Administration last week approved nivolumab as second line therapy for this patient group.
More broadly, the FDA in May approved another PD1 inhibitor, Merck’s pembrolizumab (Keytruda) for patients with DNA mismatch repair, microsatellite-high disease as second-line therapy regardless of cancer type. It was the agency’s first approval of a cancer drug based solely on a genetic biomarker without regard to the organ of origin of the cancer.
Because the benefit was so dramatic and the responses durable, this therapy was approved by the FDA based on a single-arm study and is now indicated for microsatellite instability-high metastatic colorectal cancer patients in second or third line therapy.
Michael Overman, M.D., associate professor of Gastrointestinal Medical Oncology