Immunotherapy Duo Improves Efficacy in Treatment-Resistant Colorectal Cancer

Giving two immunotherapies known as checkpoint inhibitors along with best supportive care prolonged life by two and a half months compared with supportive care alone in patients with advanced colorectal cancer that resisted previous treatments, according to phase 2 study results.

The use of Imfinzi (durvalumab) plus the experimental drug tremelimumab demonstrated a median overall survival of 6.6 months compared with 4.1 months with supportive care alone in the CO.26 trial, a randomized study run by the Canadian Cancer Clinical Trials Group. However, median progression-free sur­vival, the time from the start of treatment until disease progression, did not differ significantly between the two groups (1.8 months versus 1.9 months).

Previously, this type of therapy had not proved effective in treatment-resistant colorectal cancer except in patients with mismatch repair deficiency, said Eric X. Chen, M.D., Ph.D., an affiliate scientist at Princess Margaret Cancer Center in Toronto. Mismatch repair deficiency refers to cancer cells’ inability to repair their own DNA when damaged, which suggests they respond well to immunotherapy. A small percentage of colorectal cancers have this status, and immune checkpoint blockade has already been approved to treat them.

Immune checkpoint inhibitors interfere with proteins that keep the immune sys­tem in check. The drugs’ action frees up the immune system to better recognize and attack cancer.

Researchers embarked on this com­bination trial in the hopes that targeting two checkpoint proteins at once — PD-L1 with Imfinzi and CTLA-4 with tremelim­umab — would be effective in colorectal cancer that was not mismatch-repair defi­cient. Previous study results showed that the two agents could be combined safely.

A total of 180 patients were enrolled, with 120 getting the combination regi­men and 60 receiving best supportive care alone. After a median follow-up of 15.2 months, patients on the combina­tion treatment experienced a 28 percent or higher survival advantage. All evalu­ated subgroups — including those with RAS and BRAF gene mutation status — demonstrated superior overall survival with the duo, or doublet, regimen.

Patient-reported quality of life dropped over the course of the study, but at 12 weeks, the group receiving the drug duo was closer to meeting prespecified stan­dards than those receiving strictly best supportive care (56 percent versus 13 percent). Serious and severe symptoms occurred more often in the doublet group than in the control group. They included abdominal pain (7 percent versus 0 percent), fatigue (13 percent versus 3 percent) and lymphocytosis (23 percent versus 11 percent).

“We believe that a confirmatory phase 3 study is warranted,” Chen concluded.