The combination of durvalumab and tremelimumab yielded improved survival over best supportive care in patients with advanced refractory colorectal carcinoma, according to a new phase II trial. This was among the first trials showing that an immunotherapy combination can benefit a population that was unselected for microsatellite instability.
“At the time of initiation of our study, immune checkpoint blockade has not shown activity in refractory colorectal cancer other than [in] those with mismatch repair deficiency,” said Eric X. Chen, MD, PhD, of the University of Toronto. Chen presented results of the Canadian Cancer Trials Group CO.26 trial at the American Society of Clinical Oncology (ASCO) 2019 Gastrointestinal Cancers Symposium, held January 17–19 in San Francisco (Abstract 481).
A previous phase Ib study suggested the combination of durvalumab and tremelimumab could be combined safely. The CO.26 trial included 180 patients with advanced colorectal carcinoma that was refractory to all available therapy; they were randomized to the immunotherapy combination (D+T) along with best supportive care (BSC), or to BSC alone. Patients were excluded if they had received prior immune checkpoint blockade therapy.
Most patients in both groups had an ECOG performance status score of 1 (72%), and patients had a median age of 65 years in the D+T group and 64 years in the BSC group. Most patients were men (62% and 77%), and most were white (82% and 89%). As required by the study design, it was a heavily pretreated population. Most patients had microsatellite-stable/proficient mismatch-repair disease (98% and 80%).
The median overall survival was 6.6 months with the immunotherapy combination and 4.1 months with BSC, for a stratified hazard ratio (HR) of 0.72 (95% CI, 0.54–0.97; P = .07); this met the prespecified threshold for significance. The median progression-free survival was no different between the groups, at 1.8 months with D+T and 1.9 months with BSC, for an HR of 1.01 (95% CI, 0.76–1.34; P = .97). Subgroup analyses showed trends toward benefit with D+T in all groups.
Responses were rare, but most patients in the D+T group had stable disease, yielding an odds ratio for the disease control rate in favor of immunotherapy of 4.16 (95% CI, 1.40–12.3; P = .006). Though the comparisons were not significant, there were numerical advantages with D+T in quality of life based on the EORTC QLQ-30 questionnaire, specifically with regard to deterioration in physical function and in global health status.
More adverse events were seen with the study drugs than with BSC, but Chen said that no new safety signals emerged. In the D+T group, 64% had an adverse event of grade 3 or higher, compared with 20% in the BSC group.
“This is the first study demonstrating immune checkpoint blockade effectiveness in colorectal cancer patients unselected for mismatch repair deficiency,” Chen said. “We believe a confirmatory phase III study is warranted.”
Michael J. Overman, MD, of the University of Texas MD Anderson Cancer Center in Houston, was the discussant for the study. “This is a positive trial, but I think there are a lot of caveats to that,” he said. He noted that it was not blinded and not placebo controlled, and its statistical design yields a higher possibility of a false-positive result. It is also concerning when efficacy results are discordant, meaning the overall survival was positive but progression-free survival was not. “Before these data are incorporated into any clinical practice, we clearly need confirmation,” he said.