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Durvalumab and Tremelimumab Combination Active in Refractory Microsatellite-Stable Colorectal Cancer


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THE COMBINATION of durvalumab and tremelimumab prolonged median overall survival by 2.5 months compared with best supportive care alone in patients with advanced treatment-refractory colorectal cancer. These findings, which are from the randomized phase II Canadian Cancer Trials Group (CCTG) CO.26 study, were presented at the 2019 Gastrointestinal Cancers Symposium.1

“The CCTG study is the first study demonstrating the effectiveness of immune checkpoint blockade in patients with colorectal cancer unselected for mismatch-repair deficiency,” said Eric X. Chen, MD, PhD, of Princess Margaret Cancer Centre, Toronto.


“The CCTG study is the first study demonstrating the effectiveness of immune checkpoint blockade in patients with colorectal cancer unselected for mismatch-repair deficiency.”
— Eric X. Chen, MD, PhD

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The addition of the immune checkpoint doublet to best supportive care produced a median overall survival of 6.6 months compared with 4.1 months with supportive care alone (hazard ratio [HR] = 0.72; P = .07), but the median progression-free survival was not significantly different (1.8 months vs 1.9 months; P = .97), Dr. Chen reported.

The findings suggest that the benefit of immune checkpoint blockade therapy may not be limited to patients with colorectal cancer with mismatch-repair deficiency (dMMR). The researchers had hypothesized that targeting both the programmed cell death ligand 1 (PD-L1) with durvalumab and the cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) with tremelimumab would have additive and/or synergistic activity, based on nonredundancy of their mechanisms of action, and there is evidence that the combination can be safely combined, he said.

The study enrolled 180 patients with advanced refractory colorectal cancer. They were randomly assigned 2:1 to durvalumab plus tremelimumab with best supportive care or best supportive care alone. Patients treated with the doublet received 1,500 mg of durvalumab on day 1 of every 28-day cycle and 75 mg of tremelimumab on day 1 for the first 4 cycles. Overall survival was the primary endpoint.

A 28% Reduction in Risk

AFTER A median follow-up of 15.2 months, the unstratified hazard ratio for overall survival was 0.72 in favor of durvalumab and tremelimumab (P = .07; a two-sided P value < .10 was considered statistically significant for this analysis). The unadjusted hazard ratio was 0.70 (P = .03), also favoring active treatment, Dr. Chen reported.

The benefit in improving survival was seen across all subgroups, including primary tumor locations and BRAF and RAS (KRAS, NRAS) status, and in patients with microsatellite-stable tumors (HR = 0.55; P = .024). One patient in each arm was found on gene-sequencing analysis to have a dMMR/microsatellite instability–high tumor.

Of the 103 patients evaluable for response in the active treatment arm, one patient responded (1%) and 26 (22%) achieved stable disease. In the 46 evaluable patients in the best supportive care arm, 4 (7%) had stable disease. In the intent-to-treat analysis, the disease control rate was superior with the doublet (odds ratio = 4.16; P =.006), and this remained true when the analysis was restricted to patients with evaluable disease.

Quality of Life

THE PROPORTION of patients reporting deterioration in physical function or deterioration in global health status was not significantly different between the 2 arms at 8 or 16 weeks. Compliance with the prespecified quality-of-life surveys was relatively poor, he added.

Grade 3 or 4 adverse events were higher in the doublet arm than the control arm, including abdominal pain (7% vs 0%), fatigue (13% vs 3%), and lymphocytosis (23% vs 11%).

Dr. Chen said the encouraging findings of this study warrant further evaluation in a phase III confirmatory trial. He added that correlative studies, including those centering on mutational tumor burden and outcome, are underway.

DISCLOSURE: Dr. Chen has received honoraria from Taiho Pharmaceutical and research funding from AstraZeneca, Boston Biomedical, Bristol-Myers Squibb, and Merck.

REFERENCE

1. Chen EX, Jonker DJ, Kennecke HF, et al: CCTG CO.26 trial: A phase II randomized study of durvalumab plus tremelimumab and best supportive care (BSC) versus BSC alone in patients with advanced refractory colorectal carcinoma. 2019 Gastrointestinal Cancers Symposium. Abstract 481. Presented January 19, 2019.


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