Durvalumab plus Tremelimumab Immunotherapy Combination Extends Survival in Refractory Colorectal Cancer

June 2019, Vol 10, No 3

San Francisco, CA—The combination of the PD-1 inhibitor durvalumab ­(Imfinzi) and the investigational CTLA-4 inhibitor tremelimumab plus best supportive care improved overall survival (OS) by more than 2 months versus best supportive care alone in a phase 2 clinical trial of patients with refractory colorectal cancer (CRC), reported Eric Xueyu Chen, MD, PhD, Staff Oncologist, Princess Margaret Cancer Centre, Toronto, Canada, at the 2019 Gastrointestinal Cancers Symposium.

In the Canadian Cancer Trials Group (CCTG) CO.26 clinical trial, patients with advanced CRC refractory to all available therapy had a median OS of 6.6 months with durvalumab plus tremelimumab versus 4.1 months with best supportive care alone, at a median follow-up of 15.2 months (hazard ratio [HR], 0.72; 90% confidence interval, 0.54-0.97; P = .07).

“CCTG study is the first study dem­onstrating the effectiveness of immune checkpoint blockade in colorectal cancer patients unselected for mismatch repair deficiency,” said Dr Chen. “We believe that a confirmatory phase 3 study is warranted.”

The study included 180 patients who were not selected by microsatellite instability (MSI) status. Cell-free DNA analysis identified only 2 patients (1 in each arm) with MSI-high/mismatch repair deficiency CRC. Subgroup analysis of patients with microsatellite-stable disease confirmed the OS benefit of durvalumab and tremelimumab (HR, 0.66; P = .24). Survival favored dur­valumab plus tremelimumab in all other subgroups examined, including by primary tumor location and BRAF and RAS (KRAS, NRAS) status.

All patients eligible for the study, which was conducted at 27 centers across Canada, had advanced CRC that did not respond to standard regimens that included a fluoropyrimidine, irinotecan, oxaliplatin, and an EGFR inhibitor (if RAS wild-type). Previous therapy with a PD-1, PD-L1, or a CTLA-4 inhibitor was not allowed. Patients were randomized in a 2:1 ratio to 4 cycles of durvalu­mab 1500 mg plus tremelimumab 75 mg on day 1 of each cycle plus best supportive care or to best supportive care alone.

All patients received at least 1 previous systemic therapy; ≥75% of patients in each arm had received VEGF-targeting therapy, and >60% of the patients in each arm had received radiotherapy. All patients with RAS wild-type CRC in the doublet immunotherapy arm and 83% in the best supportive care–only arm received previous treatment with cetuximab or panitumumab.

The median progression-free survival (PFS) was similar between the 2 arms—1.8 months in the active treatment arm and 1.9 months in the control arm, which Dr Chen said was similar to results from other studies in similar patient populations.

Although only 1 patient achieved an objective response, the disease control rate was significantly superior with the immunotherapy combination than with best supportive care alone (22.6% vs 6.6%, respectively; P = .006).

No new adverse events emerged in this study. Grade 3 or 4 events were significantly higher with the active treatment versus best supportive care, including abdominal pain (7% vs 0%, respectively), fatigue (13% vs 3%), and lymphocytosis (23% vs 11%).

The proportion of patients reporting deterioration in physical function or in global health status was not significantly different between the 2 arms at 8 and 16 weeks.

The discordance between OS and PFS observed in this study has occurred in other clinical trials, according to ­Michael J. Overman, MD, Professor, Gas­trointestinal Medical Oncology, M.D. Anderson Cancer Center, Houston, who discussed the results. Large, double-blind, placebo-controlled trials are required to have confidence in results from clinical trials with discrepant end points, he said.

Dr Overman noted that the combination is probably not ready to move forward to a phase 3 study. “For confirmation, I would like to see another study in the same vein to be certain that we’re seeing an effect,” he said.

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