Immunotherapy Doublet Extends Survival in Refractory Colorectal Cancer

August 2019 Vol 10, No 8


Colorectal Cancer

The combination of the PD-1 inhibitor durvalumab and the CTLA-4 inhibitor tremelimumab added to best supportive care improved overall survival (OS) by >2 months compared with best supportive care alone in a phase 2 randomized trial of unselected patients with refractory colorectal cancer (CRC).

In the Canadian Cancer Trials Group (CCTG) CO.26 trial, with a median follow-up of 15.2 months, patients with advanced CRC that was refractory to all available therapy had an improvement in median OS of 2.5 months with randomization to durvalumab plus tremelimumab, reported Eric Xueyu Chen, MD, PhD, Staff Oncologist, Princess Margaret Cancer Centre, Toronto, Canada, at the 2019 Gastrointestinal Cancers Symposium. Median OS was 6.6 months for patients in the immunotherapy plus best supportive care arm versus 4.1 months in the arm randomized to best supportive care only.

The unstratified hazard ratio (HR) for OS was 0.72 (90% CI, 0.54-0.97; P = .07) in favor of durvalumab plus tremelimumab, which met the threshold for statistical significance, which was at a 2-sided P value <.10. The unadjusted HR for OS was 0.70 (P = .03), which also favored active treatment.

“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 180-patient study did not use microsatellite instability (MSI) status as a selection criterion. 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 benefit of durvalumab and treme­limumab on OS (HR, 0.66; P = .24). OS favored durvalumab plus tremelimumab in all other subgroups examined, including those by primary tumor location and BRAF and RAS (KRAS, NRAS) status.

Patients eligible for the CCTG CO.26 trial, which was conducted at 27 centers across Canada, were those with advanced CRC in whom all standard regimens, including those containing a fluoropyrimidine, irinotecan, oxaliplatin, and an EGFR inhibitor (if RAS wild type) had failed. Previous therapy with PD-1/PD-L1 or CTLA-4 inhibitors was not allowed. Patients were randomized in a 2:1 ratio to receive 4 cycles of durvalumab 1500 mg and tremelimumab 75 mg on day 1 of each cycle in addition to best supportive care or to best supportive care alone.

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

Median progression-free survival (PFS) was not different between 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, a partial response in the doublet arm, when including stable disease, the disease control rate was significantly superior with combination immunotherapy than with best supportive care alone (22.6% vs 6.6%, respectively; P = .006).

No new safety signals emerged with combination immunotherapy. The rates of grade 3/4 abdominal pain (7% vs 0%), fatigue (13% vs 3%), and lymphocytosis (23% vs 11%) were all significantly higher with active treatment compared with best supportive care.

As part of quality-of-life assessments, the proportion of patients reporting deterioration in physical function or in global health status was not significantly different between the 2 arms at 8 or 16 weeks.

The discordance between OS and PFS observed in CCTG CO.26 has occurred in other clinical trials, noted discussant Michael J. Overman, MD, Professor, Gastrointestinal Medical Oncology, MD Anderson Cancer Center, Houston, TX. Large, double-blind, placebo-controlled trials are required to have confidence in results from trials with discrepant end points, he said.

Dr Overman added that the combination is probably not ready to take forward to a phase 3 trial at this juncture. “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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Last modified: November 15, 2022

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