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Immunotherapy Combination Extends Survival in Advanced Refractory Colorectal Cancer

TOP - May 2019, Vol 12, No 2
The addition of the PD-1 inhibitor durvalumab (Imfinzi) and the CTLA-4 inhibitor tremelimu­mab to best supportive care improved overall survival (OS) by >2 months compared with best supportive care alone in patients with advanced refractory colorectal cancer (CRC), according to results of the phase 2 Canadian Cancer Trials Group (CCTG) CO.26 clinical trial.

At a median follow-up of 15.2 months, patients with advanced CRC who were refractory to all available treatments had an improvement in median OS of 2.5 months with randomization to durvalumab plus treme­limumab, reported Eric X. Chen, MD, PhD, Affiliate Scientist, Department of Medical Oncology and Hematology, Cancer Clinical Research Unit, Princess Margaret Cancer Centre, Toronto, at the 2019 ASCO Gastrointestinal Cancers Symposium. Median OS was 6.6 months for those in the immunotherapy plus best supportive care arm versus 4.1 months in the best supportive care only arm.

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

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

Study Details

The CCTG CO.26 trial, which was conducted at 27 centers across Canada, enrolled 180 patients 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. All patients had ≥1 previous systemic therapies, ≥75% in each arm had previous VEGF-targeting therapy, and >60% in each arm had previous radiotherapy. All patients with RAS wild-type CRC in the dual immunotherapy arm and 83% in the best supportive care only arm had previous treatment with cetuximab (Erbitux) or panitumumab (Vectibix). 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. The study investigators did not use microsatellite instability status as a selection criterion. Cell-free DNA analysis identified only 2 patients (1 in each arm) with microsatellite instability-­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 (eg, KRAS or NRAS) mutation status. Differences in progression-free survival were small—1.8 months in the active treatment arm versus 1.9 months in the control arm, which Dr Chen noted was comparable to results from other studies in similar patient populations.

Although only 1 patient achieved an objective response—a partial response in the dual-therapy arm—when including stable disease, the disease control rate was significantly superior with combination immunotherapy than with best supportive care alone (22.7% vs 6.6%; P = .006).

No new safety signals emerged with combination immunotherapy. The rates of grade 3 or 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 alone.

As part of quality-of-life assessments, the proportion of patients in the immunotherapy treatment arm reported significantly less deterioration in physical function or in global health status at 16 weeks.

Potential Implications

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

Dr Overman added that the combination immunotherapy is probably not ready to move 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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