IMMUNOTHERAPY FOR COLORECTAL CANCER

 A combination of two immunotherapies — durvalumab (Imfinzi, AstraZeneca) and tremelimumab (AstraZeneca) — improved survival outcomes in patients with advanced refractory colorectal cancer, according to new findings.

As compared to best supportive care, combination therapy increased overall survival by 2.5 months in this patient population.

"This is the first study demonstrating the effectiveness of immune checkpoint blockade in colorectal cancer patients unselected for mismatch repair deficiency," said lead author Eric X. Chen, MD, PhD, affiliate scientist, Princess Margaret Cancer Centre, Toronto, Canada.

Chen presented these results here at the Gastrointestinal Cancers Symposium (GICS) 2019.

He explained that, to date, treatment with immune checkpoint blockade has not demonstrated anti-tumor activity in patients with refractory colorectal cancer, except for a subgroup of patients with colorectal cancer and mismatch repair deficiency.

The current trial used a combination of durvalumab, a human monoclonal antibody that inhibits binding of programmed cell death ligand 1 (PD-L1) to its receptor, together with the investigational agent tremelimumab, a monoclonal antibody against the cytotoxic T-lymphocyte–associated protein 4 (CTLA-4). As the two immunotherapies act at different points in the checkpoint cascade, the combination could have additive and/or synergistic activity (as has been shown in other studies with the combination of the PD-inhibitor nivolumab (Opdivo, Bristol-Myers Squibb) and the CTLA-4 inhibitor ipilimumab (Yervoy, Bristol-Myers Squibb).

Mixed Efficacy Results

The phase 2 Canadian Cancer Clinical Trials Group (CCTG) CO.26 trial compared the combination durvalumab and tremelimumab with best supportive care.

The trial involved 180 patients with advanced refractory colorectal cancer who had progressed on all standard regimens that contained fluoropyrimidine, irinotecan, and oxaliplatin (as well as treatment with an epidermal growth factor receptor [EGFR] inhibitor if the tumor was RAS wild-type). None of the patients enrolled had a known defective mismatch repair. However, subsequent testing of baseline blood (with molecular testing for circulating tumor DNA) revealed that one patient in each group had microsatellite instability-high/mismatch repair-deficient tumors.

Patients were randomly assigned to receive 1500 mg of durvalumab intravenously on day 1 of every 28-day cycle and 75 mg of tremelimumab intravenously on day 1 for the first four cycles, plus best supportive care, or best supportive care alone.

At a median follow up of 15.2 months, overall survival was superior in the group receiving combination therapy: 6.6 months vs 4.1 months with supportive care alone (hazard ratio [HR], 0.72; P = .07).

However, there was no significant difference between study groups for progression-free survival (1.8 months vs. 1.9 months; HR, 1.01; P = .97).

A total of 103 patients receiving combination therapy and 46 in the control group were evaluable for response. In the combination therapy group, one patient (1%) achieved a partial response and 26 (25.2%) had stable disease, while among controls, four patients (8.7%) achieved stable disease. There were no complete responses in either groupIn the intent to treat population, the disease control rate for the combination therapy group was 22.7% vs 6.6% for controls (P = .006).

No new safety signals were observed with durvalumab and tremelimumab. Not surprisingly, the rates of grade 3 and 4 adverse events were higher in the combination therapy group (P < .01) and included abdominal pain (7% vs 0%), fatigue (13% vs 3%), and lymphocytosis (23% vs 11%).

However, Chen noted that the quality of life was not adversely affected by treatment.

"We believe that a confirmatory phase 3 study is warranted," Chen said. "Correlative studies are ongoing and we hope to present these results at future ASCO meetings."

Who Will Derive a Benefit?

In a discussion of the paper, Michael J. Overman, MD, professor of gastrointestinal medical oncology at The University of Texas MD Anderson Cancer Center in Houston, noted that one of the most critical aspects of the study was the microsatellite status.

"I congratulate the authors for using a very novel approach to get this answer," Overman said. "Using circulating DNA to evaluate for microsatellite status is an excellent approach."

He emphasized the importance of obtaining microsatellite status in all clinical trials. "It's extremely hard to interpret low-level activity without having knowledge in regard to microsatellite status on patients in immune-oncology gastrointestinal oncology trials," he said. "But clearly the vast majority of patients [in this trial] were microsatellite stable, and that's what this study was focused on."

Overman noted that while this was a positive trial, there are some caveats, one being that it was not blinded and non-placebo controlled. There was also discordance in the efficacy results.

"Before these data are incorporated into any clinical practice, we clearly need confirmation before we can have confidence in these findings," Overman summarized.

Another question that needs to be addressed, Overman noted, is whether there is a subset of microsatellite-stable colorectal cancer patients that can benefit from immunotherapy.  "While this study clearly has a small hint of activity, the key question for us is what group will clearly gain a more substantial benefit," he added.

The study was funded by AstraZeneca. Chen disclosed relationships with AstraZeneca, Merck, Bristol-Myers Squibb, Novartis, Boston Biomedical, Seattle Genetics, Taiho, Eisai, Reistone, and PMRI. Overman disclosed support from Bristol-Myers Squibb, MedImmune, Merck, and Roche, and relationships with BMS, Gritstone Oncology, MedImmune, and Roche/Genentech.

Gastrointestinal Cancers Symposium (GCIS) 2019: Abstract 481. Presented January 19, 2019.