The combination of mFOLFOX6, bevacizumab, and atezolizumab prolonged progression-free survival over atezolizumab monotherapy in the first-line setting for patients with mismatch repair–deficient/microsatellite instability–high (dMMR/MSI-H) metastatic colorectal cancer, according to findings from the phase III NRG-GI004/SWOG S1610 COMMIT trial published in the Journal of Clinical Oncology.
“These findings demonstrate that combining chemotherapy and bevacizumab with immunotherapy may provide a meaningful clinical benefit for patients with dMMR/MSI-H metastatic colorectal cancer,” said principal investigator of the COMMIT trial Caio Max Sao Pedro Rocha Lima, MD, of Wake Forest University School of Medicine. “The study showed not only longer progression-free survival, but also a dramatic reduction in the number of patients whose disease progressed as their best response to treatment. These results may help inform future treatment strategies for this patient population.”
Study Methods
The three-arm, prospective, open-label phase III trial randomly assigned patients with dMMR/MSI-H metastatic colorectal cancer to receive either mFOLFOX6 with bevacizumab; atezolizumab monotherapy; or mFOLFOX6, bevacizumab, and atezolizumab in a 1:1:1 ratio.
Based on results from the KEYNOTE-177 trial, the mFOLFOX6 and bevacizumab arm was closed after 20 patients were enrolled, and the remaining arms continued with a revised sample size of 100 patients.
The primary endpoint was progression-free survival in the intent-to-treat population.
Key Findings
At a median follow-up of 46 months, the median progression-free survival in the triplet arm was 24.5 months (95% confidence interval [CI] = 10.1 to not estimable) compared with 5.3 months (95% CI = 2.2–18.2) for the monotherapy arm (hazard ratio [HR] = 0.42; 95% CI = 0.22–0.80; P = .0068). At 12 months, the progression-free rates were 66.7% and 35.1% for the combination and monotherapy arms, respectively, and 24 months, the rates were 53.7% and 31.6%.
The objective response rate was 86.1% with mFOLFOX6, bevacizumab, and atezolizumab compared with 46% with atezolizumab monotherapy and the disease control rates at 12 months were 64.7% and 32.4%, respectively.
Grade 3 or higher adverse events were observed more frequently in the combination arm (34 vs 18 patients).
“Clinical trials like COMMIT are essential to advancing treatment for patients with colorectal cancer,” added co-principal investigator, Michael Overman, MD, of The University of Texas MD Anderson Cancer Center. “The study provides evidence supporting a combination approach in the first-line setting and underscores the importance of continued collaboration to identify therapies that offer the greatest benefit for patients.”
Takeaways
In an accompanying editorial, Lars Henrik Jensen, MD, PhD, of the University Hospital of Southern Denmark, Vejle Hospital, Vejle, noted that since the study did not compare current first-line standards, its findings cannot be considered practice-changing but rather as hypothesis-generating. “What, then, should change in clinical practice?” Dr. Jensen asked. “Very little. That is itself a useful conclusion.”
“COMMIT reflects the extraordinary pace of immuno-oncology over the past decade, and the discipline required to interpret a trial whose central question shifted beneath it. It reminds us that a trial is never only a scientific instrument; it is a commitment of patients' time, hope, and tolerance of toxicity. The strength of COMMIT lies in the transparency with which its data are reported, allowing oncologists to honor that commitment, to cure, eventually, every patient with dMMR colorectal cancer. That goal is within reach,” Dr. Jensen concluded.
DISCLOSURES: For full disclosures of the study authors, visit ascopubs.org.
