A new chemotherapy combination is showing significant promise in the treatment of metastatic colorectal cancer (mCRC) with specific genetic characteristics. The regimen, comprising FOLFOX chemotherapy, bevacizumab and atezolizumab, has demonstrated a substantial improvement in progression-free survival (PFS) compared to atezolizumab monotherapy in patients with deficient mismatch repair (dMMR) or microsatellite instability-high (MSI-H) mCRC, according to results presented at the 2026 ASCO Gastrointestinal Cancers Symposium.
The phase 3 COMMIT trial, as detailed at the symposium, showed a median PFS of 24.5 months for patients receiving the combination therapy, a dramatic increase from the 5.3 months observed in those treated with atezolizumab alone. This translates to a hazard ratio of 0.439 (95% confidence interval: 0.23–0.84; P = .0103), indicating a substantial reduction in the risk of disease progression. Dr. Caio Max Sao Pedro Rocha Lima, of Atrium Health Wake Forest Baptist Cancer Center, described the findings as potentially “a game changer” for first-line treatment of this patient population.
Approximately 4% to 7% of mCRCs exhibit dMMR or MSI-H abnormalities, making this a relatively specific, though impactful, area of cancer treatment. Nearly one in four colorectal cancers are metastatic, and these advanced cases present a significant clinical challenge, with a 5-year relative survival rate of around 16%. The current standard of care for this subset of patients is often immunotherapy with single-agent pembrolizumab, a PD-1 inhibitor. However, trials, such as KEYNOTE-177, have shown that nearly half of patients treated with pembrolizumab alone experience disease progression within 12 months, highlighting the need for more effective strategies.
The rationale for combining chemotherapy, bevacizumab, and atezolizumab stems from preclinical studies demonstrating synergistic tumor growth inhibition with PD-L1 inhibition plus oxaliplatin. Further support comes from the ATOMIC trial, which showed that combining FOLFOX and atezolizumab significantly improved 3-year disease-free survival in stage III dMMR/MSI-H colorectal cancer patients compared to chemotherapy alone (86.4% vs 76.6%, HR = 0.50; P < .0001). The combination of anti-VEGF agents, checkpoint inhibitors, and chemotherapy has also demonstrated synergistic activity in preclinical models by promoting vascular normalization and enhancing immune cell infiltration.
The COMMIT trial’s design evolved during its course. Initially planned as a three-arm study, it was amended after the publication of the KEYNOTE-177 results, leading to the closure of the FOLFOX and bevacizumab arm after 20 patients were enrolled. Enrollment was ultimately suspended on March 31, 2025, after 82 patients were randomized into the remaining two arms, due to the results of the CheckMate 8HW trial. A preplanned interim analysis in July 2025 led to the permanent closure of the study to further accrual. The final analysis included 41 patients in each of the two remaining arms.
Beyond PFS, the combination therapy also demonstrated a significantly higher overall response rate of 86.1% compared to 46.0% with atezolizumab monotherapy. Complete responses were observed in 36.1% of patients receiving the combination, versus 18.9% in the monotherapy arm. The disease control rate at 12 months was also markedly improved, reaching 64.7% with the combination compared to 32.4% with atezolizumab alone.
While the initial results are promising, overall survival data currently show no statistically significant difference between the two treatment arms (HR = 1.04, 95% CI = 0.47–2.28; P = .90). The 24-month overall survival rate was 67% in both groups, though investigators noted that the number of events remains limited, requiring further follow-up.
The combination therapy was associated with a higher incidence of grade 3 to 5 adverse events, occurring in 82.9% of patients compared to 43.9% in the atezolizumab monotherapy group. Common adverse events in the combination arm included neutropenia (26.8%), infection (26.8%), and hypertension (19.5%). There were five grade 5 adverse events reported in the study, including one death in the atezolizumab arm due to disease progression. In the combination arm, one death was attributed to disease progression, two were sudden deaths after prolonged treatment, and one was due to fatal hepatic hemorrhage following liver surgery.
Researchers are planning further correlative biomarker analyses to identify patient subgroups most likely to benefit from the FOLFOX, bevacizumab, and atezolizumab combination. These analyses will focus on tumor and immune microenvironment features, circulating biomarkers, and molecular correlates of response and resistance, with the goal of refining patient selection for future prospective trials.
Dr. Eric Scott Christenson, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medicine, who served as a discussant for the COMMIT trial, acknowledged the improvement in PFS but cautioned that an overall survival benefit had not yet been demonstrated and that toxicity was a concern. He suggested that the regimen may be most appropriate for a select group of patients and raised the question of whether atezolizumab is the optimal frontline treatment in this space, particularly when compared to the combination of nivolumab and ipilimumab, which demonstrated a median PFS not reached at 47 months in the CheckMate 8HW trial.
Dr. Christenson highlighted the differing plateaus observed in the monotherapy arms of the two trials, with atezolizumab showing a more rapid decline than nivolumab. He emphasized the need for overall survival data to definitively determine the preferred regimen, noting that ambiguous dMMR findings and potential misclassifications could be influencing the results. He concluded that, for fit patients with dMMR metastatic colorectal cancer, ipilimumab/nivolumab remains his first-line choice, citing the lack of overall survival benefit and the increased toxicity associated with atezolizumab plus FOLFOX/bevacizumab.
DISCLOSURE: Dr. Rocha Lima reported no relevant personal financial disclosures. Dr. Christenson reported relationships with Boston Scientific, Parabilis, Roche, Seres Therapeutics, Sirtex, TATUM Bioscience, UroGen, and NextCure.
REFERENCES
1. Rocha Lima CMS, Yothers G, George TJ, et al. Colorectal Cancer Metastatic dMMR Immunotherapy (COMMIT) study: A randomized phase III study of atezolizumab (atezo) monotherapy versus mFOLFOX6/bevacizumab/atezo (FFX/bev) in the first-line treatment of patients (pts) with deficient DNA mismatch repair (dMMR) or microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC)— NRG-GI004/SWOG-S1610. 2026 ASCO Gastrointestinal Cancers Symposium. Abstract 14. Presented January 10, 2026.
2. André T, Shiu KK, Kim TW, et al. Pembrolizumab in microsatellite-instability-high advanced colorectal cancer. N Engl J Med. 383(23):2207-2218, 2020.
3. Sinicrope FA, Ou F-S, Arnold D, et al. Randomized trial of standard chemotherapy alone or combined with atezolizumab as adjuvant therapy for patients with stage III deficient DNA mismatch repair colon cancer (Alliance A021502; ATOMIC). 2025 ASCO Annual Meeting. Abstract LBA1. Presented June 1, 2025.
4. André T, Elez E, Lenz HJ, et al. Nivolumab plus ipilimumab versus nivolumab in microsatellite instability-high metastatic colorectal cancer (CheckMate 8HW): a randomised, open-label, phase 3 trial. Lancet. 405:383-395, 2025.
