Phase III COMMIT Study Shows Promising Frontline Approach for dMMR/MSI-H Metastatic Colorectal Cancer

The phase III COMMIT trial demonstrates that intensifying first-line immunotherapy with chemotherapy and antiangiogenic therapy can substantially improve outcomes for patients with deficient mismatch repair (dMMR) or microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC). In this randomized study, the addition of fluorouracil, oxaliplatin, and leucovorin calcium (modified (m)FOLFOX6) chemotherapy and bevacizumab to the PD-L1 inhibitor atezolizumab, more than quadrupled median progression-free survival (PFS) compared with atezolizumab monotherapy, while also significantly improving response rates. These findings suggest a potential paradigm shift for a subset of patients historically treated with immune checkpoint inhibitor monotherapy.

Clinical Takeaway

In treatment-naive patients with dMMR/MSI-H metastatic colorectal cancer, first-line intensification with mFOLFOX6 chemotherapy and bevacizumab added to atezolizumab significantly improved progression-free survival and response rates compared with atezolizumab monotherapy, though it was associated with higher rates of grade ≥3 adverse events.

Drug Profile & Mechanism

• Agent:  
  • mFOLFOX6
  • bevacizumab
  • atezolizumab
• Class:
  • fluorouracil: Antimetabolite (pyrimidine analog)
  • oxaliplatin: Platinum-based alkylating-like agent
  • leucovorin calcium: Reduced folate; chemotherapy modulator
  • bevacizumab: Monoclonal antibody; vascular endothelial growth factor (VEGF) inhibitor (antiangiogenic agent)
  • atezolizumab: Immune checkpoint inhibitor; anti PD-L1 monoclonal antibody
• Mechanism of action:
  • fluorouracil: Inhibits thymidylate synthase, disrupting DNA synthesis and RNA processing
  • oxaliplatin: Forms DNA cross-links after intracellular activation, inhibiting DNA replication and transcription, leading to apoptosis; cell-cycle nonspecific
  • leucovorin calcium: Enhances fluorouracil cytotoxicity by stabilizing the fluorouracil-thymidylate synthase complex, increasing inhibition of DNA synthesis
  • bevacizumab: Binds VEGF, preventing interaction with VEGF receptors and inhibiting tumor angiogenesis
  • atezolizumab: Blocks PD-L1 interaction with PD-1 and CD80 receptors, restoring antitumor T-cell activity
• Route of administration:
  • All agents administered intravenously (IV)
• Dosing Schedule (COMMIT trial Regimen):
  • fluorouracil: Continuous IV over 46-48 hours (via portable pump) on days 1-2, every 2 weeks
  • oxaliplatin: IV infusion over 2 hours on day 1, every 2 weeks (limited number of cycles consistent with standard FOLFOX use)
  • leucovorin calcium: IV infusion over 2 hours on day 1, every 2 weeks
  • bevacizumab: IV infusion over 30-90 minutes on day 1, every 2 weeks
  • atezolizumab: IV infusion over 30-60 minutes on day 1, every 2 weeks

Target Population

• Treatment-naive patients with dMMR/MSI-H mCRC

Phase III COMMIT Trial Study Design (NCT02997228)

• Study Type: Randomized, international, phase III clinical trial
• Population: 102 patients with untreated dMMR/MSI-H mCRC
• Randomization:
  • mFOLFOX6 + bevacizumab + atezolizumab (n=41)
  • atezolizumab monotherapy (n=41)
  • Chemotherapy + bevacizumab (n=20, arm closed in 2020 following KEYNOTE-177 results)
• Follow-Up Duration:
  • Median follow-up: 3.5 years
• Estimated study completion: June 1, 2027

Endpoints

• Primary Endpoint:
  • PFS
• Key Secondary Endpoints:
  • Overall Survival (OS)
  • Objective response rate (ORR: complete + partial response)
  • Disease control rate (DCR)
  • Safety and tolerability

Efficacy Outcomes

• Primary Endpoint Results:
  • Median PFS:
    • Combination therapy: 24.5 months
    • atezolizumab alone: ~5 months
• Secondary Endpoint Results:
  • Objective Response Rate (ORR):
    • Combination therapy: 86.1%
    • atezolizumab alone: 46%
  • Disease Control Rate (1 year):
    • Combination therapy: 64.7%
    • atezolizumab alone: 32.4%
• Overall Survival:
  • OS Data immature at time of reporting
  • Median OS not yet reached
  • Hazard ratio for death is pending final analysis

Regulatory Milestones

• Approval Status: Not FDA approved for this indication
• Current Standard of Care: At present, immune checkpoint inhibitor monotherapy remains the FDA-approved first-line standard of care for patients with dMMR/MSI-H mCRC
• Regulatory Pathway: The combination of mFOLFOX6, bevacizumab, and atezolizumab is investigational and is currently supported by phase III clinical trial data from the COMMIT study
• Regulatory Review: No FDA regulatory submission has been announced to date. Additional follow-up, including overall survival outcomes and biomarker analyses is expected to inform future regulatory discussions

Safety

• Overall Safety Profile: The addition of chemotherapy and bevacizumab increased toxicity compared with atezolizumab monotherapy
• Grade ≥3 Events:
  • Combination therapy: 34 patients
  • atezolizumab: 18 patients
• Treatment-related deaths (Grade 5 events):
  • Combination therapy: 4 patients
  • atezolizumab alone: 1 patient
• Notable toxicity patterns:
  • Increased hematologic toxicity
  • Chemotherapy-associated neuropathy
  • Bevacizumab-related vascular events
  • Immune-related adverse events consistent with PD-L1 inhibition

Key Clinical Implications

✔ Demonstrates that PD-L1 monotherapy may be insufficient for a substantial subset of dMMR/MSI-H mCRC patients

✔ Establishes chemo-immunotherapy-antiangiogenic combination as a high-efficacy first-line option

✔ Confirms significant improvements in PFS and response rates compared with immunotherapy alone

✔ Highlights the need for careful patient selection given increased toxicity

✔ Supports ongoing biomarker-driven strategies to refine frontline treatment intensification

Bottom Line

The phase III COMMIT trial provides compelling evidence that adding mFOLFOX6 chemotherapy and bevacizumab to atezolizumab markedly improves disease control in treatment-naïve dMMR/MSI-H mCRC. While toxicity is increased, the magnitude of PFS and response benefit positions this “triple-punch” strategy as a potential future first-line standard of care for appropriately selected patients pending further survival and biomarker analyses.

Sources:

• American Society of Clinical Oncology. (2026, January 5). Triple-punch combo therapy slows progression of some metastatic colorectal cancers [Press release]. American Society of Clinical Oncology Gastrointestinal Cancers Symposium.
• Lima, C. M. S. P. R., et al. (2026). COMMIT: A randomized phase III trial of atezolizumab with or without mFOLFOX6 and bevacizumab as first-line therapy for dMMR/MSI-H metastatic colorectal cancer. Presented at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium, San Francisco, CA.
• National Cancer Institute. (2026). COMMIT trial (NCT02997228): A study of atezolizumab with or without chemotherapy and bevacizumab in dMMR/MSI-H metastatic colorectal cancer. ClinicalTrials.gov.
  https://clinicaltrials.gov/study/NCT02997228
• Genentech, Inc. (2026). Atezolizumab (Tecentriq®) prescribing information. https://www.gene.com