mFOLFOX/Bevacizumab/Atezolizumab Improves PFS in dMMR/MSI-H Colorectal Cancer

Findings from the phase 3 COMMIT study (NRG-GI004/SWOG-S1610; NCT02997228) demonstrate that the addition of mFOLFOX6 (oxaliplatin, leucovorin, 5-fluorouracil) and bevacizumab (Avastin) to atezolizumab (Tecentriq) significantly improves progression-free survival (PFS) compared with atezolizumab monotherapy in patients with previously untreated mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC).¹

Data from the study, presented at the 2026 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, showed that the combination regimen achieved a median PFS of 24.5 months (95% CI, 10.1–not estimable), a substantial increase over the 5.3 months (range, 2.2–18.2) observed in the monotherapy arm (HR, 0.439; 95% CI, 0.23–0.84; P =.0103). These results suggest that intensified first-line therapy may address the needs of a patient subset that experiences early progression on single-agent immune checkpoint inhibitors (ICIs).

Clinical Rationale and Trial Design

While ICIs have revolutionized the management of dMMR/MSI-H mCRC, data from the pivotal KEYNOTE-177 trial (NCT02563002) indicated that approximately 40% of patients experience primary resistance or early disease progression within 12 months of initiating pembrolizumab (Keytruda) monotherapy.² The COMMIT trial sought to overcome this limitation by leveraging the synergistic potential of chemotherapy, anti-VEGF therapy, and PD-L1 inhibition.¹

The multicenter trial randomized 102 patients from November 2017 to March 2025 to receive either atezolizumab monotherapy at 840 mg intravenously every 2 weeks or the combination arm consisting of mFOLFOX6, bevacizumab (5 mg/kg), and atezolizumab. The study was amended in 2020 to remove a chemotherapy-only arm following the establishment of ICI as the standard of care in this setting.

Efficacy and Response Depth

The primary end point of PFS crossed the prespecified O’Brien-Flemming monitoring boundary of 0.0152. Beyond the survival benefit, the combination arm demonstrated superior depth of response. The complete response (CR) rate was 36.1% for the combination therapy compared with 18.9% for monotherapy. Crucially, the rate of primary progressive disease (PD) was only 2.8% in the combination arm, whereas 32.4% of patients in the atezolizumab monotherapy arm experienced PD.

Subgroup analyses further supported the intensified approach, particularly in patients with BRAF V600E mutations (HR, 0.23; 95% CI, 0.06–0.88; P =.33) and those with right-sided primary tumors (HR, 0.39; 95% CI, 0.19–0.82).

Safety and Tolerability Profile

The enhanced efficacy of the triplet combination was accompanied by a higher incidence of treatment-related toxicities. Grade 3 to 4 adverse events (AEs) occurred in 73.2% of the combination group vs 41.5% in the monotherapy group. These included neutropenia (26.8% in the combination arm vs 0% in the monotherapy arm), infection (26.8% vs 12.2%), hypertension (19.5% vs 2.4%), and diarrhea (12.2% vs 0%).

Five grade 5 AEs were recorded. In the monotherapy arm, 1 death was attributed to disease progression. In the combination arm, 4 deaths occurred: 1 due to disease progression, 2 sudden deaths (following cycles 16 and 18), and 1 hepatic hemorrhage following a major resection where bevacizumab and oxaliplatin had been previously discontinued.

Looking ahead, “future efforts are needed to characterize the subset of [dMMR/MSI-H] CRC that require intensification of therapy beyond single-agent PD-1/PD-L1 therapy,” said Caio Max Sao Pedro Rocha Lima, MD, MS, medical oncologist-hematologist at Atrium Health Wake Forest Baptist, during the presentation.

“Ongoing correlative analyses will hopefully provide deeper mechanistic interpretation of the differential outcomes across treatment arms,” Rocha Lima concluded.

DISCLOSURES: Rocha Lima declared research funding from Amgen and Amgen Astellas BioPharma.

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. J Clin Oncol. 44, 2026 (suppl 2; abstr 14). doi:10.1200/JCO.2026.44.2_suppl.14

2. André T, Shiu KK, Kim TW, et al. Pembrolizumab in microsatellite-instability-high advanced colorectal cancer. N Engl J Med. 2020 Dec 3;383(23):2207-2218. doi: 10.1056/NEJMoa2017699. PMID: 33264544.