Atezolizumab Plus Chemotherapy Improves PFS in dMMR/MSI-H Metastatic CRC

Adding chemotherapy and bevacizumab (Avastin) to atezolizumab (Tecentriq) reduced the risk of disease progression or death by 58% compared with atezolizumab alone in patients with previously untreated deficient DNA mismatch repair (dMMR) or microsatellite instability-high (MSI-H) metastatic colorectal cancer (CRC), according to results from the phase 3 NRG-GI004/SWOG S1610 COMMIT trial (NCT02997228) published in the Journal of Clinical Oncology and a news release from NRG Oncology.^1,2 The combination also produced higher response rates and markedly reduced the rate of primary disease progression.

“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,” stated Caio Max Sao Pedro Rocha Lima, MD, of Wake Forest University School of Medicine and principal investigator of the COMMIT trial, in the press release.¹ “The study showed not only longer progression-free survival [PFS], but also a dramatic reduction in the number of patients whose disease progressed as their best response to treatment.”

What were the efficacy results of the COMMIT trial?

The combination of chemotherapy (modified FOLFOX6; mFOLFOX6 [leucovorin, fluorouracil, and oxaliplatin]), bevacizumab, and atezolizumab improved PFS vs atezolizumab alone (HR, 0.42; 95% CI, 0.22-0.80; P = .0068), a 58% reduction in the risk of progression or death. The median PFS was 24.5 months (95% CI, 10.1-not estimable) with the combination vs 5.3 months (95% CI, 2.2-18.2) with atezolizumab monotherapy. The 12- and 24-month PFS rates were 66.7% and 53.7% with the combination compared with 35.1% and 31.6% with monotherapy.

A sensitivity analysis controlling for BRAF mutation, liver metastasis, prior chemotherapy, ECOG performance status, primary tumor sidedness, race, sex, and age, sum of baseline tumor diameters, and log was performed and achieved consistent findings with these findings.

The objective response rate (ORR) was 86.1% with the combination vs 46.0% with atezolizumab alone, including complete response rates of 36.1% and 18.9%, respectively. In the combination and monotherapy arms, respectively, complete responses were achieved by 36.1% and 18.9%, and partial responses by 50.0% and 27.0%. Disease progression as best response occurred in 2.8% of patients on the combination compared with 32.4% on monotherapy. The 12-month disease control rate was 64.7% vs 32.4% (P = .009), respectively. No difference in overall survival (OS) was observed between arms (HR, 1.04; 95% CI, 0.47-2.28; P = .90), though the trial was not powered for this end point.

What is the COMMIT trial design?

COMMIT enrolled adults 18 years and older with histologically or cytologically confirmed metastatic CRC and locally assessed dMMR status by immunohistochemistry or MSI-H status by polymerase chain reaction-based testing or next-generation sequencing testing. They also had measurable disease per RECIST v1.1, an ECOG performance status of 0 to 2, and normal organ functions. Patients could not have received prior chemotherapy for metastatic CRC. However, on April 14, 2023, an amendment was activated to allow patients who received 1 cycle of FOLFOX or CAPOX (capecitabine and oxaliplatin) chemotherapy.

Patients were initially randomly assigned 1:1:1 to receive first-line therapy of mFOLFOX6 plus bevacizumab, mFOLFOX6 plus bevacizumab and atezolizumab, or atezolizumab monotherapy, stratified by BRAF V600E status, site of metastases, and prior adjuvant chemotherapy. Atezolizumab was administered intravenously at 840 mg twice weekly.

The mFOLFOX6/bevacizumab-alone arm was closed after 20 patients enrolled following results from the phase 3 KEYNOTE-177 trial (NCT02563002), which demonstrated that pembrolizumab (Keytruda) achieved superior PFS vs chemotherapy. The trial was amended to enroll patients 1:1 between atezolizumab alone and the atezolizumab combination arm; 82 patients were ultimately randomly assigned between these 2 arms before accrual was suspended because of slow enrollment. The primary end point was PFS by intention to treat; secondary end points included ORR, OS, toxicity, 12-month PFS, disease control rate, and duration of response.

What safety findings were reported?

Adverse events (AEs) were more frequent and severe with the combination regimen. Grade 3 or higher AEs of any attribution occurred in 82.9% of patients on the combination vs 43.9% with atezolizumab alone. The most common grade 3 or 4 toxicities were neutropenia (26.8% vs 0%), hypertension (19.5% vs 2.4%), and sepsis (9.7% vs 0%), which were higher with the combination. Immune-related AEs were uncommon and similar between arms. There were 5 grade 5 AEs overall: 1 in the atezolizumab-alone arm because of disease progression, and 4 in the combination arm, including 2 sudden deaths and 1 case of hepatic hemorrhage following an extended hepatectomy.

“Clinical trials like COMMIT are essential to advancing treatment for patients with colorectal cancer,” stated Michael Overman, MD, of The University of Texas MD Anderson Cancer Center and co-principal investigator of the trial, in the press release.¹ “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.”

References

1. Combination immunotherapy and chemotherapy improves progression-free survival for patients with metastatic dMMR colorectal cancer. News release. NRG Oncology. July 29, 2026. Accessed July 30, 2026. https://tinyurl.com/ns3p3kkw
2. Rocha Lima CMSP, Yothers G, George TJ, et al. COMMIT: a randomized study of mFOLFOX6/bevacizumab/atezolizumab or atezolizumab alone as first-line treatment of deficient DNA mismatch repair metastatic colorectal cancer. J Clin Oncol. Published online July 29, 2026. doi:10.1200/JCO-25-03052