Atezolizumab Combination Therapies Show Promise in dMMR/MSI-H Colorectal Cancer
Atezolizumab combined with chemotherapy shows significant benefits in dMMR/MSI-H colorectal cancer. In stage III disease, the ATOMIC trial demonstrated improved 3-year DFS (86.3% vs 76.2%) with atezolizumab plus mFOLFOX6. For metastatic disease, the COMMIT trial showed superior PFS (24.5 vs 5.3 months) with atezolizumab, bevacizumab, and FOLFOX versus atezolizumab monotherapy.
Atezolizumab in combination with chemotherapy regimens has demonstrated significant benefits for patients with mismatch repair-deficient or microsatellite instability-high colorectal cancer across different disease stages. In the adjuvant setting for stage III disease, adding atezolizumab to mFOLFOX6 significantly improved disease-free survival, while in metastatic disease, a combination of atezolizumab, bevacizumab, and FOLFOX showed superior progression-free survival compared to atezolizumab monotherapy.
In the phase 3 ATOMIC trial, atezolizumab plus mFOLFOX6 significantly improved disease-free survival compared with mFOLFOX6 alone in patients with stage III mismatch repair-deficient colon cancer. With a median follow-up of 40.9 months, patients receiving the combination achieved a 3-year DFS rate of 86.3% compared with 76.2% for those receiving mFOLFOX6 alone, representing a hazard ratio of 0.50. The treatment effect was similar in 630 patients with central confirmation of tumor dMMR status.
An analysis stratified by duration of mFOLFOX6 treatment revealed that DFS was improved with atezolizumab for patients who received more than 6 cycles of mFOLFOX6, with a hazard ratio of 0.41. However, there was no observed advantage in the atezolizumab group when patients received 6 cycles or fewer of mFOLFOX6. The overall survival analysis, with a median follow-up of 45.8 months, showed no significant OS difference between the treatment arms, with 5-year OS rates of 89.7% in the combination group and 87.9% in the mFOLFOX6 alone group.
In the metastatic setting, the phase 3 COMMIT trial evaluated a regimen combining atezolizumab plus bevacizumab and standard chemotherapy versus atezolizumab monotherapy in previously untreated dMMR/MSI-H metastatic colorectal cancer. Median progression-free survival with the combination was 24.5 months compared with 5.3 months with atezolizumab alone, representing a hazard ratio of 0.439. The combination reduced early progression by about 10-fold and almost doubled both partial and complete response rates compared with atezolizumab monotherapy.
The progression-free survival rate at 12 months was 66.7% with the combination versus 35.1% with single-agent atezolizumab; at 24 months these rates were 53.7% and 31.6%, respectively. The overall response rate also favored the regimen of atezolizumab, bevacizumab, and FOLFOX at 86.1% compared with 46.0% with atezolizumab monotherapy, including complete responses in 36.1% versus 18.9% in the monotherapy arm. At the time of analysis, there was no difference regarding overall survival between the treatment arms.
The COMMIT trial was initially designed as a three-arm study comparing FOLFOX and bevacizumab, FOLFOX and bevacizumab plus atezolizumab, and atezolizumab alone. After the KEYNOTE-177 results were published in 2020, the study was amended and the FOLFOX and bevacizumab arm was closed. Enrollment to the COMMIT trial was suspended on March 31, 2025, after 82 patients were randomly assigned to the two comparative arms, because of the results of the CheckMate 8HW trial.
In the ATOMIC trial, grade 3 and 4 adverse events occurred in 84.1% of patients in the atezolizumab plus mFOLFOX6 arm versus 71.9% in the mFOLFOX6 alone arm. The most common grade 3/4 toxicities across the atezolizumab group were decreased neutrophil count (43.6%), peripheral sensory neuropathy (18.5%), diarrhea (12.1%), and fatigue (10.1%). Grade 5 events occurred in 6 patients in the combination group and 2 in the mFOLFOX6 alone group, with investigators determining 2 of the deaths in the combination arm to be related to treatment.
The ATOMIC trial represents the first phase 3 trial to evaluate the addition of an immune checkpoint inhibitor to standard adjuvant chemotherapy for this specific patient population. The COMMIT trial findings suggest that the combination regimen may be particularly beneficial for patients with more aggressive disease biology or higher tumor burden, including those with older age, BRAF V600E mutation, prior adjuvant therapy, right-sided primary tumors, and higher baseline disease burden.