About 95% of patients with mCRC are proficient MMR or MSS with subsequent resistant to first generation immune checkpoint inhibitors. In this trial sponsored by the Italian GONO Foundation provide preliminary evidence of benefit from the addition of atezolizumab to first-line FOLFOXIRI plus bevacizumab metastatic colorectal cancer patients by exploiting the immunomodulatory properties of both an active chemotherapy regimen, such as the triplet FOLFOXIRI, and the anti-angiogenic agent, bevacizumab.

In this randomized trial, 218 previously untreated mCRC patients were randomized in a 1:2 ratio to receive upfront FOLFOXIRI plus bevacizumab in the control arm, or the same regimen plus atezolizumab in the experimental arm. Treatment induction was administered up to 8 cycles, and then followed by maintenance with 5 mg bevacizumab with or without atezolizumab according to the randomization arm, until disease progression, and after disease progression, the reintroduction of the same agents received upfront was recommended. The primary end point was the progression-free survival.

There was no molecular selection according to RAS, BRAF, or mismatch repair status. patient characteristics were well-balanced between the 2 arms.

The study met its primary endpoint of PFS with a small benefit observed in patients with pMMR tumors. mPFS was 13·1m in the atezo group and 11·5m in the control group (HR=0·71, p=0·015) in the ITT population. In the pMMR cohort (201 patients), the mPFS was 13m in the atezo group and 13m in the control group (HR=0.79, p=0.73).

There was a trend towards OS benefit in both ITT population and patients with pMMR, mOS was 33m in the atezo group vs 27.2m in the control group (HR=0.81, P=0.136). In the pMMR cohort, the mOS was 30.8m in the atezo group vs 26.9m in the control group (HR=0.83, P=0.172)

In multivariate analysis of the pMMR cohort, significant interaction was found between PFS and OS and treatment in specific biomarker-defined subgroups favoring atezolizumab addition in immunologically active tumors with High TMB (P = .014) and Immunoscore-IC (P = .060). Pts having IS IC-high tumors derived higher OS benefit from adding atezo (HR 0.44, 95%CI 0.19-1.03), than those with IS IC-low tumors (HR 1.15, 95% CI 0.67-1.97).