In an Italian phase II trial (AtezoTRIBE) reported in The Lancet Oncology, Antoniotti et al found that the addition of atezolizumab to FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, irinotecan) and bevacizumab improved progression-free survival in the first-line treatment of patients with metastatic colorectal cancer.

As stated by the investigators, “Immune checkpoint inhibitors have not shown clinical benefit to patients with metastatic colorectal cancer who had proficient mismatch repair (pMMR) or microsatellite stable (MSS) tumours in previous studies. Both an active combination chemotherapy ([eg,] FOLFOXIRI…) and bevacizumab seem able to increase the immunogenicity of pMMR or MSS tumours.”

Study Details

In the open-label, multicenter trial, 218 patients were randomly assigned 2:1 between November 2018 and February 2020 to receive FOLFOXIRI (irinotecan at 165 mg/m², oxaliplatin at 85 mg/m², leucovorin at 200 mg/m², and fluorouracil at 3,200 mg/m² via 48-hour infusion) plus bevacizumab at 5 mg/kg with (n = 145) or without (n = 73) atezolizumab at 840 mg. Combination treatments were administered for up to eight 14-day cycles, followed by maintenance fluorouracil and leucovorin plus bevacizumab with or without atezolizumab, according to random assignment, until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival in the intent-to-treat population.

Progression-Free Survival

At data cutoff (in August 2021), median follow-up was 19.9 months (interquartile range = 17.3–23.9 months). Median progression-free survival was 13.1 months (80% confidence interval [CI] = 12.5–13.8 months) in the atezolizumab group and 11.5 months (80% CI = 10.0–12.6 months) in the control group (hazard ratio = 0.69, 80% CI = 0.56–0.85, P = .012). Separation of the Kaplan-Meier curves was observed after approximately 7 months. In analysis adjusting for the stratification factors of center, performance status, primary tumor site, and previous exposure to adjuvant treatment, the adjusted hazard ratio was 0.70 (80% CI = 0.57–0.87, P = .018).

In subgroup analysis, greater benefit of the addition of atezolizumab was observed among patients with MMR-deficient tumors, high tumor mutation burden, and high Immunoscore IC tumors.

At data cutoff, death had occurred in 29% of patients in the atezolizumab group vs 38% of the control group.

Adverse Events

Grade 3 or 4 adverse events occurred in 67% of patients in the atezolizumab group vs 61% of the control group, with the most common in the atezolizumab group being neutropenia (42% vs 36% in control group), diarrhea (15% vs 13%), and febrile neutropenia (10% vs 10%). Serious adverse events occurred in 27% vs 26% of patients. Grade 3 or 4 potentially immune-related adverse events were reported in four patients (3%) in the atezolizumab group (pneumonia in 1, aminotransferase increase in 2, and hyperglycemia in 1). Treatment-related death occurred in two patients (1%) in the atezolizumab group (due to acute myocardial infarction and bronchopulmonary hemorrhage, respectively) and in no patients in the control group.

The investigators concluded, “The addition of atezolizumab to first-line FOLFOXIRI plus bevacizumab is safe and improved progression-free survival in patients with previously untreated metastatic colorectal cancer.”

Chiara Cremolini, PhD, of the Unit of Medical Oncology, University Hospital of Pisa, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by the GONO Foundation, ARCO Foundation, F. Hoffmann-La Roche, and Roche. For full disclosures of the study authors, visit thelancet.com.