Prolonged PFS Observed With Addition of Atezolizumab to FOLFOXIRI and Bevacizumab for Metastatic CRC

Atezolizumab plus fluorouracil, leucovorin, oxaliplatin, and irinotecan resulted in a tolerable safety profile and improved progression-free survival vs the control regimen in patients with metastatic colorectal cancer.

The addition of atezolizumab (Tecentriq) to fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI), and bevacizumab (Avastin) resulted in an improvement in progression-free survival (PFS) for patients with metastatic colorectal cancer vs FOLFOXIRI alone, according to results from the phase 2 AtezoTribe trial (NCT03721653)published in The Lancet Oncology.

At the median follow-up was 19.9 months, 73% of patients havd disease progression. The median PFS was 13.1 months (80% CI, 12.5-13.8) in the atezolizumab group and 11.5 months (80% CI, 10.0-12.6) in the control group (HR, 0.69; 80% CI, 0.56-0.85; P = .012). The difference maintained significance after adjusting for stratification factors (adjusted HR, 0.70; 80% CI, 0.57-0.87; P = .018). The 22-months restricted mean survival time was 13.6 months (80% CI, 12.9-14.4) in the atezolizumab group vs 11.9 months (80% CI, 11.0-12.9) in the control group.

A total of 218 patients were enrolled, of whom 73 were included in the control group and 145 were in the atezolizumab group in the intent-to-treat population. For the safety population, 72 patients in the control group and 142 in the atezolizumab group were included. The median age was 61 years, and all patients were White.

A total of 97% of patients were tested for mismatch repair (MMR) status, of whom 6% were mismatch repair deficient (dMMR). Tumor mutational burden was assessed in 63% of patients, and 12% were tumor mutational burden high (TMB-H).

Investigators did not find a significant effect in the post-hoc subgroup analysis which included age, sex, ECOG performance status, primary tumor site, and previous adjuvant therapy. There was a significant interaction was observed between MMR status (Pinteraction = .010), tumor mutational burden (Pinteraction = .0061), Immunoscore IC (Pinteraction = .0029), and treatment group. The multivariate analysis showed that dMMR, TMB-H, and high Immunoscore IC tumors were independently associated with PFS in the atezolizumab group.

In the post-hoc analysis for the dMMR subgroup, 54% of patients had disease progression. The median PFS was not reached in the atezolizumab group, while patients in the control group had a median PFS of 6.6 months (80% CI, 4.5-27.5; HR, 0.11; 80% CI, 0.04-0.35; log-rank P = .0021). In patients who were MMR proficient (pMMR), 74% had disease progression. The median PFS in the atezolizumab group was 12.9 months (80% CI, 11.9-13.3) vs 11.4 months (80% CI, 10.0-12.6) in the control group (HR, 0.78; 80% CI, 0.62-0.97; log-rank P = .071).

An objective response was observed in 59% of patients in the atezolizumab group vs 64% in the control group (OR, 0.78; 80% CI, 0.54-1.15; P = .21). A complete response (CR) was observed in 6% of patients in the atezolizumab group and 52% had a partial response (PR), while 5% had a CR and 59% had a PR in the control group. R0 resection of metastases was seen in 26% of patients in the atezolizumab group and 37% of patients in the control group (OR, 0.61; 80% CI, 0.41-0.90; P = .051).

A total of 67% of patients in the atezolizumab group had grade 3 or 4 adverse effects (AEs) compared with 61% in the control group. The most frequent grade 3 or 4 AEs were neutropenia (42% vs 36%), diarrhea (15% vs 13%), febrile neutropenia (10% vs 10%), stomatitis (4% vs 8%), and venous thromboembolism (4% vs 6%) in the atezolizumab and control groups, respectively.

Immune-related AEs were reported in in 3% of patients in the atezolizumab group and 1% in the control group. Serious AEs were reported in 27% of patients in the atezolizumab group and 26% in the control group.

Discontinuation of treatment occurred only in 2% of patients in the atezolizumab group because of drug-related AEs. Reasons for discontinuation included stomatitis, hand-foot syndrome, intestinal sub-obstruction, and neutropenia. Dose reductions were necessary in 65% of patients in the atezolizumab group and 57% in the control group.

Overall, 32% of patients had died by data cutoff. Most patients died from disease progression including 82% in the control group and 81% in the atezolizumab group. Additionally, 5% of patients died in the atezolizumab group from acute myocardial infarction and bronchopulmonary hemorrhage. In the control group, 18% of patients died from ischemic stroke, pneumonia, or an unknown cause, and 14% in the atezolizumab group from an acute cardiac event, cachexia, hematemesis, or unknown cause.

Reference

Antoniotti C, Rossini D, Pietrantonio F, et al. Upfront FOLFOXIRI plus bevacizumab with or without atezolizumab in the treatment of patients with metastatic colorectal cancer (AtezoTRIBE): a multicentre, open-label, randomised, controlled, phase 2 trial. Lancet Oncol. Published online May 27, 2022. doi:10.1016/S1470-2045(22)00274-1