Addition of atezolizumab to FOLFOXIRI and bevacizumab led to limited increase in survival in metastatic colorectal cancer

1. The median progression-free survival was marginally increased in the atezolizumab group.

2. Adverse events of grades 3 and 4 occurred similarly between both groups, with the most common ones being neutropenia, diarrhea, febrile neutropenia, stomatitis, and venous thromboembolism

Evidence Rating Level: 1 (Excellent)

Study Rundown: Immune checkpoint inhibitors have been efficacious in colorectal cancer but are restricted to those with metastatic colorectal cancer with deficient mismatch repair (dMMR) or microsatellite instable (MSI) tumours. Alternatively, a combination of FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) and bevacizumab has shown enhanced immunogenicity in such tumours. This study explored the addition of atezolizumab (an anti-PD L1 agent) to FOLFOXIRI and bevacizumab (a VEGF inhibitor) in patients with metastatic colorectal cancer. Patients were randomly assigned to receive FOLFOXIRI and bevacizumab, with or without atezolizumab. Median progression-free survival (PFS) was higher in the atezolizumab group and a post-hoc subgroup analysis showed that atezolizumab provided a larger benefit to patients with dMMR tumours, high tumour mutational burden tumours, and high Immunoscore IC tumours (a measure of CD8 T cells, number of PD-L1 cells and proximity to each other). It is important to note that this trial was designed before immune checkpoint inhibitors were proven to be efficacious in dMMR metastatic colorectal cancer. Frequency of adverse events between both groups was not significantly different. Most common grades 3 and 4 adverse events were neutropenia, diarrhea, febrile neutropenia, stomatitis and venous thromboembolism. Grades 3 and 4 potentially immune-related adverse events were pneumonia, an increase in aminotransferase, and hyperglycemia. Limitations to this study include a low generalizability due to an all-white and Italian patient demographic, as well as the use of a post-hoc subgroup analysis. The strength of this study is that it supports other studies’ claims on the efficacy of other immune checkpoint inhibitors on dMMR metastatic colorectal cancer, as this trial was initially designed before the proven efficacy. Overall, the study showed that the addition of atezolizumab to current chemotherapy treatments may improve survival but further studies will be important to determine the magnitude of difference for clinical relevance.

Click to read the study in The Lancet Oncology

Click to read an accompanying editorial in: The Lancet Oncology

Relevant Reading: Latest evidence on immune checkpoint inhibitors in metastatic colorectal cancer: a 2022 update

In-Depth [randomized control trial]: This phase II multicenter study in Italy randomly assigned 218 patients in a 1:2 ratio to receive FOLFOXIRI and bevacizumab, with or without the addition of atezolizumab; 73 in the control group and 145 in the atezolizumab group. Median PFS was 13.1 months and 11.5 months in the atezolizumab and control groups, respectively (hazard ratio [HR] 0.69; 80% confidence interval [CI], 0.56 to 0.85; p=0.012). In the proficient MMR subgroup, the atezolizumab group’s median PFS was 12.9 months, whereas the control group’s PFS was 11.4 months (HR 0.78 [80% CI 0.62 to 0.97], p=0·071). A higher Immunoscore IC was associated with benefit (HR 0.35 [0.16-0.73], p = 0.0029) independent of TMB and dMMR status. Adverse events of grades 3 and 4 occurred in 67% of patients in the atezolizumab group and 61% in the control group. The most frequent grades 3 and 4 adverse events were neutropenia (42% in atezolizumab group and 36% in control group), diarrhea (15% and 13%), febrile neutropenia (10% and 10%), stomatitis (4% and 6%) and venous thromboembolism (4% and 6%). Most common grades 3 and 4 immune-related events were pneumonia (<1%), aminotransferase increase (<1%) and hyperglycemia (1%). Overall, addition of atezolizumab to FOLFOXIRI and bevacizumab increased PFS with some signal that the pMMR population may benefit; however, the PFS is a marginal increase and highlights further studies for confirmation of efficacy. The novel biomarker Immunoscore IC’s ability to predict benefit in this population generates important hypothesis for future clinical trials.

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