Overall survival (OS) from the AtezoTRIBE study at around 4 years of median follow-up and updated outcomes according to tumour immune-related biomarkers, both in the intention-to-treat (ITT) population and the cohort of patients with proficient mismatch repair (pMMR) tumours indicate that first-line FOLFOXIRI plus bevacizumab and atezolizumab improves OS in patients with metastatic colorectal cancer (mCRC); the pMMR group, patients with Immunoscore Immune-Checkpoint (IC)-high and/or tumour mutational burden (TMB)-high tumours are identified as a subgroup of interest to further develop this treatment.
Based on updated results from a prospective, open-label, investigator-driven randomised phase II AtezoTRIBE study, a phase III study will be conducted to further investigate the value of adding atezolizumab to upfront FOLFOXIRI plus bevacizumab in patients with pMMR and Immunoscore IC-high mCRC. Updated results from the AtezoTRIBE are published by Dr. Chiara Cremolini of the Unit of Medical Oncology 2, University Hospital of Pisa and Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa in Pisa, Italy and colleagues on 12 June 2024 in the JCO.
The authors wrote that although immunotherapy has improved the outcome of patients with deficient MMR mCRC (approximately 5%), the attempt to make this treatment option efficacious also in pMMR tumours has reported more failures than successes, and no randomised studies demonstrated before benefit from first-generation immune-checkpoint inhibitors (ICIs) alone or in combination with other drugs.
The AtezoTRIBE team showed previously significantly longer progression-free survival (PFS) with first-line FOLFOXIRI plus bevacizumab and atezolizumab compared with FOLFOXIRI plus bevacizumab in patients with mCRC. The primary endpoint of the study was PFS analyzed in ITT population. Secondary endpoints included OS, second PFS (defined as a time between the first and second evidence of disease progression or death from any cause), safety, and objective response rate (ORR). PFS, second PFS, and ORR were based on investigator-reported measurements, according to RECIST v1.1 criteria.
Exploratory post hoc analyses were performed to investigate the potential predictive impact of MMR, TMB, and Immunoscore IC status. TMB, assessed by FoundationOne CDx assay, was defined low or high if <10 or ≥10 mutations per Mb were detected. For the Immunoscore IC test, a single tumour tissue section was stained for PD-L1 and CD8 and scanned at high resolution. Densities, proximity, and clustering of PD-L1 cells and CD8 T cells in the tumour core were quantified by digital pathology.
A risk score was computed incorporating quantitative and spatial variables, and dichotomised into two categories. The low-risk group, with high density and proximity of CD8 and PD-L1 cells, was defined as Immunoscore IC-high, whereas the high-risk group, with low density and proximity of CD8 and PD-L1 cells, was defined as Immunoscore IC-low.
In the AtezoTRIBE study, patients with unresectable and previously untreated mCRC, age 18-75 years, and ECOG performance status of 0-2 if age 70 years and younger, or 0 if age 71-75 years, were eligible. Patients were stratified according to centre, ECOG performance status, primary tumour location, and previous adjuvant treatment, and randomly assigned (1:2) to FOLFOXIRI plus bevacizumab (73 patients) or FOLFOXIRI plus bevacizumab and atezolizumab (145 patients). At the first evidence of disease progression, the reintroduction of the same regimens received upfront, according to random assignment, was suggested.
Median follow-up was 45.2 months (IQR, 42.6-49.2). In the ITT population, median OS was 33.0 and 27.2 months for FOLFOXIRI plus bevacizumab and atezolizumab and FOLFOXIRI plus bevacizumab groups, respectively (hazard ratio [HR] 0.78, 80% confidence interval [CI] 0.61 to 0.98; p = 0.084). An interaction effect between Immunoscore IC and treatment arm was observed (pint 0.089), with higher benefit from atezolizumab in the Immunoscore IC-high group.
In the pMMR cohort of 202 patients, median OS was 30.8 and 29.2 months for FOLFOXIRI plus bevacizumab and atezolizumab and FOLFOXIRI plus bevacizumab groups (HR 0.80, 80% CI 0.63 to 1.02; p = 0.117). Interactions between treatment group and TMB and Immunoscore IC were reported (pint 0.043 and 0.092, respectively), with patients bearing TMB-high and Immunoscore IC-high tumours deriving higher benefit from the addition of atezolizumab.
The authors concluded that at an extended follow-up of approximately 4 years, the addition of atezolizumab to first-line FOLFOXIRI plus bevacizumab significantly prolongs PFS and OS in patients with mCRC, with no difference in response rate and a manageable safety profile. Subgroup analyses highlight the role of Immunoscore IC as a potential predictor of benefit both in the ITT population and in the pMMR subgroup, where a significant interaction is reported also according to TMB.
However, these findings are based on unplanned post hoc subgroup analyses and should be considered hypothesis-generating. Nevertheless, Immunoscore IC provides a synthetic description of the spatial distribution of the immune contexture and its ability to predict benefit from ICIs was recently demonstrated also in non–small cell lung cancer.
The study findings were presented previously in part at the ESMO 2021 Annual Congress (18 September 2021; Paris, France) and at the 2023 ASCO Annual Meeting (4 June 2023; Chicago, IL, US).
The study was supported by GONO Foundation, ARCO Foundation, F. Hoffmann-La Roche, and Roche, Bando Ricerca Salute Toscana 2018.
Reference
Antoniotti C, Rossini D, Pietrantonio F, et al. Upfront Fluorouracil, Leucovorin, Oxaliplatin, and Irinotecan Plus Bevacizumab With or Without Atezolizumab for Patients With Metastatic Colorectal Cancer: Updated and Overall Survival Results of the ATEZOTRIBE Study. JCO; Published online 12 June 2024. DOI: https://doi.org/10.1200/JCO.23.02728