Journal Article

AtezoTRIBE: a randomised phase II study of FOLFOXIRI plus bevacizumab alone or in combination with atezolizumab as initial therapy for patients with unresectable metastatic colorectal cancer

Cremolini, Chiara, Boni, Luca, Marmorino, Federica, Boccaccino, Alessandra, Tamburini, Emiliano, Moretto, Roberto, Antoniotti, Carlotta, Pietrantonio, Filippo, Tamberi, Stefano, Falcone, Alfredo, Morano, Federica, Lonardi, Sara, Bergamo, Francesca, Grassi, Elisa, Racca, Patrizia, Borelli, Beatrice, Corallo, Salvatore, Brunella, Di Stefano, Rossini, Daniele, Aprile, Giuseppe, Salvatore, Lisa, Tortora, Giampaolo

2020

Overview

Background Immune checkpoint inhibitors (ICIs) reported remarkable achievements in several solid tumours. However, in metastatic colorectal cancer (mCRC) promising results are limited to patients with deficient mismatch repair/microsatellite instability-high (dMMR/MSI-high) tumours due to their immune-enriched microenvironment. Combining cytotoxic agents and bevacizumab in mCRC with proficient mismatch repair/microsatellite stability (pMMR/MSS) could make ICIs efficacious by increasing the exposure of neoantigens, especially with highly active chemotherapy regimens, inducing immunogenic cell death, increasing the tumoral infiltration of CD8+ T-cells and reducing tumour-associated myeloid-derived suppressor cells. VEGF-blockade also plays an immunomodulatory role by inhibiting the expansion of T regulatory lymphocytes. Consistently with this rationale, a phase Ib study combined the anti-PDL-1 atezolizumab with FOLFOX/bevacizumab as first-line treatment of mCRC, irrespective of microsatellite status, and reported interesting activity and efficacy results, without safety concerns. Phase III trials led to identify FOLFOXIRI plus bevacizumab as an upfront therapeutic option in selected mCRC patients. Drawing from these considerations, the combination of atezolizumab with an intensified upfront treatment (FOLFOXIRI) and bevacizumab could be worthy of investigation. Methods AtezoTRIBE is a prospective, open label, phase II, comparative trial in which initially unresectable and previously untreated mCRC patients, irrespective of microsatellite status, are randomized in a 1:2 ratio to receive up to 8 cycles of FOLFOXIRI/bevacizumab alone or in combination with atezolizumab, followed by maintenance with bevacizumab plus 5-fluoruracil/leucovorin with or without atezolizumab according to treatment arm until disease progression. The primary endpoint is PFS. Assuming a median PFS of 12 months for standard arm, 201 patients should be randomized in a 1:2 ratio to detect a hazard ratio of 0.66 in favour of the experimental arm. A safety run-in phase including the first 6 patients enrolled in the FOLFOXIRI/bevacizumab/atezolizumab arm was planned, and no unexpected adverse events or severe toxicities were highlighted by the Safety Monitoring Committee. Discussion The AtezoTRIBE study aims at assessing whether the addition of atezolizumab to an intensified chemotherapy plus bevacizumab might be an efficacious upfront strategy for the treatment of mCRC, irrespective of the microsatellite status. Trial registration AtezoTRIBE is registered at Clinicaltrials.gov ( NCT03721653 ), October 26th, 2018 and at EUDRACT (2017–000977-35), Februray 28th, 2017 .

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Aged / Analysis / Antibodies, Monoclonal, Humanized - administration & dosage / Antigens / Antineoplastic Agents - administration & dosage / Antineoplastic Agents, Immunological - administration & dosage / Antineoplastic Combined Chemotherapy Protocols - administration & dosage / Apoptosis / Atezolizumab / Bevacizumab / Bevacizumab - administration & dosage / Biomedical and Life Sciences / Biomedicine / Camptothecin - administration & dosage / Camptothecin - analogs & derivatives / Cancer metastasis / Cancer patients / Cancer Research / Cancer therapies / Care and treatment / CD8 antigen / Cell death / Chemotherapy / Clinical trials / Colorectal cancer / Colorectal carcinoma / Colorectal Neoplasms - drug therapy / Colorectal Neoplasms - genetics / Colorectal Neoplasms - pathology / Cytotoxic agents / Cytotoxicity / Drug Administration Schedule / Endothelial growth factors / Fluorouracil - administration & dosage / FOLFOXIRI / Health Promotion and Disease Prevention / Humans / Immune checkpoint inhibitors / Immune response / Immunogenicity / Immunomodulation / Immunomodulators / Immunotherapy / Italy / Leucovorin - administration & dosage / Lymphocytes / Lymphocytes T / Medical and radiation oncology / Medicine/Public Health / Metastases / Metastasis / Metastatic colorectal cancer / Microsatellite Instability / Mismatch repair / Monoclonal antibodies / Neoantigens / Oncology / Organoplatinum Compounds - administration & dosage / Patients / Prospective Studies / Safety / Solid tumors / Study Protocol / Suppressor cells / Surgical Oncology / T cells / Targeted cancer therapy / Tumors / Vascular endothelial growth factor