Upfront folfoxiri plus bevacizumab for metastatic colorectal cancer: program of translational analyses of the phase III randomized tribe2 trial

The present work focuses on clinical and translational results from the no-profit phase III randomized TRIBE2 trial conducted by the Gruppo Oncologico del Nord Ovest (GONO) and coordinated by the Unit of Medical Oncology 2 at the Azienda Ospedaliero-Universitaria Pisana. The study aimed at comparing the efficacy of a preplanned strategy of upfront exposure to the three cytotoxic drugs in the FOLFOXIRI (fluorouracil, leucovorin, irinotecan and oxaliplatin) regimen followed by the reintroduction of doublets (first-line mFOLFOX6 [fluorouracil, leucovorin, and oxaliplatin], followed by FOLFIRI [fluorouracil, leucovorin, and irinotecan] after disease progression), with a sustained inhibition of angiogenesis with bevacizumab, in previously untreated metastatic colorectal cancer patients. During the last three years I was in charge of following patients enrolled in the TRIBE2 trial and I was responsible for data collection and monitoring not only at the Azienda Ospedaliero-Universitaria Pisana, but also at the other 58 Italian participating centres. Main inclusion TRIBE2 trial criteria included the availability of tumour specimens collected before study treatment. These procedures allowed us to collect tissue samples of metastatic colorectal cancer patients, that were, therefore, available for translational analyses. The first chapter of the present thesis describes the current landscape of the first-line treatment of metastatic colorectal cancer patients and illustrates an evidence-based algorithm that summarizes an updated perspective on the choice of the best therapy for each patient. The aim of this chapter is to provide the reader with a frame to properly understand the background of the design of the TRIBE2 trial and the unmet needs that the study attempted to address. The second chapter focuses on the elucidation of the TRIBE2 trial’s procedures and the summary of the trial’s results about primary and secondary endpoints, and their interpretation for the application to the clinical practice. The third chapter reports the results of an individual patient data-based meta-analysis from five randomized trials, including the TRIBE2 study, providing a robust estimation of the added value of FOLFOXIRI plus bevacizumab over conventional doublets plus bevacizumab. Finally, the fourth and the fifth chapter describe the results of two translational projects moving from the TRIBE2 study: a comprehensive genomic profiling by means of a next-generation sequencing (NGS) approach, including the assessment of microsatellite instability (MSI) status, tumour mutational load (TML) and actionable genomic alterations; the evaluation of two distinct molecular classifications based on gene expression profiles on tumour tissues, including the consensus molecular subtypes (CMS) and CRCA subtypes. Other translational projects including samples from patients enrolled in the TRIBE2 study are currently ongoing and will help to throw light on the complex molecular landscape of metastatic colorectal cancer and on the optimization of the treatment with FOLFOXIRI plus bevacizumab, by an improved selection of candidate patients.