A Clinical-biological Prospective Cohort of Patients With BRAFV600E-mutated Metastatic Colorectal Cancer

Despite substantial progress made in the first- and second line mCRC settings, there are still unmet clinical needs for patients harboring BRAFV600E mutations, especially those with microsatellite stability (MSS) / proficient mismatch repair (pMMR) tumor. The overall survival and access to different treatment in the real-life setting are unknown. Moreover, patient prognosis remains poor and therapeutic resistance to combinations with BRAF inhibitors, is at present, nearly universal. Therefore, it seems essential to prospectively collect clinical and biological data about this rare mCRC subtype. These data will allow us to improve knowledge and to identify clinical and biological factors that could drive therapeutic decisions, predict resistance to treatments, and that are prognostic for survival. In this context, we designed this large, prospective, cohort study to collect clinical data and biological samples to be used for research but also to gather real-world clinical data concerning the treatments and the survival outcomes in patients with BRAFV600E mCRC.

This collection of clinical and biological data (tumor tissue and blood samples) will allow us to identify predictive and prognostic biomarkers with several research work packages planned:

i. To evaluate the circulating tumor DNA (ctDNA) during the metastatic first-, second-, and third-line treatment to:

* Evaluate its positive and negative predictive value. * Identify molecular alterations preceding and explaining clinical resistance during BRAF/EGFR inhibition therapy and immunotherapy.

ii. To evaluate BRAFV600E mCRC immune environment both at the tumor and blood level (immunomonitoring).

iii. To study specific the dMMR/MSI BRAFV600E subgroup. Furthermore, the data collected will describe the therapeutic management of BRAFV600E mCRC patients in the routine-practice setting which will bring very useful data. The results of the COBRAF study could lay the groundwork to better understand BRAFV600E mCRC and to identify prognostic and predictive biomarkers helping the development of new therapeutic approaches in this population.

• Collection of prospective data about BRAFV600E mCRC [Time frame: Throughout study completion, up to 5 years]
• Correlation between prognostic markers and progression-free survival [Time frame: From date of first diagnosis of mCRC and date of first progression or death, up to 5 years]
• Correlation between prognostic markers and overall survival [Time frame: Throughout study completion, up to 5 years]
• Objective response rate [Time frame: From baseline to first disease progression, up to 5 years]
• Disease control rate [Time frame: From baseline to first disease progression, up to 5 years]
• Progression-free survival [Time frame: From baseline to first disease progression, up to 5 years]
• ctDNA kinetics modeling outcome parameters [Time frame: From date of first diagnosis of mCRC until the date of first disease progression, up to 5 years]
• Correlation between predictive biomarkers and response to treatment [Time frame: Throughout study completion, up to 5 years]