**6.1 Standard treatment**

Doublet chemotherapy remains the standard of care for metastatic BRAF MT CRC in patients with appropriate performance status [36, 37]. First-line chemotherapy options include 5 fluorouracil, leucovorin and oxaliplatin (FOLFOX), 5-fluorouracil, leucovorin and irinotecan (FOLFIRI) and capecitabine plus oxaliplatin. A retrospective study reported no difference in median PFS between irinotecan-based or oxaliplatin-based chemotherapy regimens in the first line for BRAF-MT CRC [38].

A more intensive triplet chemotherapy regime has been proposed based on 5 fluorouracil, leucovorin, oxaliplatin and irinotecan with bevacizumab (FOLFOXIRI+bev). A phase II trial of FOLFOXIRI and bevacizumab in the metastatic CRC population

showed a statistically significant benefit to progression free survival and trend towards improved overall survival at the expense of greater incidence of grade three toxicities [39]. An exploratory analysis of the BRAF-MT cohort (25 patients in a pooled population) reported a median PFS of 11.8 months, median OS of 24.1 months and an impressive response rate of 72%, including one patient with complete response [40]. This was followed up by the open label phase III TRIBE study comparing FOLFIRI plus bevacizumab with FOLFOXIRI with bevacizumab [41]. In the molecular subgroup analysis, 28 out of 391 cases were BRAF mutant. There was a trend towards benefit in overall survival (19.0 months in the FOLFOXIRI plus bevacizumab arm vs. 10.7 months in the FOLFIRI plus bevacizumab arm, HR 0.54); however, this was not statistically significant. This was also seen in median PFS (7.5 vs. 9.5 months, HR 0.57) and best overall response (56 vs. 42%). While not statistically significant, this regime has been proposed in the first line setting for BRAF-MT mCRC patients with good performance status given the overall survival data.
