Antitumor efficacy of dual blockade with encorafenib plus cetuximab in combination with chemotherapy in human BRAFV600E mutant colorectal cancer

Purpose: Encorafenib plus cetuximab is an effective therapeutic option in chemorefractory BRAFV600E mCRC. However, there is a need to improve the efficacy of this molecular targeted therapy and evaluate regimens suitable for untreated BRAFV600E mCRC patients. Experimental design: We performed a series of in vivo studies using BRAFV600EmCRC tumor xenografts. Mice were randomized to receive: 5-fluoruracil, irinotecan or oxaliplatin regimens (FOLFIRI or FOLFOX), encorafenib plus cetuximab (E+C) or the combination. Treatments included long term treatment until progression, with de-escalation strategies replicating maintenance treatments. Transcriptomic changes after progression on cytotoxic chemotherapy or targeted therapy were assessed. Results: Antitumor activity of either FOLFIRI or E+C was better in first-line as compared to second-line, with partial cross-resistance seen between cytotoxic regimen and targeted therapy with average 62% loss of efficacy for FOLFIRI after E+C and 45% loss of efficacy of E+C after FOLFIRI (p<0.001 for both). FOLFIRI treated models had upregulation of EMT and MAPK pathway activation, where E+C treated models had suppressed MAPK signaling. In contrast, with chemotherapy with E+C, EMT and MAPK signaling remained suppressed. FOLFOX or FOLFIRI, each in combination with E+C, were the most active first-line treatments as compared to E+C or to chemotherapy alone. Further, FOLFOX in combination with E+C as first-line induction therapy, followed by E+C +/- 5-FU as maintenance therapy, was the most effective strategy for long term disease control. Conclusions: These results support the combination of cytotoxic chemotherapy and molecular targeted therapy as a promising therapeutic approach in the first-line treatment of BRAFV600E mCRC.