Data from Antitumor efficacy of dual blockade with encorafenib plus cetuximab in combination with chemotherapy in human <i>BRAFV600E</i> mutant colorectal cancer.

Abstract

<div>Abstract<p>Purpose: Encorafenib plus cetuximab is an effective therapeutic option in chemorefractory <i>BRAFV600E </i>mCRC. However, there is a need to improve the efficacy of this molecular targeted therapy and evaluate regimens suitable for untreated <i>BRAFV600E </i>mCRC patients. Experimental Design: We performed a series of <i>in vivo </i>studies using <i>BRAFV600E<sup></sup></i>mCRC 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 <i>BRAFV600E</i> mCRC.</p></div>