Antitumor Efficacy of Dual Blockade with Encorafenib þ Cetuximab in Combination with Chemotherapy in Human BRAFV600E-Mutant Colorectal Cancer

Abstract

Purpose: Encorafenib þ cetuximab (EþC) is an effective therapeutic option in chemorefractory BRAFV600E metastatic colorectal cancer (mCRC). However, there is a need to improve the efficacy of this molecular-targeted therapy and evaluate regimens suitable for untreated BRAFV600E in patients with mCRC. Experimental Design: We performed a series of in vivo studies using BRAFV600E mCRC tumor xenografts. Mice were randomized to receive 5-fluoruracil (5-FU), irinotecan, or oxaliplatin regimens (FOLFIRI or FOLFOX), (EþC) or the combination. Patients received long-term treatment until disease progression, with deescalation strategies used to mimic maintenance therapy. Transcriptomic changes after progression on cytotoxic chemotherapy or targeted therapy were assessed. Results: Antitumor activity of either FOLFIRI or EþC was better as first-line treatment as compared with second-line, with partial cross-resistance seen between a cytotoxic regimen and targeted therapy with an average 62% loss of efficacy for FOLFIRI after EþC and a 45% loss of efficacy of EþC after FOLFIRI (P < 0.001 for both). FOLFIRI-treated models had upregulation of epithelial–mesenchymal transition (EMT) and MAPK pathway activation, where EþC treated models had suppressed MAPK signaling. In contrast, with chemotherapy with EþC, EMT and MAPK signaling remained suppressed. FOLFOX or FOLFIRI, each in combination with EþC, were the most active first-line treatments as compared with EþC or to chemotherapy alone. Furthermore, FOLFOX in combination with EþC as first-line induction therapy, followed by EþC ± 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.