Data from Antitumor Efficacy of Dual Blockade with Encorafenib + Cetuximab in Combination with Chemotherapy in Human &lt;i&gt;BRAF&lt;/i&gt;&lt;sup&gt;V600E&lt;/sup&gt;-Mutant Colorectal Cancer

Josep Tabernero,Melanie Woods,Amanda Anderson,Davide Ciardiello,Fortunato Ciardiello,Scott Kopetz,Stefania Napolitano,Lucia Altucci,Giulia Martini,Oscar Eduardo Villareal,Teresa Troiani,Vincenzo Famiglietti,Vincenzo De Falco,Erika Martinelli,Hey Min Lee,Carminia M Della Corte ,Preeti Kanikarla Marie ,Alexey V Sorokin ,Van K Morris ,Oluwadara Coker ,Natalie W Fowlkes

doi:10.1158/1078-0432.c.6618070.v3

Abstract

<div>AbstractPurpose:Encorafenib + cetuximab (E+C) 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), (E+C) 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 E+C 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 E+C and a 45% loss of efficacy of E+C after FOLFIRI (P < 0.001 for both). FOLFIRI-treated models had upregulation of epithelial–mesenchymal transition (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 with E+C or to chemotherapy alone. Furthermore, 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.</div>

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