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

Authors

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

Publication Date

6-13-2023

Journal

Clinical Cancer Research

Abstract

PURPOSE: 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.

Keywords

Animals, Mice, Antineoplastic Combined Chemotherapy Protocols, Camptothecin, Cetuximab, Colonic Neoplasms, Colorectal Neoplasms, Fluorouracil, Leucovorin, Humans, Xenograft Model Antitumor Assays

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Supplementary Materials

PMID: 37040395