Reference Detail

Ref Type

Journal Article

PMID

(37040395)

Authors

Napolitano S, Woods M, Lee HM, De Falco V, Martini G, Della Corte CM, Martinelli E, Famiglietti V, Ciardiello D, Anderson A, Fowlkes NW, Villareal OE, Sorokin A, Kanikarla P, Coker O, Morris V, Altucci L, Tabernero J, Troiani T, Ciardiello F, Kopetz S

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	29	12	2023 Jun 13	2299-2309	Clin Cancer Res

URL

Abstract Text

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.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.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.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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF V600E	colorectal cancer	sensitive	Cetuximab + Encorafenib + Fluorouracil + Irinotecan + Leucovorin	Preclinical - Pdx	Actionable	In a preclinical study, treatment with the combination of Erbitux (cetuximab), Braftovi (encorafenib), and FOLFIRI resulted in increased tumor growth inhibition and tumor regression compared to Erbitux (cetuximab) plus Braftovi (encorafenib) or FOLFIRI alone in patient-derived xenograft (PDX) models of colorectal cancer harboring BRAF V600E and increased survival and tumor growth inhibition in cell line xenograft models (PMID: 37040395).	37040395
BRAF V600E	colorectal cancer	sensitive	Cetuximab + Encorafenib + Fluorouracil + Leucovorin + Oxaliplatin	Preclinical - Cell line xenograft	Actionable	In a preclinical study, treatment with the combination of Erbitux (cetuximab), Braftovi (encorafenib), and FOLFOX resulted in increased tumor growth inhibition and survival compared to Erbitux (cetuximab) plus Braftovi (encorafenib) or FOLFOX alone in colorectal cancer cell line xenograft models harboring BRAF V600E (PMID: 37040395).	37040395