A Phase Ib/II Trial of Combined BRAF and EGFR Inhibition in BRAF V600E Positive Metastatic Colorectal Cancer and Other Cancers: The EVICT (Erlotinib and Vemurafenib In Combination Trial) Study.
Humans
Vemurafenib
Erlotinib Hydrochloride
/ adverse effects
Proto-Oncogene Proteins B-raf
/ genetics
Colorectal Neoplasms
/ drug therapy
Indoles
Sulfonamides
Colonic Neoplasms
/ drug therapy
Protein Kinase Inhibitors
/ adverse effects
Rectal Neoplasms
/ drug therapy
Mutation
ErbB Receptors
/ genetics
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
ISSN: 1557-3265
Titre abrégé: Clin Cancer Res
Pays: United States
ID NLM: 9502500
Informations de publication
Date de publication:
14 03 2023
14 03 2023
Historique:
received:
07
10
2022
revised:
02
11
2022
accepted:
11
01
2023
pubmed:
14
1
2023
medline:
16
3
2023
entrez:
13
1
2023
Statut:
ppublish
Résumé
BRAF V600E mutant metastatic colorectal cancer represents a significant clinical problem, with combination approaches being developed clinically with oral BRAF inhibitors combined with EGFR-targeting antibodies. While compelling preclinical data have highlighted the effectiveness of combination therapy with vemurafenib and small-molecule EGFR inhibitors, gefitinib or erlotinib, in colorectal cancer, this therapeutic strategy has not been investigated in clinical studies. We conducted a phase Ib/II dose-escalation/expansion trial investigating the safety/efficacy of the BRAF inhibitor vemurafenib and EGFR inhibitor erlotinib. Thirty-two patients with BRAF V600E positive metastatic colorectal cancer (mCRC) and 7 patients with other cancers were enrolled. No dose-limiting toxicities were observed in escalation, with vemurafenib 960 mg twice daily with erlotinib 150 mg daily selected as the recommended phase II dose. Among 31 evaluable patients with mCRC and 7 with other cancers, overall response rates were 32% [10/31, 16% (5/31) confirmed] and 43% (3/7), respectively, with clinical benefit rates of 65% and 100%. Early ctDNA dynamics were predictive of treatment efficacy, and serial ctDNA monitoring revealed distinct patterns of convergent genomic evolution associated with acquired treatment resistance, with frequent emergence of MAPK pathway alterations, including polyclonal KRAS, NRAS, and MAP2K1 mutations, and MET amplification. The Erlotinib and Vemurafenib In Combination Trial study demonstrated a safe and novel combination of two oral inhibitors targeting BRAF and EGFR. The dynamic assessment of serial ctDNA was a useful measure of underlying genomic changes in response to this combination and in understanding potential mechanisms of resistance.
Identifiants
pubmed: 36638198
pii: 715756
doi: 10.1158/1078-0432.CCR-22-3094
pmc: PMC10011885
doi:
Substances chimiques
Vemurafenib
207SMY3FQT
Erlotinib Hydrochloride
DA87705X9K
Proto-Oncogene Proteins B-raf
EC 2.7.11.1
Indoles
0
Sulfonamides
0
Protein Kinase Inhibitors
0
ErbB Receptors
EC 2.7.10.1
BRAF protein, human
EC 2.7.11.1
EGFR protein, human
EC 2.7.10.1
Types de publication
Clinical Trial, Phase I
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1017-1030Informations de copyright
©2023 The Authors; Published by the American Association for Cancer Research.
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