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Title: 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.
Austin Authors: Tan, Lavinia;Tran, Ben;Tie, Jeanne;Markman, Ben;Ananda, Sumi;Tebbutt, Niall C ;Michael, Michael;Link, Emma;Wong, Stephen Q;Chandrashekar, Sushma;Guinto, Jerick;Ritchie, David;Koldej, Rachel;Solomon, Benjamin J;McArthur, Grant A;Hicks, Rodney J;Gibbs, Peter;Dawson, Sarah-Jane;Desai, Jayesh
Affiliation: Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
Monash Health, Melbourne, Victoria, Australia.
Olivia Newton-John Cancer Wellness and Research Centre
ACRF Translational Research Laboratory, Royal Melbourne Hospital, Melbourne, Victoria, Australia.
The University of Melbourne Department of Medicine, St Vincent's Hospital, Melbourne, Victoria, Australia.
Division of Personalized Oncology, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
Issue Date: 14-Mar-2023
Date: 2023
Publication information: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research 2023-03-14; 29(6)
Abstract: 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.
DOI: 10.1158/1078-0432.CCR-22-3094
ORCID: 0000-0001-5641-4972
Journal: Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Start page: 1017
End page: 1030
PubMed URL: 36638198
PubMed URL:
ISSN: 1557-3265
Type: Journal Article
Subjects: BRAF
Colorectal cancer
Erlotinib Hydrochloride/adverse effects
Proto-Oncogene Proteins B-raf/genetics
Proto-Oncogene Proteins B-raf/metabolism
Colorectal Neoplasms/drug therapy
Colorectal Neoplasms/genetics
Colorectal Neoplasms/pathology
Colonic Neoplasms/drug therapy
Protein Kinase Inhibitors/adverse effects
Rectal Neoplasms/drug therapy
ErbB Receptors/genetics
ErbB Receptors/metabolism
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