Reference Detail

Ref Type

Journal Article

PMID

(36638198)

Authors

Tan L, Tran B, Tie J, Markman B, Ananda S, Tebbutt NC, Michael M, Link E, Wong SQ, Chandrashekar S, Guinto J, Ritchie D, Koldej R, Solomon BJ, McArthur GA, Hicks RJ, Gibbs P, Dawson SJ, Desai J

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	29	6	2023 Mar 14	1017-1030	Clin Cancer Res

URL

Abstract Text

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.

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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	Erlotinib + Vemurafenib	Phase Ib/II	Actionable	In a Phase Ib/II trial (EVICT), the combination of Zelboraf (vemurafenib) and Tarceva (erlotinib) resulted in an overall response rate of 16% (5/31; 5 partial responses), a clinical benefit rate of 65% (20/31), a median progression-free survival of 3.9 months, and a median overall survival of 6.3 months in patients with colorectal cancer harboring BRAF V600E (PMID: 36638198).	36638198
BRAF V600E	Advanced Solid Tumor	predicted - sensitive	Erlotinib + Vemurafenib	Case Reports/Case Series	Actionable	In a Phase Ib/II trial (EVICT), the combination of Zelboraf (vemurafenib) and Tarceva (erlotinib) resulted in an overall response rate of 43% (3/7), a clinical benefit rate of 100%, and a median PFS of 5.5 months in patients with advanced solid tumors other tan colorectal cancer harboring BRAF V600E (PMID: 36638198).	36638198