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|Ref Type||Journal Article|
|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||Phase Ib/II Trial of BRAF and EGFR inhibition in BRAFV600E metastatic colorectal cancer and other cancers: EVICT (Erlotinib and Vemurafenib In Combination Trial).|
|Journal||Clinical cancer research : an official journal of the American Association for Cancer Research|
|Date||2023 Jan 13|
|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-tageting antibodies. Whilst compelling preclinical data has highlighted the effectiveness of combination therapy with vemurafenib and small-molecule EGFR inhibitors, gefitinib or erlotinib in CRC, 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 960mg/twice-daily with erlotinib 150mg/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 EVICT 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 undertsnidng potential mechanisms of resistance.|
|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|