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

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

Author(s): 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;
Details: Publication Year 2023-03-14,Volume 29,Issue #6,Page 1017-1030
Journal Title: Clinical Cancer Research
Abstract: PURPOSE: 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. PATIENTS AND METHODS: We conducted a phase Ib/II dose-escalation/expansion trial investigating the safety/efficacy of the BRAF inhibitor vemurafenib and EGFR inhibitor erlotinib. RESULTS: 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. CONCLUSIONS: 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.
Publisher: AACR
Keywords: Humans; Vemurafenib; Erlotinib Hydrochloride/adverse effects; Proto-Oncogene Proteins B-raf/genetics/metabolism; Colorectal Neoplasms/drug therapy/genetics/pathology; Indoles; Sulfonamides; Colonic Neoplasms/drug therapy; Protein Kinase Inhibitors/adverse effects; Rectal Neoplasms/drug therapy; Mutation; ErbB Receptors/genetics/metabolism
Research Division(s): Personalised Oncology
PubMed ID: 36638198
Publisher's Version: https://doi.org/10.1158/1078-0432.CCR-22-3094
Open Access at Publisher's Site: https://doi.org/10.1158/1078-0432.CCR-22-3094
Terms of Use/Rights Notice: Refer to copyright notice on published article.
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Creation Date: 2023-03-17 10:45:17

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