• Ryan B Corcoran, Chloe E Atreya, Gerald S Falchook, Eunice L Kwak, David P Ryan, Johanna C Bendell, Omid Hamid, Wells A Messersmith, Adil Daud, Razelle Kurzrock, Mariaelena Pierobon, Peng Sun, Elizabeth Cunningham, Shonda Little, Keith Orford, Monica Motwani, Yuchen Bai, Kiran Patel, Alan P Venook, and Scott Kopetz.
• Ryan B. Corcoran, Eunice L. Kwak, and David P. Ryan, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA; Chloe E. Atreya, Adil Daud, and Alan P. Venook, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco; Omid Hamid, Angeles Clinic and Research Institute, Los Angeles, CA; Gerald S. Falchook, Sarah Cannon Research Institute at HealthONE, Denver; Wells A. Messersmith, University of Colorado Cancer Center and University of Colorado, Aurora, CO; Johanna C. Bendell, Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN; Razelle Kurzrock and Scott Kopetz, University of Texas, MD Anderson Cancer Center, Houston, TX; Mariaelena Pierobon, Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA; Peng Sun, Elizabeth Cunningham, Shonda Little, Keith Orford, Monica Motwani, and Yuchen Bai, GlaxoSmithKline, Philadelphia, PA; and Kiran Patel, Incyte, Wilmington, DE. rbcorcoran@partners.org.
• J. Clin. Oncol. 2015 Dec 1; 33 (34): 4023-31.

PurposeTo evaluate dabrafenib, a selective BRAF inhibitor, combined with trametinib, a selective MEK inhibitor, in patients with BRAF V600-mutant metastatic colorectal cancer (mCRC).Patients And MethodsA total of 43 patients with BRAF V600-mutant mCRC were treated with dabrafenib (150 mg twice daily) plus trametinib (2 mg daily), 17 of whom were enrolled onto a pharmacodynamic cohort undergoing mandatory biopsies before and during treatment. Archival tissues were analyzed for microsatellite instability, PTEN status, and 487-gene sequencing. Patient-derived xenografts were established from core biopsy samples.ResultsOf 43 patients, five (12%) achieved a partial response or better, including one (2%) complete response, with duration of response > 36 months; 24 patients (56%) achieved stable disease as best confirmed response. Ten patients (23%) remained in the study > 6 months. All nine evaluable during-treatment biopsies had reduced levels of phosphorylated ERK relative to pretreatment biopsies (average decrease ± standard deviation, 47% ± 24%). Mutational analysis revealed that the patient achieving a complete response and two of three evaluable patients achieving a partial response had PIK3CA mutations. Neither PTEN loss nor microsatellite instability correlated with efficacy. Responses to dabrafenib plus trametinib were comparable in patient-derived xenograft-bearing mice and the biopsied lesions from each corresponding patient.ConclusionThe combination of dabrafenib plus trametinib has activity in a subset of patients with BRAF V600-mutant mCRC. Mitogen-activated protein kinase signaling was inhibited in all patients evaluated, but to a lesser degree than observed in BRAF-mutant melanoma with dabrafenib alone. PIK3CA mutations were identified in responding patients and thus do not preclude response to this regimen. Additional studies targeting the mitogen-activated protein kinase pathway in this disease are warranted.© 2015 by American Society of Clinical Oncology.

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