Ryan B Corcoran1, Chloe E Atreya2, Gerald S Falchook2, Eunice L Kwak2, David P Ryan2, Johanna C Bendell2, Omid Hamid2, Wells A Messersmith2, Adil Daud2, Razelle Kurzrock2, Mariaelena Pierobon2, Peng Sun2, Elizabeth Cunningham2, Shonda Little2, Keith Orford2, Monica Motwani2, Yuchen Bai2, Kiran Patel2, Alan P Venook2, Scott Kopetz2. 1. 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. 2. 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.
Abstract
PURPOSE: To 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 METHODS: A 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. RESULTS: Of 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. CONCLUSION: The 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.
PURPOSE: To 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 METHODS: A 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. RESULTS: Of 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. CONCLUSION: The 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.
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