达拉非尼和曲美替尼联合抑制BRAF和MEK在BRAF V600突变型结直肠癌中的应用
Combined BRAF and MEK Inhibition With Dabrafenib and Trametinib in BRAF V600-Mutant Colorectal Cancer.
作者信息
Corcoran Ryan B, Atreya Chloe E, Falchook Gerald S, Kwak Eunice L, Ryan David P, Bendell Johanna C, Hamid Omid, Messersmith Wells A, Daud Adil, Kurzrock Razelle, Pierobon Mariaelena, Sun Peng, Cunningham Elizabeth, Little Shonda, Orford Keith, Motwani Monica, Bai Yuchen, Patel Kiran, Venook Alan P, Kopetz Scott
机构信息
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.
出版信息
J Clin Oncol. 2015 Dec 1;33(34):4023-31. doi: 10.1200/JCO.2015.63.2471. Epub 2015 Sep 21.
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.
目的
评估选择性BRAF抑制剂达拉非尼联合选择性MEK抑制剂曲美替尼治疗BRAF V600突变转移性结直肠癌（mCRC）患者的疗效。
患者与方法
43例BRAF V600突变mCRC患者接受达拉非尼（每日2次，每次150 mg）加曲美替尼（每日2 mg）治疗，其中17例纳入药效学队列，在治疗前和治疗期间进行强制活检。对存档组织进行微卫星不稳定性、PTEN状态和487基因测序分析。从核心活检样本建立患者来源的异种移植模型。
结果
43例患者中，5例（12%）获得部分缓解或更好疗效，包括1例（2%）完全缓解，缓解持续时间>36个月；24例患者（56%）病情稳定为最佳确认疗效。10例患者（23%）研究持续时间>6个月。所有9次可评估的治疗期间活检显示，与治疗前活检相比，磷酸化ERK水平降低（平均降低±标准差，47%±24%）。突变分析显示，获得完全缓解的患者以及3例可评估的获得部分缓解患者中的2例存在PIK3CA突变。PTEN缺失和微卫星不稳定性均与疗效无关。携带患者来源异种移植模型的小鼠和各相应患者的活检病变对达拉非尼加曲美替尼的反应相当。
结论
达拉非尼加曲美替尼联合方案对部分BRAF V600突变mCRC患者有活性。所有评估患者的丝裂原活化蛋白激酶信号均受到抑制，但程度低于单用达拉非尼治疗的BRAF突变黑色素瘤患者。在有反应的患者中鉴定出PIK3CA突变，因此不排除对该方案有反应。有必要针对该疾病开展更多靶向丝裂原活化蛋白激酶途径的研究。
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