达拉非尼联合曲美替尼治疗BRAF突变型黑色素瘤脑转移患者（COMBI-MB）：一项多中心、多队列、开放标签的2期试验。
Dabrafenib plus trametinib in patients with BRAF-mutant melanoma brain metastases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial.
作者信息
Davies Michael A, Saiag Philippe, Robert Caroline, Grob Jean-Jacques, Flaherty Keith T, Arance Ana, Chiarion-Sileni Vanna, Thomas Luc, Lesimple Thierry, Mortier Laurent, Moschos Stergios J, Hogg David, Márquez-Rodas Iván, Del Vecchio Michele, Lebbé Céleste, Meyer Nicolas, Zhang Ying, Huang Yingjie, Mookerjee Bijoyesh, Long Georgina V
机构信息
Melanoma Medical Oncology and Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Service de Dermatologie Générale et Oncologique, Hôpital A Paré, Assistance Publique-Hôpitaux de Paris, Boulogne Billancourt, France; EA 4340, Université Versailles Saint-Quentin-en-Yvelines, Boulogne Billancourt, France.
出版信息
Lancet Oncol. 2017 Jul;18(7):863-873. doi: 10.1016/S1470-2045(17)30429-1. Epub 2017 Jun 4.
BACKGROUND
Dabrafenib plus trametinib improves clinical outcomes in BRAF-mutant metastatic melanoma without brain metastases; however, the activity of dabrafenib plus trametinib has not been studied in active melanoma brain metastases. Here, we report results from the phase 2 COMBI-MB trial. Our aim was to build on the current body of evidence of targeted therapy in melanoma brain metastases through an evaluation of dabrafenib plus trametinib in patients with BRAF-mutant melanoma brain metastases.
METHODS
This ongoing, multicentre, multicohort, open-label, phase 2 study evaluated oral dabrafenib (150 mg twice per day) plus oral trametinib (2 mg once per day) in four patient cohorts with melanoma brain metastases enrolled from 32 hospitals and institutions in Europe, North America, and Australia: (A) BRAF-positive, asymptomatic melanoma brain metastases, with no previous local brain therapy, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; (B) BRAF-positive, asymptomatic melanoma brain metastases, with previous local brain therapy, and an ECOG performance status of 0 or 1; (C) BRAF-positive, asymptomatic melanoma brain metastases, with or without previous local brain therapy, and an ECOG performance status of 0 or 1; and (D) BRAF-positive, symptomatic melanoma brain metastases, with or without previous local brain therapy, and an ECOG performance status of 0, 1, or 2. The primary endpoint was investigator-assessed intracranial response in cohort A in the all-treated-patients population. Secondary endpoints included intracranial response in cohorts B, C, and D. This study is registered with ClinicalTrials.gov, number NCT02039947.
FINDINGS
Between Feb 28, 2014, and Aug 5, 2016, 125 patients were enrolled in the study: 76 patients in cohort A; 16 patients in cohort B; 16 patients in cohort C; and 17 patients in cohort D. At the data cutoff (Nov 28, 2016) after a median follow-up of 8·5 months (IQR 5·5-14·0), 44 (58%; 95% CI 46-69) of 76 patients in cohort A achieved an intracranial response. Intracranial response by investigator assessment was also achieved in nine (56%; 95% CI 30-80) of 16 patients in cohort B, seven (44%; 20-70) of 16 patients in cohort C, and ten (59%; 33-82) of 17 patients in cohort D. The most common serious adverse events related to study treatment were pyrexia for dabrafenib (eight [6%] of 125 patients) and decreased ejection fraction (five [4%]) for trametinib. The most common grade 3 or worse adverse events, regardless of study drug relationship, were pyrexia (four [3%] of 125) and headache (three [2%]).
INTERPRETATION
Dabrafenib plus trametinib was active with a manageable safety profile in this melanoma population that was consistent with previous dabrafenib plus trametinib studies in patients with BRAF-mutant melanoma without brain metastases, but the median duration of response was relatively short. These results provide evidence of clinical benefit with dabrafenib plus trametinib and support the need for additional research to further improve outcomes in patients with melanoma brain metastases.
FUNDING
Novartis.
背景
达拉非尼联合曲美替尼可改善BRAF突变的无脑转移转移性黑色素瘤患者的临床结局；然而，达拉非尼联合曲美替尼在活动性黑色素瘤脑转移中的活性尚未得到研究。在此，我们报告2期COMBI-MB试验的结果。我们的目的是通过评估达拉非尼联合曲美替尼在BRAF突变的黑色素瘤脑转移患者中的疗效，以补充目前黑色素瘤脑转移靶向治疗的证据。
方法
这项正在进行的多中心、多队列、开放标签的2期研究，评估了口服达拉非尼（每日两次，每次150 mg）联合口服曲美替尼（每日一次，每次2 mg），共纳入来自欧洲、北美和澳大利亚32家医院和机构的4个黑色素瘤脑转移患者队列：（A）BRAF阳性、无症状的黑色素瘤脑转移患者，既往未接受过局部脑治疗，东部肿瘤协作组（ECOG）体能状态为0或1；（B）BRAF阳性、无症状的黑色素瘤脑转移患者，既往接受过局部脑治疗，ECOG体能状态为0或1；（C）BRAF阳性、无症状的黑色素瘤脑转移患者，既往接受或未接受过局部脑治疗，ECOG体能状态为0或1；（D）BRAF阳性、有症状的黑色素瘤脑转移患者，既往接受或未接受过局部脑治疗，ECOG体能状态为0、1或2。主要终点是在所有接受治疗的患者群体中，研究者评估的队列A的颅内反应。次要终点包括队列B、C和D中的颅内反应。本研究已在ClinicalTrials.gov注册，编号为NCT02039947。
结果
2014年2月28日至2016年8月5日期间，125例患者入组本研究：队列A 76例患者；队列B 16例患者；队列C 16例患者；队列D 17例患者。在数据截止日期（2016年11月28日），中位随访8.5个月（IQR 5.5 - 14.0）后，队列A的76例患者中有44例（58%；95%CI 46 - 69）达到颅内反应。队列B的16例患者中有9例（56%；95%CI 30 - 80）、队列C的16例患者中有7例（44%；20 - 70）、队列D的17例患者中有10例（59%；33 - 82）通过研究者评估达到颅内反应。与研究治疗相关的最常见严重不良事件是达拉非尼引起的发热（125例患者中有8例[6%]）和曲美替尼引起的射血分数降低（5例[4%]）。无论与研究药物的关系如何，最常见的3级或更严重不良事件是发热（125例中有4例[3%]）和头痛（3例[2%]）。
解读
在该黑色素瘤人群中，达拉非尼联合曲美替尼具有活性，安全性可控，这与之前达拉非尼联合曲美替尼在无脑转移的BRAF突变黑色素瘤患者中的研究一致，但中位反应持续时间相对较短。这些结果提供了达拉非尼联合曲美替尼具有临床获益的证据，并支持开展更多研究以进一步改善黑色素瘤脑转移患者的结局。
资助
诺华公司。
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