Dabrafenib plus trametinib in patients with previously untreated BRAFV600E-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial
Dabrafenib plus trametinib in patients with previously untreated BRAFV600E-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial
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DOI：
10.1016/s1470-2045(17)30679-4
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发表时间：
2017-10-01
期刊：
影响因子：
51.1
通讯作者：
Johnson, Bruce E.
中科院分区：
文献类型：
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作者：
Planchard, David;Smit, Egbert F.;Johnson, Bruce E.
背景BRAF（V600 E）突变发生在1-2%的肺腺癌中，并作为致癌驱动因子。达拉非尼单用或与曲美替尼联合使用，在既往接受过治疗的BRAF（V600 E）突变转移性非小细胞肺癌（NSCLC）患者中显示出显著的抗肿瘤活性。我们的目的是评估达拉非尼加曲美替尼治疗既往未经治疗的BRAF（V600 E）突变转移性NSCLC患者的活性和安全性。成年人（≥ 18岁）既往未接受过治疗的转移性BRAF（V600 E）-来自北美、欧洲和亚洲8个国家19个中心的突变型NSCLC入组队列C。患者接受每日两次口服达拉非尼150 mg+每日一次口服曲美替尼2 mg，直至疾病进展、不可接受的不良事件、撤回知情同意或死亡。主要终点为经评估的总体缓解，定义为根据实体瘤缓解评价标准第1.1版获得确认的完全缓解或部分缓解的患者百分比。在方案定义的人群（既往未接受过治疗的患者）中，按意向治疗进行主要和安全性分析。该研究正在进行中，但不再招募患者。本试验已在ClinicalTrials注册。在2014年4月16日至2015年12月28日期间，36名患者入组并接受一线达拉非尼加曲美替尼治疗。数据截止日期（2017年4月28日）时，中位随访时间为15.9个月（IQR 7.8-22.0）。经评估确认总体缓解的患者比例为23例（64%，95% CI 46-79），其中2例（6%）患者达到完全缓解，21例（58%）患者达到部分缓解。所有患者均发生1起或多起任何级别的不良事件，25例（69%）发生1起或多起3级或4级事件。最常见的（发生在2例以上患者中）3级或4级不良事件为发热（4例[11%]）、丙氨酸氨基转移酶升高（4例[11%]）、高血压（4例[11%]）和呕吐（3例[8%]）。超过2例患者发生的严重不良事件包括丙氨酸氨基转移酶升高（5例[14%]）、发热（4例[11%]）、天冬氨酸氨基转移酶升高（3例[8%]）和射血分数降低（3例[8%]）。报告了1例被认为与研究治疗无关的致命性严重不良事件（心跳呼吸骤停）。解读达拉非尼加曲美替尼代表了一种新疗法，在既往未经治疗的BRAFV 600 E突变型NSCLC患者中具有临床意义的抗肿瘤活性和可管理的安全性特征。
Background BRAF(V600E) mutation occurs in 1-2% of lung adenocarcinomas and acts as an oncogenic driver. Dabrafenib, alone or combined with trametinib, has shown substantial antitumour activity in patients with previously treated BRAF(V600E)-mutant metastatic non-small-cell lung cancer (NSCLC). We aimed to assess the activity and safety of dabrafenib plus trametinib treatment in previously untreated patients with BRAF(V600E)-mutant metastatic NSCLC.Methods In this phase 2, sequentially enrolled, multicohort, multicentre, non-randomised, open-label study, adults (>= 18 years of age) with previously untreated metastatic BRAF(V600E)-mutant NSCLC were enrolled into cohort C from 19 centres in eight countries within North America, Europe, and Asia. Patients received oral dabrafenib 150 mg twice per day plus oral trametinib 2 mg once per day until disease progression, unacceptable adverse events, consent withdrawal, or death. The primary endpoint was investigator-assessed overall response, defined as the percentage of patients who achieved a confirmed complete response or partial response per Response Evaluation Criteria In Solid Tumors version 1.1. The primary and safety analyses were by intention to treat in the protocol-defined population (previously untreated patients). The study is ongoing, but no longer recruiting patients. This trial is registered with ClinicalTrials. gov, number NCT01336634.Findings Between April 16, 2014, and Dec 28, 2015, 36 patients were enrolled and treated with first-line dabrafenib plus trametinib. Median follow-up was 15.9 months (IQR 7.8-22.0) at the data cutoff (April 28, 2017). The proportion of patients with investigator-assessed confirmed overall response was 23 (64%, 95% CI 46-79), with two (6%) patients achieving a complete response and 21 (58%) a partial response. All patients had one or more adverse event of any grade, and 25 (69%) had one or more grade 3 or 4 event. The most common (occurring in more than two patients) grade 3 or 4 adverse events were pyrexia (four [11%]), alanine aminotransferase increase (four [11%]), hypertension (four [11%]), and vomiting (three [8%]). Serious adverse events occurring in more than two patients included alanine aminotransferase increase (five [14%]), pyrexia (four [11%]), aspartate aminotransferase increase (three [8%]), and ejection fraction decrease (three [8%]). One fatal serious adverse event deemed unrelated to study treatment was reported (cardiorespiratory arrest).Interpretation Dabrafenib plus trametinib represents a new therapy with clinically meaningful antitumour activity and a manageable safety profile in patients with previously untreated BRAFV600E-mutant NSCLC.