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《柳叶刀肿瘤分册》:肺癌的一线治疗新方案获突破

230人阅读  09月13日
肺癌
来源:桓兴医讯

据估计,全球每年约有3.6万人(约占肺癌患者总数的1-3%)被诊断为BRAF V600阳性NSCLC。2017年4月5日,欧盟委员会批准了诺华的Tafinlar(dabrafenib)与Mekinist(trametinib)组合用于治疗BRAF V600阳性晚期或转移性非小细胞肺癌(NSCLC)患者。该批准标志着欧盟所有28个成员国以及冰岛和挪威的此类患者首次得到针对性治疗方案,而以前几乎没有方法治疗。

http://thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30679-4/fulltext

在既往未治疗过的BRAFV600E突变的转移性非小细胞肺癌患者中用达拉非尼(dabrafenib)+曲美替尼(trametinib)治疗:一项开放标签的2期临床试验

背景

BRAFV600E突变发挥致癌基因的作用,约有1-2%的肺腺癌会出现BRAFV600E突变,单独使用达拉非尼(dabrafenib)或联合曲美替尼(trametinib)用于既往未治疗过的BRAFV600E突变的转移性非小细胞肺癌患者,已显示出明显的抗肿瘤活性。在此,我们在既往未治疗过的BRAFV600E突变的转移性非小细胞肺癌患者中旨在评价达拉非尼(dabrafenib)+曲美替尼(trametinib)的有效性和安全性。

方法

在这项2期、连续入组、多队列、多中心、非随机化、开放标签的研究中,将既往未治疗过的BRAFV600E突变的转移性非小细胞肺癌成年患者(≥18岁)入组到C队列,这些患者来自北美、欧洲、亚洲的8个国家19家医疗中心。患者每日两次口服达拉非尼150mg+每日一次曲美替尼2mg,直至出现疾病进展、不可耐受的不良反应、患者要求终止试验或死亡。主要终点为研究人员评价的总缓解率,总缓解率为按照“实体瘤疗效评价标准1.1版”确认为完全缓解或部分缓解患者的百分比。通过意向性治疗在研究方案确定的患者群(既往未治疗过的患者)中进行主要分析和安全性分析。研究仍在进行,但不再招募患者,这项临床试验已在ClinicalTrials.gov网站注册,注册号NCT01336634。

结果

2014年4月16日至2014年12月28日,入组并用达拉非尼+曲美替尼一线治疗了36名患者,数据锁定日(2017年4月28日)的中位随访时间15.9个月(IQR,7.8–22.0),研究人员评价的确切总缓解患者的比例为23名(64%,95%CI,46–79),其中2名患者(6%)获得完全缓解、21名(58%)部分缓解。所有患者有一种及一种以上的各种级别的不良反应,25名(69%)有3、4级不良反应,最常见(超过2名患者出现)的3、4级不良反应为发热(4名[11%])、丙氨酸转氨酶升高(4名[11%])、高血压(4名[11%])和呕吐(3名[8%])。超过2名患者出现的严重不良反应包括丙氨酸转氨酶升高(5名[14%])、发热(4名[11%)、天冬氨酸转氨酸升高(3名[8%])、射血分数下降(3名[8%])。报告了1次致命性不良反应(呼吸心跳骤停),判定与研究性治疗不相关。

解释

在既往未治疗过的BRAFV600E突变的转移性非小细胞肺癌患者中,达拉非尼+曲美替尼是一种新的治疗方案,临床抗肿瘤效果佳、安全可控。

Dabrafenib plus trametinib in patientswith previously untreated BRAFV600E-mutantmetastatic non-small-cell lung cancer: an open-label, phase 2 trial 

Background

BRAFV600E mutation occursin 1–2% of lung adenocarcinomas and acts as an oncogenic driver. Dabrafenib,alone or combined with trametinib, has shown substantial antitumour activity inpatients with previously treated BRAFV600E-mutantmetastatic non-small-cell lung cancer (NSCLC). We aimed to assess the activityand safety of dabrafenib plus trametinib treatment in previously untreatedpatients with BRAFV600E-mutant metastatic NSCLC.

Methods

In this phase 2,sequentially enrolled, multicohort, multicentre, non-randomised, open-labelstudy, adults (≥18 years of age) with previously untreated metastatic BRAFV600E-mutant NSCLCwere enrolled into cohort C from 19 centres in eight countries within NorthAmerica, Europe, and Asia. Patients received oral dabrafenib 150 mg twice perday plus oral trametinib 2 mg once per day until disease progression,unacceptable adverse events, consent withdrawal, or death. The primary endpointwas investigator-assessed overall response, defined as the percentage ofpatients who achieved a confirmed complete response or partial response perResponse Evaluation Criteria In Solid Tumors version 1.1. The primary andsafety analyses were by intention to treat in the protocol-defined population(previously untreated patients). The study is ongoing, but no longer recruitingpatients. This trial is registered withClinicalTrials.gov, number NCT01336634.

Findings

Between April16, 2014, and Dec 28, 2015, 36 patients were enrolled and treated withfirst-line dabrafenib plus trametinib. Median follow-up was 15·9 months (IQR7·8–22·0) at the data cutoff (April 28, 2017). The proportion of patients withinvestigator-assessed confirmed overall response was 23 (64%, 95% CI 46–79),with two (6%) patients achieving a complete response and 21 (58%) a partialresponse. 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 twopatients) grade 3 or 4 adverse events were pyrexia (four [11%]), alanineaminotransferase increase (four [11%]), hypertension (four [11%]), and vomiting(three [8%]). Serious adverse events occurring in more than two patientsincluded alanine aminotransferase increase (five [14%]), pyrexia (four [11%]),aspartate aminotransferase increase (three [8%]), and ejection fractiondecrease (three [8%]). One fatal serious adverse event deemed unrelated tostudy treatment was reported (cardiorespiratory arrest).

Interpretation

Dabrafenib plustrametinib represents a new therapy with clinically meaningful antitumouractivity and a manageable safety profile in patients with previously untreatedBRAFV600E-mutant NSCLC.

责任编辑:肿瘤资讯-Ruby

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