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Vemurafenib in non-small-cell lung cancer patients with BRAFV600 and BRAFnonV600 mutations.
文献信息
| DOI | 10.1016/j.annonc.2019.10.022 |
|---|---|
| PMID | 31959346 |
| 期刊 | Annals of oncology : official journal of the European Society for Medical Oncology |
| 影响因子 | 65.4 |
| JCR 分区 | Q1 |
| 发表年份 | 2020 |
| 被引次数 | 82 |
| 关键词 | BRAF，篮式试验，生物标志物，肺癌，个性化治疗 |
| 文献类型 | Journal Article, Research Support, Non-U.S. Gov't |
| ISSN | 0923-7534 |
| 页码 | 289-294 |
| 期号 | 31(2) |
| 作者 | J Mazieres, C Cropet, L Montané, F Barlesi, P J Souquet, X Quantin, C Dubos-Arvis, J Otto, L Favier, V Avrillon, J Cadranel, D Moro-Sibilot, I Monnet, V Westeel, J Le Treut, E Brain, J Trédaniel, M Jaffro, S Collot, G R Ferretti, C Tiffon, C Mahier-Ait Oukhatar, J Y Blay |
一句话小结
这项研究评估了vemurafenib在非小细胞肺癌（NSCLC）患者中的疗效，特别是针对BRAF突变的影响，结果显示BRAFV600突变的患者中有44.9%的客观反应率，而BRAF非V600突变患者未见有效反应，提示常规筛查应包括BRAFV600突变，以优化治疗策略。研究强调了针对特定基因突变的个体化治疗在NSCLC管理中的重要性。
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BRAF · 篮式试验 · 生物标志物 · 肺癌 · 个性化治疗
摘要
背景
在非小细胞肺癌（NSCLC）患者中，BRAF突变发生率为1%-5%，这些突变是该癌症的治疗靶点，但确切突变对临床疗效的影响尚不明确。法国国家癌症研究所（INCA）启动了AcSé vemurafenib试验，以评估vemurafenib在各种BRAF突变癌症中的疗效和安全性。我们在此报告NSCLC队列的结果。
患者与方法
在INCA认证的分子遗传学中心筛查肿瘤样本中的BRAF突变。对于在接受≥1线治疗后进展的BRAF突变肿瘤患者，建议使用vemurafenib 960毫克，每日两次。从2014年10月到2018年7月，共有118名患者被纳入NSCLC队列。主要结果是每8周评估的客观反应率（ORR）（RECIST v1.1）。计划采用序贯贝叶斯方法，ORR的无效界限设定为10%。如果没有早期停止，若估计的ORR为≥30%，则治疗被认为有意义，概率为90%。次要结果包括耐受性、反应持续时间、无进展生存期（PFS）和总生存期（OS）。
结果
在118名入组患者中，101名表现出BRAFV600突变，17名表现出BRAF非V600突变；中位随访时间为23.9个月。在BRAF非V600队列中未观察到客观反应，因此该队列被停止。在BRAFV600队列中，43/96名患者有客观反应。贝叶斯估计的成功率均值为44.9% [95%置信区间（CI）35.2%-54.8%]。ORR的≥30%概率为99.9%。中位反应持续时间为6.4个月，中位PFS为5.2个月（95% CI 3.8-6.8），OS为10个月（95% CI 6.8-15.7）。vemurafenib的安全性特征与之前的出版物一致。
结论
常规的NSCLC生物标志物筛查应包括BRAFV600突变。vemurafenib单药治疗对BRAFV600突变的NSCLC患者有效，但对BRAF非V600突变患者无效。
试验注册
ClinicalTrials.gov标识符：NCT02304809。
英文摘要
BACKGROUND BRAF mutations occurring in 1%-5% of patients with non-small-cell lung cancer (NSCLC) are therapeutic targets for these cancers but the impact of the exact mutation on clinical activity is unclear. The French National Cancer Institute (INCA) launched the AcSé vemurafenib trial to assess the efficacy and safety of vemurafenib in cancers with various BRAF mutations. We herein report the results of the NSCLC cohort.
PATIENTS AND METHODS Tumour samples were screened for BRAF mutations in INCA-certified molecular genetic centres. Patients with BRAF-mutated tumours progressing after ≥1 line of treatment were proposed vemurafenib 960 mg twice daily. Between October 2014 and July 2018, 118 patients were enrolled in the NSCLC cohort. The primary outcome was the objective response rate (ORR) assessed every 8 weeks (RECIST v1.1). A sequential Bayesian approach was planned with an inefficacy bound of 10% for ORR. If no early stopping occurred, the treatment was of interest if the estimated ORR was ≥30% with a 90% probability. Secondary outcomes were tolerance, response duration, progression-free survival (PFS), and overall survival (OS).
RESULTS Of the 118 patients enrolled, 101 presented with a BRAFV600 mutation and 17 with BRAFnonV600 mutations; the median follow-up was 23.9 months. In the BRAFnonV600 cohort, no objective response was observed and this cohort was stopped. In the BRAFV600 cohort, 43/96 patients had objective responses. The mean Bayesian estimated success rate was 44.9% [95% confidence intervals (CI) 35.2%-54.8%]. The ORR had a 99.9% probability of being ≥30%. Median response duration was 6.4 months, median PFS was 5.2 months (95% CI 3.8-6.8), and OS was 10 months (95% CI 6.8-15.7). The vemurafenib safety profile was consistent with previous publications.
CONCLUSION Routine biomarker screening of NSCLC should include BRAFV600 mutations. Vemurafenib monotherapy is effective for treating patients with BRAFV600-mutated NSCLC but not those with BRAFnonV600 mutations.
TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT02304809.
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主要研究问题
- BRAFV600和BRAFnonV600突变在非小细胞肺癌中的临床表现有何不同？
- 除了vemurafenib，还有哪些治疗方案适用于BRAFV600突变的非小细胞肺癌患者？
- 在进行vemurafenib治疗时，如何监测患者的耐受性和副作用？
- 该研究的结果对未来非小细胞肺癌的生物标志物筛查有何启示？
- 针对BRAFnonV600突变的非小细胞肺癌患者，当前的研究有哪些潜在的治疗方向？
核心洞察
1. 研究背景和目的
BRAF突变在非小细胞肺癌（NSCLC）患者中发生率为1%-5%，这些突变被认为是治疗的靶点。然而，不同类型的BRAF突变对临床疗效的影响尚不明确。为了评估贝美替尼（vemurafenib）在不同BRAF突变类型中的疗效与安全性，法国国家癌症研究所（INCA）启动了AcSé vemurafenib试验。本研究旨在报告NSCLC队列的结果，特别关注BRAFV600和BRAFnonV600突变患者的反应。
2. 主要方法和发现
研究通过在INCA认证的分子基因中心筛查肿瘤样本中的BRAF突变，招募了经过至少一线治疗后进展的BRAF突变患者，给予贝美替尼960 mg每日两次的治疗。共招募118名患者，BRAFV600突变患者101例，BRAFnonV600突变患者17例。主要终点为客观反应率（ORR），每8周评估一次，采用RECIST v1.1标准。在BRAFV600突变组中，43/96患者显示出客观反应，平均贝叶斯估计成功率为44.9%，且ORR的90%概率≥30%。在BRAFnonV600组中未观察到客观反应，因此该组提前终止。BRAFV600组的中位反应持续时间为6.4个月，中位无进展生存期（PFS）为5.2个月，中位总生存期（OS）为10个月。贝美替尼的安全性与以往研究一致。
3. 核心结论
常规的生物标志物筛查应包括BRAFV600突变的检测。贝美替尼单药治疗对BRAFV600突变的NSCLC患者有效，但对BRAFnonV600突变患者则无效。
4. 研究意义和影响
本研究的结果强调了在NSCLC患者中进行BRAF突变筛查的重要性，特别是BRAFV600突变患者的治疗选择上。贝美替尼作为靶向治疗的有效性为BRAF突变型非小细胞肺癌患者提供了新的治疗方案，而对BRAFnonV600突变患者的无效则提示了不同突变类型在治疗反应上的差异。这为临床实践提供了依据，促进了个性化治疗的发展，可能会影响未来的临床决策和治疗指南。
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