Advances in the treatment of<em>BRAF</em>V600-mutant non-small cell lung cancer

赵媛媛; 周建英; 范　云; 王佳蕾; 黄鼎智; 李峻岭; 史美祺; 刘基巍; 姚　煜; 邬　麟; 姚文秀; 张　力

doi:10.19401/j.cnki.1007-3639.2021.12.001

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Advances in the treatment ofBRAFV600-mutant non-small cell lung cancer

更新时间：2025-12-31

- Advances in the treatment ofBRAFV600-mutant non-small cell lung cancer
- China Oncology Vol. 31, Issue 12, Pages: 1145-1152(2021)
- 作者机构：
  
  1. 中山大学附肿瘤防治中心肿瘤内科,广东,广州,510060
  2. 浙江大学医学院附属第一医院呼吸内科,浙江,杭州,310003
  3. 中国科学院大学附属肿瘤医院 / 浙江省肿瘤医院肿瘤内科,浙江,杭州,310022
  4. 复旦大学附属肿瘤医院肿瘤内科，复旦大学医学院肿瘤学系,上海,200032
  5. 天津市肿瘤医院肺部肿瘤内科,天津,300181
  6. 中国医学科学院肿瘤医院内科,北京,100021
  7. 江苏省肿瘤医院肿瘤内科,江苏,南京,210009
  8. 大连医科大学附属第一医院肿瘤科,辽宁,大连,116011
  9. 西安交通大学第一附属医院肿瘤内科,陕西,西安,710061
  10. 四川省肿瘤医院肿瘤内科,四川,成都,610042
- 作者简介：
- 基金信息：
- DOI：10.19401/j.cnki.1007-3639.2021.12.001
  CLC：
- Published Online：07 January 2022，
  
  Published：07 January 2021
- 稿件说明：
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赵媛媛, 周建英, 范　云, 王佳蕾, 黄鼎智, 李峻岭, 史美祺, 刘基巍, 姚　煜, 邬　麟, 姚文秀, 张　力 .

赵媛媛, 周建英, 范　云, et al. Advances in the treatment ofBRAFV600-mutant non-small cell lung cancer[J]. China Oncology, 2021, 31(12): 1145-1152.
赵媛媛, 周建英, 范　云, 王佳蕾, 黄鼎智, 李峻岭, 史美祺, 刘基巍, 姚　煜, 邬　麟, 姚文秀, 张　力 . DOI： 10.19401/j.cnki.1007-3639.2021.12.001.

赵媛媛, 周建英, 范　云, et al. Advances in the treatment ofBRAFV600-mutant non-small cell lung cancer[J]. China Oncology, 2021, 31(12): 1145-1152. DOI： 10.19401/j.cnki.1007-3639.2021.12.001.

摘要

肺癌是中国发病率和死亡率均排在第一位的恶性肿瘤，其中非小细胞肺癌（non-small cell lung cancer，NSCLC）约占肺癌的85%。鼠类肉瘤病毒癌基因同源物B1（V-Raf murine sarcoma viral oncogene homolog B1，BRAF）突变在NSCLC中的发生率为1.5%~3.5%，而BRAF V600约占所有BRAF突变的50%，其中V600E突变最为常见。国内外研究显示，NSCLC中的BRAF突变在男女比例和吸烟状态等方面的差异并不一致，而在病理学类型上，BRAF突变（尤其是BRAF V600E突变）的NSCLC患者均以腺癌为主。BRAF V600突变NSCLC患者的预后差，总生存期（overall survival，OS）较短。在此类患者的药物治疗方面，目前化疗和免疫治疗的临床获益并不理想，化疗的无进展生存期（progression-free survival，PFS）仅为1.5~4.2个月；免疫检查点抑制剂治疗BRAF突变NSCLC患者的PFS也只有2.5~5.3个月。而近年来靶向治疗的应用，为肺癌BRAF突变患者带来了新的希望。Ⅱ期临床试验VE-BASKET使用了BRAF抑制剂维莫非尼治疗BRAF V600E突变型NSCLC，最终结果显示，患者中位PFS和OS分别为6.5和15.4个月，初步证明了该药的有效性；但安全性仍需关注，约77%的患者发生了3/4级不良事件（adverse event，AE）。另一种BRAF抑制剂达拉非尼，对于BRAF V600E突变NSCLC患者，在Ⅱ期临床试验BRF113928的三个队列中，分别证明了该药作为单药治疗经治患者（队列A）、联合丝裂原活化蛋白激酶（mitogen-activated protein kinase，MAPK）激酶（MAPK kinases，MEK）抑制剂曲美替尼治疗经治患者（队列B）以及联合曲美替尼治疗初治患者（队列C）均具有显著疗效，客观缓解率（objective response rate，ORR）分别为33.0%、63.2%和64.0%，PFS分别为5.5、9.7和14.6个月。近期，该研究的5年长期生存随访数据还报告了队列B和C患者的5年OS率分别为19%和22%。BRF113928研究表明，无论作为一线治疗还是后线治疗，达拉非尼联合曲美替尼治疗BRAF V600突变NSCLC患者均具有良好的疗效，且优于BRAF单药靶向治疗。在安全性方面，常见AE为发热和消化道不良反应等，且大多为1~2级，而3/4级AE或因AE而中断治疗的发生率相对较低，总体上安全可控。在现有治疗药物的开发基础上，BRAF V600E突变NSCLC仍有许多值得深入探索的方向，如：① 将BRAF抑制剂用于辅助/新辅助治疗；② 靶向联合免疫治疗或抗血管生成药物；③ 双靶耐药后，探索耐药机制以开发新靶向药物或新联合治疗模式，或研发新型BRAF抑制剂，或尝试探索双靶耐药后“再挑战”等。近年来的一些病例报告或探索性研究已经提供了这些方向的线索。目前，达拉非尼联合曲美替尼已被美国国家综合癌症网络（National Comprehensive Cancer Network，NCCN）和欧洲肿瘤内科学会（European Society for Medical Oncology，ESMO）等多个指南优先推荐为BRAF V600E/V600突变NSCLC患者的优选治疗。将聚焦于BRAF V600突变NSCLC患者，对其临床/病理学特征及治疗进展进行系统阐述。

Abstract

Lung cancer has the highest morbidity and mortality among malignant tumors in China. Non-small cell lung cancer (NSCLC) represents approximately 85% of all new lung cancer diagnoses. V-Raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations emerge in about 1.5%-3.5% of the NSCLC cases. BRAF V600 accounts for about 50% of all BRAF mutations

among which V600E mutation is the most common. It has been reported that the proportion of men and women and smoking status in patients with BRAF-mutant NSCLC are still disputed. Pathological characteristics show that patients with BRAF-mutant NSCLC (especially BRAF V600E mutation) mainly have adenocarcinoma. Patients with BRAF V600-mutant NSCLC have poor prognosis and short overall survival (OS). The clinical benefits of chemotherapy or immunotherapy for BRAF-mutant NSCLC are not ideal as reported in the current studies. The progression-free survival (PFS) of patients with BRAF-mutant NSCLC treated with chemotherapy is only 1.5-4.2 months

while the PFS of those treated with immune checkpoint inhibitors is 2.5-5.3 months. In recent years

the application of targeted therapy has brought new breakthroughs to the treatment of BRAF V600-mutant NSCLC patients. VE-BASKET was a phase Ⅱ clinical trial

in which the BRAF inhibitor vemurafenib was used to treat BRAF V600E-mutant NSCLC. The final analysis results showed that the median PFS and OS of those patients were 6.5 months and 15.4 months respectively

which preliminarily proved the effectiveness of vemurafenib. However

about 77% of all patients had grade 3/4 adverse events (AEs) which need to be paid more attention. Dabrafenib

another BRAF inhibitor

has achieved significant efficacy in patients with BRAF V600E-mutant NSCLC in the phase Ⅱ clinical trial BRF113928. All patients were divided into three cohorts with dabrafenib monotherapy (cohort A)

treated patients with combination therapy of dabrafenib plus mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor trametinib (cohort B) and untreated patients with combination therapy of dabrafenib plus trametinib (cohort C). The objective response rate (ORR) was 33%

63.2% and 64%

and PFS was 5.5

9.7 and 14.6 months in cohort A

B and C

respectively. Recently

the 5-year overall survival (OS) data of this study have also shown that 5-year OS rates of patients in cohort B and C were 19% and 22%

respectively. BRF113928 suggested that dabrafenib plus trametinib had good efficacy in both naive- treatment and treated patients with BRAF V600-mutant NSCLC

which was better than single-agent BRAF inhibition. The safety outcomes showed that the common AEs were fever and gastrointestinal reaction. And most of them were grade 1-2

while the incidence of grade 3/4 AEs or interruption of treatment due to AEs were relatively low. Dabrafenib is generally safe and controllable. Based on the development of existing therapeutic drugs

many research subjects of BRAF V600E-mutant NSCLC is worthy to be explored

including using BRAF inhibitors for adjuvant/neoadjuvant therapy

combination with immunotherapy or antiangiogenic drugs

exploring the drug resistance mechanism to develop new targeted drugs or new combined treatment modes

developing new BRAF inhibitors and exploring the BRAF inhibitors "re-challenge" after dual-target drug resistance. Some related case reports or exploratory studies in recent years have provided clues to these directions. At present

dabrafenib plus trametinib has been preferably recommended for the treatment of BRAF V600E/V600-mutant NSCLC by some guidelines

such as National Comprehensive Cancer Network (NCCN) guidelines of the United States and European Society for Medical Oncology (ESMO) guidelines. This article focused on patients with BRAF V600-mutant NSCLC

and summarized their clinical or pathological characteristics and the treatment progress.

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Advances in the treatment ofBRAFV600-mutant non-small cell lung cancer

DOI：10.19401/j.cnki.1007-3639.2021.12.001

摘要

Abstract

关键词

Keywords

references