BRAF抑制剂治疗非小细胞肺癌的进展

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Abstract

近年来，靶向药物在非小细胞肺癌（non-small cell lung cancer, NSCLC）的治疗中占据着举足轻重的地位，针对表皮生长因子受体（epidermal growth factor receptor, EGFR）的靶向药物已在临床上广泛应用，具有里程碑意义。BRAF抑制剂是针对鼠类肉瘤病毒癌基因同源物B1（V-raf murine sarcoma viral oncogene homolog B1, BRAF）基因突变为靶点的靶向药物，对特定优势人群有明显的临床疗效，且毒副作用小，患者易耐受。近期发现，与其他靶向药物一样，BRAF抑制剂也存在耐药现象，其耐药机制正在研究中。本文就BRAF抑制剂的作用机制、临床应用、不良反应及耐药问题进行综述。

Translated abstract

In recent years, targeted drugs occupy a pivotal position in the treatment of non-small cell lung cancer (NSCLC), drugs targeting epidermal growth factor receptor (EGFR) has been widely used in clinical practice, it is of milestone significance. V-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitors targeted at BRAF gene have obviously clinical efficacy to specific advantages populations with little side-effect, and be well tolerated. It is discovered recently that drug resistance also exists in BRAF inhibitors like other targeted drugs, the mechanism of drug resistance is being studied. In this paper, a review were performed in the mechanism, clinical application, adverse reactions and the drug resistance of BRAF inhibitors.

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Most cited references 19

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Combined vemurafenib and cobimetinib in BRAF-mutated melanoma.

James Larkin, Paolo Ascierto, Brigitte Dréno … (2014)

The combined inhibition of BRAF and MEK is hypothesized to improve clinical outcomes in patients with melanoma by preventing or delaying the onset of resistance observed with BRAF inhibitors alone. This randomized phase 3 study evaluated the combination of the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib. We randomly assigned 495 patients with previously untreated unresectable locally advanced or metastatic BRAF V600 mutation-positive melanoma to receive vemurafenib and cobimetinib (combination group) or vemurafenib and placebo (control group). The primary end point was investigator-assessed progression-free survival. The median progression-free survival was 9.9 months in the combination group and 6.2 months in the control group (hazard ratio for death or disease progression, 0.51; 95% confidence interval [CI], 0.39 to 0.68; P<0.001). The rate of complete or partial response in the combination group was 68%, as compared with 45% in the control group (P<0.001), including rates of complete response of 10% in the combination group and 4% in the control group. Progression-free survival as assessed by independent review was similar to investigator-assessed progression-free survival. Interim analyses of overall survival showed 9-month survival rates of 81% (95% CI, 75 to 87) in the combination group and 73% (95% CI, 65 to 80) in the control group. Vemurafenib and cobimetinib was associated with a nonsignificantly higher incidence of adverse events of grade 3 or higher, as compared with vemurafenib and placebo (65% vs. 59%), and there was no significant difference in the rate of study-drug discontinuation. The number of secondary cutaneous cancers decreased with the combination therapy. The addition of cobimetinib to vemurafenib was associated with a significant improvement in progression-free survival among patients with BRAF V600-mutated metastatic melanoma, at the cost of some increase in toxicity. (Funded by F. Hoffmann-La Roche/Genentech; coBRIM ClinicalTrials.gov number, NCT01689519.).

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Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial.

Gerald Falchook, Georgina V Long, Razelle Kurzrock … (2012)

Dabrafenib is an inhibitor of BRAF kinase that is selective for mutant BRAF. We aimed to assess its safety and tolerability and to establish a recommended phase 2 dose in patients with incurable solid tumours, especially those with melanoma and untreated, asymptomatic brain metastases. We undertook a phase 1 trial between May 27, 2009, and March 20, 2012, at eight study centres in Australia and the USA. Eligible patients had incurable solid tumours, were 18 years or older, and had adequate organ function. BRAF mutations were mandatory for inclusion later in the study because of an absence of activity in patients with wild-type BRAF. We used an accelerated dose titration method, with the first dose cohort receiving 12 mg dabrafenib daily in a 21-day cycle. Once doses had been established, we expanded the cohorts to include up to 20 patients. On the basis of initial data, we chose a recommended phase 2 dose. Efficacy at the recommended phase 2 dose was studied in patients with BRAF-mutant tumours, including those with non-Val600Glu mutations, in three cohorts: metastatic melanoma, melanoma with untreated brain metastases, and non-melanoma solid tumours. This study is registered with ClinicalTrials.gov, number NCT00880321. We enrolled 184 patients, of whom 156 had metastatic melanoma. The most common treatment-related adverse events of grade 2 or worse were cutaneous squamous-cell carcinoma (20 patients, 11%), fatigue (14, 8%), and pyrexia (11, 6%). Dose reductions were necessary in 13 (7%) patients. No deaths or discontinuations resulted from adverse events, and 140 (76%) patients had no treatment-related adverse events worse than grade 2. Doses were increased to 300 mg twice daily, with no maximum tolerated dose recorded. On the basis of safety, pharmacokinetic, and response data, we selected a recommended phase 2 dose of 150 mg twice daily. At the recommended phase 2 dose in 36 patients with Val600 BRAF-mutant melanoma, responses were reported in 25 (69%, 95% CI 51·9-83·7) and confirmed responses in 18 (50%, 32·9-67·1). 21 (78%, 57·7-91·4) of 27 patients with Val600Glu BRAF-mutant melanoma responded and 15 (56%, 35·3-74·5) had a confirmed response. In Val600 BRAF-mutant melanoma, responses were durable, with 17 patients (47%) on treatment for more than 6 months. Responses were recorded in patients with non-Val600Glu BRAF mutations. In patients with melanoma and untreated brain metastases, nine of ten patients had reductions in size of brain lesions. In 28 patients with BRAF-mutant non-melanoma solid tumours, apparent antitumour activity was noted in a gastrointestinal stromal tumour, papillary thyroid cancers, non-small-cell lung cancer, ovarian cancer, and colorectal cancer. Dabrafenib is safe in patients with solid tumours, and an active inhibitor of Val600-mutant BRAF with responses noted in patients with melanoma, brain metastases, and other solid tumours. GlaxoSmithKline. Copyright © 2012 Elsevier Ltd. All rights reserved.

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Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1.

Kadoaki Ohashi, Lecia V. Sequist, Maria Arcila … (2012)

Acquired resistance to EGF receptor (EGFR) tyrosine kinase inhibitors (TKIs) is inevitable in metastatic EGFR-mutant lung cancers. Here, we modeled disease progression using EGFR-mutant human tumor cell lines. Although five of six models displayed alterations already found in humans, one harbored an unexpected secondary NRAS Q61K mutation; resistant cells were sensitive to concurrent EGFR and MEK inhibition but to neither alone. Prompted by this finding and because RAS/RAF/MEK mutations are known mediators of acquired resistance in other solid tumors (colon cancers, gastrointestinal stromal tumors, and melanomas) responsive to targeted therapies, we analyzed the frequency of secondary KRAS/NRAS/BRAF/MEK1 gene mutations in the largest collection to date of lung cancers with acquired resistance to EGFR TKIs. No recurrent NRAS, KRAS, or MEK1 mutations were found in 212, 195, or 146 patient samples, respectively, but 2 of 195 (1%) were found to have mutations in BRAF (G469A and V600E). Ectopic expression of mutant NRAS or BRAF in drug-sensitive EGFR-mutant cells conferred resistance to EGFR TKIs that was overcome by addition of a MEK inhibitor. Collectively, these positive and negative results provide deeper insight into mechanisms of acquired resistance to EGFR TKIs in lung cancer and inform ongoing clinical trials designed to overcome resistance. In the context of emerging knowledge about mechanisms of acquired resistance to targeted therapies in various cancers, our data highlight the notion that, even though solid tumors share common signaling cascades, mediators of acquired resistance must be elucidated for each disease separately in the context of treatment.

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Author and article information

Contributors

宋霞 SONG Xia

Journal

Journal ID (nlm-ta): Zhongguo Fei Ai Za Zhi

Journal ID (iso-abbrev): Zhongguo Fei Ai Za Zhi

Journal ID (publisher-id): ZGFAZZ

Title: Chinese Journal of Lung Cancer

Publisher: 中国肺癌杂志编辑部 (天津市和平区南京路228号300020 )

ISSN (Print): 1009-3419

ISSN (Electronic): 1999-6187

Publication date (Print): 20 October 2016

Volume: 19

Issue: 10

Pages: 711-714

Affiliations

[1 ] 030013 太原，山西医科大学附属肿瘤医院呼吸科 Department of Respiratory, Shanxi Cancer Hospital, Affiliated Cancer Hospital of Shanxi Medical University, Taiyuan 030013, China

[2 ] 030012 太原，山西省人民医院消化科 Department of Gastroenterology, Shanxi Province People's Hospital, Taiyuan 030012, China

Author notes

宋霞, Xia SONG, E-mail: songxia76@ 123456hotmail.com

Article

Publisher ID: zgfazz-19-10-711

DOI: 10.3779/j.issn.1009-3419.2016.10.13

PMC ID: 5973409

PubMed ID: 27760604

SO-VID: 9afd8168-8f68-4374-a013-c3d70ad97d5a

License:

This is an open access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 3.0) License. See: https://creativecommons.org/licenses/by/3.0/

History

Date received : 20 March 2016

Date revision received : 18 April 2016

Date accepted : 20 April 2016

BRAF抑制剂治疗非小细胞肺癌的进展 Translated title: Progress in the Treatment of Non-small Cell Lung Cancer with BRAF Inhibitors

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Abstract

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Inflamed lung in vitro co-culture models

Most cited references 19

Combined vemurafenib and cobimetinib in BRAF-mutated melanoma.

Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial.

Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1.

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