关键词: 非小细胞肺癌, 鼠类肉瘤滤过性毒菌致癌基因同源体B1, 突变, 抑制剂, 丝裂原活化蛋白激酶激酶抑制剂

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.

Key words: Non-small cell lung cancer, V-Raf murine sarcoma viral oncogene homolog B1, Mutation, Inhibitor, Mitogen- activated protein kinase kinase inhibitor