Efficacy, safety, and biomarker analysis of ensartinib in crizotinib-resistant, ALK-positive non-small-cell lung cancer: a multicentre, phase 2 trial.
恩沙替尼治疗克唑替尼耐药、ALK阳性非小细胞肺癌的疗效、安全性和生物标志物分析: 一项多中心 2 期试验。
- 作者列表："Yang Y","Zhou J","Zhou J","Feng J","Zhuang W","Chen J","Zhao J","Zhong W","Zhao Y","Zhang Y","Song Y","Hu Y","Yu Z","Gong Y","Chen Y","Ye F","Zhang S","Cao L","Fan Y","Wu G","Guo Y","Zhou C","Ma K","Fang J","Feng W","Liu Y","Zheng Z","Li G","Wu N","Song W","Liu X","Zhao S","Ding L","Mao L","Selvaggi G","Yuan X","Fu Y","Wang T","Xiao S","Zhang L
BACKGROUND:Ensartinib is a potent new-generation ALK inhibitor with high activity against a broad range of known crizotinib-resistant ALK mutations and CNS metastases. We aimed to assess the efficacy and safety of ensartinib in ALK-positive patients with non-small-cell lung cancer (NSCLC), in whom crizotinib therapy was unsuccessful. The associations between ensartinib efficacy and crizotinib-resistant mutations were also explored. METHODS:We did a single-arm, open-label, phase 2 study at 27 centres in China. Patients were aged 18 years or older, had stage IIIb or stage IV ALK-positive NSCLC that had progressed while they were on crizotinib therapy, an Eastern Cooperative Oncology Group performance status of 2 or less, had measurable disease, and had received fewer than three previous treatments. Patients with CNS metastases were included if these metastases were asymptomatic and did not require steroid therapy. All patients received 225 mg ensartinib orally once daily on a continuous dosing schedule. The primary outcome was the proportion of patients with an objective response according to the Response Evaluation Criteria in Solid Tumors (version 1.1), as assessed by an independent review committee in all patients who received at least one dose of ensartinib with no major violations of the inclusion criteria (ie, the full analysis set). Safety was assessed in all enrolled patients who received at least one dose of ensartinib. This trial was registered with ClinicalTrials.gov, NCT03215693. FINDINGS:Between Sept 28, 2017, and April 11, 2018, 160 patients were enrolled and had at least one dose of ensartinib (safety analysis set). Four patients had inclusion violations and were excluded from the efficacy analysis, which thus included 156 patients (full analysis set). 97 (62%) patients in the full analysis set had brain metastases. 76 (52% [95% CI 43-60]) of 147 patients in the full analysis set, with responses that could be assessed by the independent review committee, had an objective response. 28 (70% [53-83]) of 40 patients with measurable brain metastases as assessed by the independent review committee had an intracranial objective response. 145 (91%) of 160 patients had at least one treatment-related adverse event, which were mostly grade 1 or 2. The most common treatment-related adverse events were rash (89 [56%]), increased alanine aminotransferase concentrations (74 [46%]), and increased aspartate aminotransferase concentrations (65 [41%]). INTERPRETATION:Ensartinib has activity and is well tolerated in patients with crizotinib-refractory, ALK-positive NSCLC, including those with brain metastases. The role of ensartinib in patients in whom other second-generation ALK inhibitors have been unsuccessful warrants further studies. FUNDING:Betta Pharmaceuticals.
背景: Ensartinib是一种有效的新一代ALK抑制剂，对广泛的已知克唑替尼耐药ALK突变和CNS转移具有高活性。我们的目的是评估恩沙替尼治疗ALK阳性非小细胞肺癌 (NSCLC) 患者 (其中克唑替尼治疗不成功) 的疗效和安全性。还探讨了ensartinib疗效与克唑替尼耐药突变之间的相关性。 方法: 我们在中国 27 个中心进行了一项单臂、开放标签、 2 期研究。患者年龄 ≥ 18 岁，患有IIIb期或IV期ALK阳性NSCLC，在接受克唑替尼治疗时进展，东部肿瘤协作组的表现状态 ≤ 2，患有可测量的疾病，并且之前接受的治疗少于三次。如果这些转移无症状且不需要类固醇治疗，则包括CNS转移的患者。所有患者均按连续给药方案每日一次口服 225 mg ensartinib。主要结局是根据实体瘤疗效评价标准 (1.1 版) 客观缓解的患者比例，由独立审查委员会对所有接受至少 1 剂恩沙替尼且未严重违反纳入标准 (即完整分析集) 的患者进行评估。在接受至少 1 剂ensartinib治疗的所有入组患者中评估安全性.本试验在ClinicalTrials.gov注册，nct03215693。 结果: 在 2017 年 9 月 28 日和 2018 年 4 月 11 日之间，160 例患者被纳入并且至少使用了 1 剂ensartinib (安全性分析集)。4 例患者存在违规纳入，并被排除在功效分析之外，因此纳入了 156 例患者 (全分析集)。全分析组中 97 例 (62%) 患者有脑转移。在完全分析集中的 52% 例患者中，有 76 例 (95% [147 CI 43-60]) 有客观反应，反应可由独立审查委员会评估。由独立审查委员会评估的具有可测量的脑转移的 40 例患者中的 28 例 (70% [53-83]) 具有颅内客观缓解。145 例患者中有 91% 例 (160) 发生至少 1 例治疗相关不良事件，多为 1 级或 2 级。最常见的治疗相关不良事件为皮疹 (89 [56%]) 、丙氨酸氨基转移酶浓度升高 (74 [46%]) 和天冬氨酸氨基转移酶浓度升高 (65 [41%])。 解读: 恩沙替尼在克唑替尼难治性、ALK阳性NSCLC患者 (包括脑转移患者) 中具有活性且耐受性良好。Ensartinib在其他第二代ALK抑制剂未成功的患者中的作用值得进一步研究。 资助: Betta Pharmaceuticals。
METHODS::Pulmonary artery sling is a rare congenital anomaly of the origin and course of the left pulmonary artery. Patients with this condition typically present with respiratory failure in young infancy, and asymptomatic cases are uncommon. We describe the case of an adult patient with a lung adenocarcinoma of the right upper lobe, extending into the hilum and superior mediastinum, and with a previously unknown pulmonary artery sling anomaly. The local invasiveness of the tumor and the peculiar vascular anatomy contributed to a unique surgical scenario, wherein multiple reconstructive procedures were required.
METHODS::Patients with idiopathic pulmonary fibrosis (IPF) have higher risk of developing lung cancer, for example, squamous cell carcinoma (SCC), and show poor prognosis, while the molecular basis has not been fully investigated. Here we conducted DNA methylome analysis of lung SCC using 20 SCC samples with/without IPF, and noncancerous lung tissue samples from smokers/nonsmokers, using Infinium HumanMethylation 450K array. SCC was clustered into low- and high-methylation epigenotypes by hierarchical clustering analysis. Genes hypermethylated in SCC significantly included genes targeted by polycomb repressive complex in embryonic stem cells, and genes associated with Gene Ontology terms, for example, "transcription" and "cell adhesion," while genes hypermethylated specifically in high-methylation subgroup significantly included genes associated with "negative regulation of growth." Low-methylation subgroup significantly correlated with IPF (78%, vs. 17% in high-methylation subgroup, p = 0.04), and the correlation was validated by additional Infinium analysis of SCC samples (n = 44 in total), and data from The Cancer Genome Atlas (n = 390). The correlation between low-methylation subgroup and IPF was further validated by quantitative methylation analysis of marker genes commonly hypermethylated in SCC (HOXA2, HOXA9 and PCDHGB6), and markers specifically hypermethylated in high-methylation subgroup (DLEC1, CFTR, MT1M, CRIP3 and ALDH7A1) in 77 SCC cases using pyrosequencing (p = 0.003). Furthermore, low-methylation epigenotype significantly correlated with poorer prognosis among all SCC patients, or among patients without IPF. Multivariate analysis showed that low-methylation epigenotype is an independent predictor of poor prognosis. These may suggest that lung SCC could be stratified into molecular subtypes with distinct prognosis, and low-methylation lung SCC that significantly correlates with IPF shows unfavorable outcome.
METHODS::The role of Fyn-related kinase (FRK) in malignant tumors remains controversial. Our study investigated the function of FRK in lung cancer. Immunohistochemistry staining and generating a knockout of FRK by CRISPR/Cas9 in H1299 (FRK-KO-H1299) cells were strategies used to explore the role of FRK. Immunohistochemistry staining indicated that FRK expression was elevated in 223 lung cancer tissues compared to 26 distant normal lung tissues. FRK contributed to poor survival status in lung cancer patients and acted as a predictor for poor prognosis of lung cancer. Knockout of FRK by CRISPR/Cas9 markedly inhibited proliferation, invasion, colony formation and epithelial-mesenchymal transition (EMT) process in the lung cancer cell line H1299. Further exploration indicated that FRK-KO damaged the stemness phenotype of H1299 by inhibiting CD44 and CD133 expression. Seahorse detection and a U-13 C flux assay revealed that FRK-KO induced metabolism reprogramming by inhibiting the Warburg effect and changing the energy type in H1299 cells. Epidermal growth factor stimulation recovered the expression of FRK and biological functions, metabolic reprogramming and stemness phenotype of H1299 cells. FRK plays an oncogenic role in lung cancer cells via a novel regulation mechanism of enhancing the stemness of H1299 cells by inducing metabolism reprogramming, which finally promotes EMT and metastasis. Our study also indicates that FRK could be used as a potential therapeutic target for drug development.