Osimertinib plus savolitinib in patients with EGFR mutation-positive, MET-amplified, non-small-cell lung cancer after progression on EGFR tyrosine kinase inhibitors: interim results from a multicentre, open-label, phase 1b study.
- 作者列表："Sequist LV","Han JY","Ahn MJ","Cho BC","Yu H","Kim SW","Yang JC","Lee JS","Su WC","Kowalski D","Orlov S","Cantarini M","Verheijen RB","Mellemgaard A","Ottesen L","Frewer P","Ou X","Oxnard G
BACKGROUND:Preclinical data suggest that EGFR tyrosine kinase inhibitors (TKIs) plus MET TKIs are a possible treatment for EGFR mutation-positive lung cancers with MET-driven acquired resistance. Phase 1 safety data of savolitinib (also known as AZD6094, HMPL-504, volitinib), a potent, selective MET TKI, plus osimertinib, a third-generation EGFR TKI, have provided recommended doses for study. Here, we report the assessment of osimertinib plus savolitinib in two global expansion cohorts of the TATTON study. METHODS:In this multi-arm, multicentre, open-label, phase 1b study, we enrolled adult patients (aged ≥18 years) with locally advanced or metastatic, MET-amplified, EGFR mutation-positive non-small-cell lung cancer, who had progressed on EGFR TKIs. We considered two expansion cohorts: parts B and D. Part B consisted of three cohorts of patients: those who had been previously treated with a third-generation EGFR TKI (B1) and those who had not been previously treated with a third-generation EGFR TKI who were either Thr790Met negative (B2) or Thr790Met positive (B3). In part B, patients received oral osimertinib 80 mg and savolitinib 600 mg daily; after a protocol amendment (March 12, 2018), patients who weighed no more than 55 kg received a 300 mg dose of savolitinib. Part D enrolled patients who had not previously received a third-generation EGFR TKI and were Thr790Met negative; these patients received osimertinib 80 mg plus savolitinib 300 mg. Primary endpoints were safety and tolerability, which were assessed in all dosed patients. Secondary endpoints included the proportion of patients who had an objective response per RECIST 1.1 and was assessed in all dosed patients and all patients with centrally confirmed MET amplification. Here, we present an interim analysis with data cutoff on March 29, 2019. This study is registered with ClinicalTrials.gov, NCT02143466. FINDINGS:Between May 26, 2015, and Feb 14, 2019, we enrolled 144 patients into part B and 42 patients into part D. In part B, 138 patients received osimertinib plus savolitinib 600 mg (n=130) or 300 mg (n=8). In part D, 42 patients received osimertinib plus savolitinib 300 mg. 79 (57%) of 138 patients in part B and 16 (38%) of 42 patients in part D had adverse events of grade 3 or worse. 115 (83%) patients in part B and 25 (60%) patients in part D had adverse events possibly related to savolitinib and serious adverse events were reported in 62 (45%) patients in part B and 11 (26%) patients in part D; two adverse events leading to death (acute renal failure and death, cause unknown) were possibly related to treatment in part B. Objective partial responses were observed in 66 (48%; 95% CI 39-56) patients in part B and 23 (64%; 46-79) in part D. INTERPRETATION:The combination of osimertinib and savolitinib has acceptable risk-benefit profile and encouraging antitumour activity in patients with MET-amplified, EGFR mutation-positive, advanced NSCLC, who had disease progression on a previous EGFR TKI. This combination might be a potential treatment option for patients with MET-driven resistance to EGFR TKIs. FUNDING:AstraZeneca.
背景: 临床前数据表明，EGFR酪氨酸激酶抑制剂 (TKIs) 加MET tki是一种可能的治疗EGFR突变阳性肺癌与MET驱动的获得性耐药。Savolitinib (也称为AZD6094，HMPL-504，volitinib)，一种强效的选择性MET TKI，加上奥希替尼，第三代EGFR TKI，已为研究提供推荐剂量。在此，我们报告了在TATTON研究的两个全球扩展队列中对奥希替尼和萨沃替尼的评估。 方法: 在这项多臂、多中心、开放标签、 1b期研究中，我们招募了局部晚期或转移性MET扩增的成年患者 (年龄 ≥ 18 岁)，EGFR突变阳性的非小细胞肺癌，在EGFR TKIs上进展。我们考虑了两个扩展队列: B部分和D部分。B部分由三组患者组成: 既往接受过第三代EGFR TKI (B1) 治疗的患者和那些以前没有接受过第三代EGFR TKI治疗的患者，他们要么是Thr790Met阴性 (B2)，要么是Thr790Met阳性 (B3)。在B部分，患者接受口服奥希替尼 80 mg和savolitinib 600 mg每日; 方案修订后 (2018 年 3 月 12 日)，体重不超过 55千克kg的患者接受 300 mg剂量的savolitinib.D部分纳入了既往未接受过第三代EGFR TKI且Thr790Met阴性的患者; 这些患者接受奥希替尼 80 mg加savolitinib 300 mg.主要终点是安全性和耐受性，在所有给药患者中进行评估。次要终点包括每RECIST 1.1 客观缓解的患者比例，并在所有给药患者和所有经中心证实的MET扩增患者中进行评估.在此，我们提出了一项中期分析，数据截止日期为 2019 年 3 月 29 日。本研究在clinicaltrials.Gov注册，nct02143466。 结果: 在 2015 年 5 月 26 日至 20 19 年 2 月 14 日期间，我们将 144 例患者纳入B部分，42 例患者纳入D部分。在B部分中，138 例患者接受奥希替尼加沙伏替尼 600 mg (n = 130) 或 300 mg (n = 8)。在D部分中，42 例患者接受奥希替尼加savolitinib 300 mg。B部分 57% 例患者中的 79 例 (138) 和D部分 42 例患者中的 16 例 (38%) 具有 3 级或更严重的不良事件。B部分 115 (83%) 例患者和D部分 25 (60%) 例患者发生可能与萨沃替尼相关的不良事件，62 例 (45%) 报告了严重不良事件B部分的患者和D部分的 11 (26%) 患者; 导致死亡的两个不良事件(急性肾衰竭和死亡，原因不明) 可能与B部分的治疗有关。B部分患者中 66 例 (48%; 95% CI 39-56) 和D部分患者中 23 例 (64%; 46-79) 观察到客观部分缓解。 解释: 奥希替尼和萨沃替尼的联合用药在MET扩增、EGFR突变阳性的晚期NSCLC患者中具有可接受的风险-效益特征和令人鼓舞的抗肿瘤活性，既往EGFR TKI患者有疾病进展。这种组合可能是对EGFR tki具有MET驱动的抗性的患者的潜在治疗选择。 资助: 阿斯利康。
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.