Yi-Long Wu, Guangdong General Hospital and Guangdong Academy of Medical Sciences; Li Zhang, Sun Yat-sen University Cancer Center, Guangdong; Xiaoqing Liu, Affiliated Hospital of the Chinese Academy of Military Medical Sciences, Beijing; Sylvia Zhao and Bin Peng, Novartis Institutes for Biomedical Research, Shanghai, People's Republic of China; Dong-Wan Kim, Seoul National University Hospital; Dae Ho Lee, University of Ulsan College of Medicine; Myung-Ju Ahn, Samsung Medical Center, Seoul, Republic of Korea; James Chih-Hsin Yang, National Taiwan University Hospital, Taipei; Wu-Chou Su, National Cheng Kung University Hospital, Tainan, Taiwan; Johan F. Vansteenkiste, University Hospital KU Leuven, Leuven, Belgium; Enriqueta Felip, Vall d'Hebron University Hospital, Barcelona, Spain; Vincent Chia and Philippe Pultar, Novartis Pharmaceuticals, East Hanover, NJ; Sabine Glaser and Mikhail Akimov, Novartis Pharma AG, Basel, Switzerland; and Daniel S.W. Tan, National Cancer Centre Singapore, Singapore.
J Clin Oncol. 2018 Nov 1;36(31):3101-3109. doi: 10.1200/JCO.2018.77.7326. Epub 2018 Aug 29.
MET dysregulation occurs in up to 26% of non-small-cell lung cancers (NSCLCs) after epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) treatment. Capmatinib (INC280) is a potent and selective MET inhibitor with preclinical activity in combination with gefitinib in EGFR-mutant, MET-amplified/overexpressing models of acquired EGFR-TKI resistance. This phase Ib/II study investigated the safety and efficacy of capmatinib plus gefitinib in patients with EGFR-mutated, MET-dysregulated (amplified/overexpressing) NSCLC who experienced disease progression while receiving EGFR-TKI treatment.
Patients in phase Ib received capmatinib 100- to 800-mg capsules once per day or 200- to 600-mg capsules or tablets twice per day, plus gefitinib 250 mg once per day. Patients in phase II received the recommended phase II dose. The primary end point was the overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
Sixty-one patients were treated in phase Ib, and 100 were treated in phase II. The recommended phase II dose was capmatinib 400 mg twice per day plus gefitinib 250 mg once per day. Preliminary clinical activity was observed, with an ORR across phase Ib/II of 27%. Increased activity was seen in patients with high MET-amplified tumors, with a phase II ORR of 47% in patients with a MET gene copy number ≥ 6. Across phases Ib and II, the most common drug-related adverse events were nausea (28%), peripheral edema (22%), decreased appetite (21%), and rash (20%); the most common drug-related grade 3/4 adverse events were increased amylase and lipase levels (both 6%). No significant drug-drug interactions between capmatinib and gefitinib were evident.
This study, focused on a predominant EGFR-TKI resistance mechanism in patients with EGFR-mutated NSCLC, shows that the combination of capmatinib with gefitinib is a promising treatment for patients with EGFR-mutated, MET-dysregulated NSCLC, particularly MET-amplified disease.
表皮生长因子受体（EGFR）-酪氨酸激酶抑制剂（TKI）治疗后，多达 26%的非小细胞肺癌（NSCLC）出现 MET 失调。卡马替尼（INC280）是一种有效的选择性 MET 抑制剂，在 EGFR 突变、MET 扩增/过表达获得性 EGFR-TKI 耐药模型中与吉非替尼联合具有临床前活性。这项 Ib/II 期研究调查了卡马替尼联合吉非替尼治疗接受 EGFR-TKI 治疗后疾病进展的 EGFR 突变、MET 失调（扩增/过表达）NSCLC 患者的安全性和疗效。
Ib 期患者接受卡马替尼 100-800mg 胶囊，每日一次或 200-600mg 胶囊或片剂，每日两次，加吉非替尼 250mg，每日一次。II 期患者接受推荐的 II 期剂量。主要终点是根据实体瘤反应评价标准（RECIST）1.1 版评估的总缓解率（ORR）。
61 例患者在 Ib 期接受治疗，100 例患者在 II 期接受治疗。推荐的 II 期剂量为卡马替尼 400mg 每日两次，加吉非替尼 250mg 每日一次。初步临床活性观察到，Ib/II 期的 ORR 为 27%。在 MET 高扩增肿瘤患者中观察到更高的活性，MET 基因拷贝数≥6 的患者 II 期 ORR 为 47%。在 Ib 期和 II 期，最常见的药物相关不良事件是恶心（28%）、外周水肿（22%）、食欲下降（21%）和皮疹（20%）；最常见的药物相关 3/4 级不良事件是淀粉酶和脂肪酶水平升高（均为 6%）。卡马替尼和吉非替尼之间没有明显的药物相互作用。
这项研究集中于 EGFR 突变 NSCLC 患者的主要 EGFR-TKI 耐药机制，表明卡马替尼联合吉非替尼是治疗 EGFR 突变、MET 失调 NSCLC 的一种有前途的治疗方法，特别是 MET 扩增疾病。
