J Clin Oncol 2018 11 29;36(31):3101-3109. Epub 2018 Aug 29.
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.
Purpose: 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.
Methods: 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.
Results: 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.
Conclusion: 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.