Phase Ib/II Study of Capmatinib (INC280) Plus Gefitinib after Failure of Epidermal Growth Factor Receptor (EGFR) Inhibitor Therapy in Patients with EGFR-Mutated, MET Factor-Dysregulated Non-Small-Cell Lung Cancer
Journal
Journal of Clinical Oncology
Journal Volume
36
Journal Issue
31
Pages
3101-3109
Date Issued
2018
Author(s)
Wu Y.-L
Zhang L
Kim D.-W
Liu X
Lee D.H
Ahn M.-J
Vansteenkiste J.F
Su W.-C
Felip E
Chia V
Glaser S
Pultar P
Zhao S
Peng B
Akimov M
Tan D.S.W.
Abstract
Purpose Mesenchymal-epithelial transition factor (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 EGFRmutated 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. ? 2018 by American Society of Clinical Oncology.
SDGs
Other Subjects
afatinib; alanine aminotransferase; amylase; aspartate aminotransferase; bilirubin; capmatinib; creatinine; epidermal growth factor receptor; epidermal growth factor receptor kinase inhibitor; erlotinib; gefitinib; icotinib; scatter factor receptor; triacylglycerol lipase; antineoplastic agent; capmatinib; EGFR protein, human; epidermal growth factor receptor; gefitinib; imidazole derivative; MET protein, human; scatter factor receptor; triazine derivative; adenosquamous carcinoma; adult; aged; alanine aminotransferase blood level; amylase blood level; Article; aspartate aminotransferase blood level; bilirubin blood level; cancer combination chemotherapy; cancer patient; cancer resistance; chemotherapy induced anemia; chemotherapy induced emesis; constipation; controlled study; coughing; creatinine blood level; decreased appetite; diarrhea; disease activity; disease exacerbation; dizziness; drug blood level; drug dose increase; drug efficacy; drug eruption; drug safety; drug tolerability; drug withdrawal; dyspnea; fatigue; female; gene amplification; gene dosage; gene mutation; gene overexpression; heart infarction; hemoptysis; human; hyperbilirubinemia; hypoalbuminemia; insomnia; large cell lung carcinoma; lung adenocarcinoma; lung adenosquamous cell carcinoma; lung carcinoma; major clinical study; male; microcapsule; middle aged; multiple cycle treatment; nausea; non small cell lung cancer; paronychia; peripheral edema; pharmacodynamics; pharmacokinetic parameters; phase 1 clinical trial; phase 2 clinical trial; pneumonia; priority journal; recommended drug dose; response evaluation criteria in solid tumors; side effect; tablet formulation; treatment response; triacylglycerol lipase blood level; clinical trial; genetics; lung tumor; maximum tolerated dose; metabolism; mutation; non small cell lung cancer; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Female; Gefitinib; Humans; Imidazoles; Lung Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Mutation; Proto-Oncogene Proteins c-met; Triazines
Publisher
American Society of Clinical Oncology
Type
journal article