Phase Ib/II Study of Capmatinib (INC280) Plus Gefitinib After Failure of Endothelial Growth Factor Receptor (EGFR) Inhibitor Therapy in Patients With EGFR-Mutated, MET Factor–Dysregulated Non–Small-Cell Lung Cancer
Mené sur 61 puis 100 patients atteints d'un cancer du pumon non à petites cellules présentant une mutation EGFR et une surexpression/amplification du gène MET, cet essai de phase Ib/II évalue la dose maximale tolérée, l'efficacité, du point de vue du taux de réponse globale, et la toxicité d'un traitement à base de capmatinib, un inhibiteur de MET, en combinaison avec du géfitinib, après l'échec d'un traitement à base d'inhibiteurs anti-EGFR
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 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.