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

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 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.

TATTON: a multi-arm, phase Ib trial of osimertinib combined with selumetinib, savolitinib, or durvalumab in EGFR-mutant lung cancer

“…26 The most promising results come from a phase Ib/II combination trial of gefitinib and capmatinib (47% ORR) in patients with MET-amplified resistance to prior EGFR-TKI. 17 The tolerability of osimertinib monotherapy suggests it is well suited for combination. In TATTON, only 5% of patients treated with osimertinib 80 mg daily required dose reduction, and 30% had grade 3 osimertinib-related toxicities.…”

Development and full validation of an LC–MS/MS methodology to quantify capmatinib (INC280) following intragastric administration to rats

“…2‐Fluoro‐ N ‐methyl‐4‐{7‐[(quinolin‐6‐yl)methyl]imidazo[1,2‐b][1,2,4]triazin‐2‐yl}benzamide (capmatinib, INC280), is a novel, highly specific, selective and potent ATP‐competitive inhibitor of the proto‐oncogene MET with in vitro and in vivo activities against preclinical cancer models with MET activation, such as biochemical (IC50, 0.13 n m ) and cellular assays across a range of tumor types and MET‐dependent tumor models in animals at tolerable doses (Sohn et al, ; Wu et al, ).…”

First-in-human phase I study of BPI-9016M, a dual MET/Axl inhibitor, in patients with non-small cell lung cancer

“…Moreover, a phase 1 study of cabozantinib in Japanese NSCLC patients demonstrated that the rate of discontinuation due to an AE was 10% [27]. In a phase Ib/ II study of capmatinib plus gefitinib in patients with EGFR-mutated, MET-dysregulated NSCLC, 27 of 161 patients (17%) reported AEs that led to study drug discontinuation [28]. A phase I dose-escalation study of capmatinibin Japanese patients with advanced solid tumors reported that 21 patients (47.7%) experienced one or more dose interruptions during the study, with the dose interruption only once in nine patients (20.5%) [16].…”

“…Tepotinib and gefitinib combination significantly improved response rate in patients with MET amplification or overexpression [32]. Capmatinib has also been evaluated in combination with gefitinib in patients with EGFR-mutant NSCLC who progressed on previous gefitinib treatment, the overall ORR was 27%, while strong antitumor activities were seen in patients with high MET-amplified tumors (ORR47%) [28]. Crizotinib, a dual c-MET and ALK inhibitor, has been studied in METex14-altered NSCLC patients with an unconfirmed response rate of up to 44% [33].…”