Tepotinib plus gefitinib in patients with EGFR-mutant non-small-cell lung cancer with MET overexpression or MET amplification and acquired resistance to previous EGFR inhibitor (INSIGHT study): an open-label, phase 1b/2, multicentre, randomised trial

Background We evaluated the efficacy and safety of tepotinib, a potent and highly selective oral MET inhibitor, plus gefitinib in patients with epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) with MET overexpression (immunohistochemistry [IHC]2+ or IHC3+) or MET amplification having acquired resistance to EGFR inhibition. Methods In this open-label, phase 1b/2, multicentre, randomised trial (the INSIGHT study), we enrolled adult patients (≥18 years) with advanced or metastatic NSCLC, and Eastern Cooperative Oncology Group performance status of 0 or 1, from academic medical centres and community clinics in six Asian countries. In phase 1b, patients received oral tepotinib 300 mg or 500 mg plus gefitinib 250 mg once daily. In phase 2, patients with EGFR-mutant, T790M-negative NSCLC MET overexpression or MET amplification were randomly assigned (initially in a 1:1 ratio and then 2:1 following a protocol amendment) to tepotinib plus gefitinib at the recommended phase 2 dose or to standard platinum doublet chemotherapy. Randomisation was done centrally via an interactive voice-response system. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS) and safety. Subgroup analyses were preplanned in patients with high MET overexpression (IHC3+) or MET amplification (mean gene copy number ≥5 or MET to centromere of chromosome 7 ratio ≥2). Efficacy and patient characteristics were assessed on an intention-to-treat basis and safety was assessed for all patients who received at least one dose of study medication. Low recruitment led to early termination of phase 2, so all analyses are considered to be exploratory. This study is registered with ClinicalTrials.gov, NCT01982955, and the European Union Drug Regulating Authorities Clinical Trials Database, Eudra-CT 2016-001604-28. Findings From Dec 23, 2013, to May 25, 2017, 18 patients were enrolled in phase 1b (n=6 in the 300 mg tepotinib group; n=12 in the 500 mg tepotinib group) and 55 patients in phase 2 (n=31 in the tepotinib plus gefitinib group; n=24 in the chemotherapy group). No dose-limiting toxicities were observed in phase 1b, so tepotinib 500 mg was used as the recommended phase 2 dose. In phase 2, survival outcomes were similar between groups: median PFS was 4·9 months in the tepotinib plus gefitinib group (90% CI 3·9–6·9) versus 4·4 months in the chemotherapy group (90% CI 4·2–6·8; hazard ratio [HR] 0·67, 90% CI 0·35–1·28). Median OS was 17·3 months in the tepotinib plus gefitinib group (12·1–37·3) versus 18·7 months in the chemotherapy group (15·9–20·7; HR 0·69, 0·34–1·41). PFS and OS were longer with tepotinib plus gefitinib than with chemotherapy in patients with high (IHC3+) MET overexpression (n=34; median PFS 8·3 months [4·1–16·6] vs 4·4 months [4·1–6·8]; HR 0·35, 0·17–0·74; median OS 37·3 months [90% CI 24·2–37·3] vs 17·9 months [12·0–20·7]; HR 0·33, 0·14–0·76) or MET amplification (n=19; median PFS 16·6 months [8·3–not estimable] vs 4·2 months [1·4–7·0]; HR 0·13, 0·04–0·43; median OS 37·3 months [90% CI not estimable] vs 13·1 months [3·25–not estimable]; HR 0·08, 0·01–0·51). The most frequent treatment-related grade 3 or worse adverse events were increased amylase (5 [16%] of 31 patients) and lipase (4 [13%]) concentrations in the tepotinib plus gefitinib group and anaemia (7 [30%] of 23 patients) and decreased neutrophil count (3 [13%]) in the chemotherapy group. Interpretation Despite early study termination, in a preplanned subgroup analysis, our findings suggest improved anti activity for tepotinib plus gefitinib compared with standard chemotherapy in patients with EGFR-mutant NSCLC and MET amplification, warranting further exploration. Funding Merck KGaA.