Tepotinib plus Gefitinib in Patients with EGFR-Mutant NSCLC with MET Amplification (METamp): Final Analysis of INSIGHT

초록

Background In the INSIGHT trial primary analysis (NCT01982955; median follow-up: 21.8 months), tepotinib (a highly selective, once daily [QD] MET inhibitor) + gefitinib improved efficacy versus chemotherapy in patients with EGFR-mutant NSCLC, and resistance to anti-EGFR therapy due to METamp. Here, we report final analyses from INSIGHT (data cut-off: September 3, 2021; median follow-up: 57.5 months). Previously presented at AACR 2022. Methods Patients with EGFR-mutant (T790M-negative) NSCLC and anti-EGFR resistance, with METamp (MET gene copy number ≥5 and/or MET:CEP7 ≥2 by FISH) and/or MET overexpression (IHC 2+/3+), were randomized to tepotinib 500 mg (450 mg active moiety) + gefitinib 250 mg QD or chemotherapy. Primary endpoint was progression-free survival (PFS) per investigator. Preplanned analyses evaluated patients with METamp. Results 19/55 randomized patients (34.5%) had METamp (MET IHC 3+, n=17; median age: 60.4 years; never-smokers: 68.4%; prior EGFR inhibitors: gefitinib [57.9%], afatinib [21.1%], erlotinib [10.5%], and icotinib [10.5%]). Median duration of tepotinib + gefitinib was 11.3 months (range: 1.1–56.5), with treatment duration >1 year in six patients (31.6%), and >4 years in three patients (15.8%). Two patients continued treatment outside the study (total duration >5 years). Tepotinib + gefitinib improved PFS (hazard ratio [HR] 0.13; 90% confidence interval [CI]: 0.04, 0.43), overall survival (OS; HR 0.10; 90% CI: 0.02, 0.36), objective response rate, and duration of response versus chemotherapy (Table). Treatment-related Grade ≥3 adverse events occurred in seven patients (58.3%) with tepotinib + gefitinib, and five (71.4%) with chemotherapy; most reported (>20%) were increased amylase and increased lipase (both 33.3%) with tepotinib + gefitinib, and anemia, decreased white blood cell count, and decreased neutrophil count (all 28.6%) with chemotherapy. Conclusions Tepotinib + gefitinib greatly improved PFS and OS versus chemotherapy in patients with EGFR-mutant NSCLC with METamp.