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 potent, highly selective, once daily [QD] MET inhibitor) + gefitinib improved efficacy vs chemotherapy (CT) in patients (pts) with EGFR-mutant (m) NSCLC and resistance to anti-EGFR therapy due to METamp (Wu et al, Lancet Respir Med 2020). Here we report final analyses from INSIGHT (data cut-off: Sept 3, 2021; median follow-up: 57.5 months). Methods: Pts with EGFR-m (T790M-negative) NSCLC and anti-EGFR resistance, with MET gene copy number (GCN) ≥5 and/or MET:CEP7 ≥2 by FISH (METamp), and/or MET IHC 2+/3+ (MET overexpression), were randomized to tepotinib 500 mg (450 mg active moiety) + gefitinib 250 mg QD or CT. Primary endpoint was progression-free survival (PFS) per investigator. Preplanned analyses evaluated pts with METamp. Result: In 19/55 randomized pts (34.5%) with METamp (GCN ≥5, n=18; MET:CEP7 ≥2, n=13; MET IHC 3+, n=17), median age was 60.4 years, 68.4% were never-smokers, and prior EGFR inhibitors were 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 6 pts (31.6%) and >4 years in 3 pts (15.8%). Two pts continued treatment outside the study. Tepotinib + gefitinib (n=12) improved outcomes vs CT (n=7). Respectively, median PFS was 16.6 vs 4.2 months (HR=0.13; 90% CI: 0.04, 0.43), median overall survival (OS) was 37.3 vs 13.1 months (HR=0.10; 0.02, 0.36), objective response rate was 67% vs 43% (odds ratio=2.67; 0.37, 19.56), and median duration of response was 19.9 (7.0, not estimable [ne]) vs 2.8 months (2.8, ne). Treatment-related Grade ≥3 AEs occurred in 7 pts (58.3%) with tepotinib + gefitinib and 5 (71.4%) with CT. In pts with MET IHC 3+ (n=34; including 17 pts with METamp), tepotinib + gefitinib also improved PFS (HR 0.35; 90% CI: 0.17, 0.74) and OS (HR 0.44; 0.23, 0.84) vs CT. Conclusion: Tepotinib + gefitinib improved PFS and OS vs CT in pts with EGFR-m NSCLC with METamp. INSIGHT 2 is evaluating tepotinib + osimertinib in this setting.