Tepotinib plus gefitinib in patients with EGFR-mutant NSCLC with MET amplification: Final analysis of INSIGHT

초록

Aims: We report the final analyses from the INSIGHT trial (NCT01982955; data cut-off: September 3, 2021; median follow-up: 57.5 months), which assessed the combination of tepotinib (apotentMET-TKI) and gefitinib versus chemotherapy in patients with EGFR-mutant NSCLC and resistance to anti-EGFR therapy due to MET amplification(MET amp). Methods: Patients with EGFR-mutant (T790M-negative) NSCLC and anti-EGFR resistance, with MET amp (MET gene copy number (GCN)≥ 5 and/or MET:CEP7 ≥ 2 by FISH) and/or MET overexpression (IHC2+/3+), were randomized to tepotinib 500 mg (450 mg active moiety) + gefitinib 250 mg QD or chemotherapy. The primary endpoint was progression-free survival(PFS) per investigator assessment. Pre-planned analyses evaluated patients with MET amp. Results: In 19/55 randomized patients (34.5%) with MET amp (GCN ≥ 5, n = 18; MET:CEP7 ≥ 2, n = 13; MET IHC3+, n = 17), the 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%). The median duration of tepotinib + gefitinib treatment was 11.3 months (range:1.1–56.5). Two patients continued treatment outside the study. Tepotinib + gefitinib improved PFS (median 16.6 months (90% CI: 8.3, 22.1)) versus chemotherapy (median 4.2 months (90% CI: 1.4, 7.0)): HR .13 (90% CI: .04, .43). Overall survival (HR .10; 90% CI: .02, .36), objective response rate (OR 2.67; 90% CI: .37, 19.56) and duration of response also improved with the combination in comparison to chemotherapy.Treatment-related Grade ≥ 3 AEs occurred in seven patients (58.3%) with tepotinib + gefitinib and five (71.4%) with chemotherapy. In patients with MET IHC 3+(n=34, including 17 patients with MET amp), tepotinib + gefitinib also markedly improved PFS (HR .35; 90% CI: .17, .74) and OS (HR .44; 90% CI: .23, .84) versus chemotherapy. Conclusions: Tepotinib + gefitinib significantly improved PFS and OS versus chemotherapy in patients with EGFR-mutant NSCLC with MET amp.