摘要
EGFR inhibitors have revolutionized the treatment of advanced non-small-cell lung cancer(NSCLC).Mefatinib is a novel,bioavailable,second-generation,irreversible pan-EGFR inhibitor.This phase Ib/II open-label,single-arm,multi-center study investigated the efficacy,safety,biomarker,and resistance mechanisms of mefatinib in the first-line treatment of patients with advanced EGFR-mutant NSCLC.This study included 106 patients with EGFR-mutant stage IIIB-IV NSCLC who received first-line mefatinib at a daily dose of either 60 mg(n=51)or 80 mg(n=55).The primary endpoint was progression-free survival(PFS).Secondary endpoints were overall response rate(ORR),disease control rate(DCR),overall survival(OS),and safety.The cohort achieved an ORR of 84.9%and DCR of 97.2%.The median PFS was 15.4 months and the median OS was 31.6 months.Brain metastasis was detected in 29%of patients(n=31)at diagnosis and demonstrated an ORR of 87.1%,PFS of 12.8 months,and OS of 25.2 months.Adverse events primarily involved skin and gastrointestinal toxicities,which were well-tolerated and manageable.Analyses of mutation profiles were performed using targeted sequencing of plasma samples at baseline,first follow-up 6 weeks from starting mefatinib therapy(F1),and at progression.Patients with concurrent TP53 mutations had comparable PFS as wild-type TP53(14.0 vs 15.4 months;p=0.315).Furthermore,circulating tumor DNA clearance was associated with longer PFS(p=0.040)and OS(p=0.002).EGFR T790M was the predominant molecular mechanism of mefatinib resistance(42.1%,16/38).First-line mefatinib provides durable PFS and an acceptable toxicity profile in patients with advanced EGFR-mutant NSCLC.
基金
This work was sponsored by Hangzhou Zhongmei Huadong Pharmaceutical Co.Ltd.and supported by a grant from the Key R&D Program of Zhejiang Province(2020C03027).
