A Phase 1b Study of Savolitinib Plus Gefitinib for Patients with <i>EGFR</i>-Mutated <i>MET</i>-Amplified Advanced Non-Small-Cell Lung Cancer

Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are recommended first-line treatments in EGFR-mutated non-small-cell lung cancer (NSCLC). However, acquired resistance (eg MET amplification) is common. Savolitinib (volitinib, HMPL-504, AZD6094) is an oral, potent, and highly selective MET-TKI.Methods: In this phase 1b, open-label, multicentre study, we enrolled Chinese patients with EGFR-mutated, advanced NSCLC, whose disease progressed during or after treatment with prior EGFR-TKIs. In the safety run-in, patients received savolitinib 600 or 800 mg plus gefitinib 250 mg orally, once-daily and dose-limiting toxicities were recorded. In the expansion phase, patients with MET amplification received savolitinib plus gefitinib. The primary endpoints were safety and tolerability. Secondary endpoints included antitumour activity and pharmacokinetics.Findings: No dose-limiting toxicities were reported in either dose group during the safety run-in (n= 13). Savolitinib 600 mg plus gefitinib 250 mg once daily was selected as the recommended phase 2 dose and evaluated in the expansion phase (n= 51). The objective response rates in EGFR T790M-negative,-positive and-unknown patients were 52%(12/23), 9%(2/23), and 40%(2/5), respectively. Thirty-five patients (69%) were evaluable for longitudinal circulating tumour DNA analysis. Pharmacokinetic parameters for savolitinib plus gefitinib were consistent with previous monotherapy studies, showing no evidence of drug-drug interactions. Adverse events of grade 3 or more in the safety run-in and expansion phases (n= 57) were reported in 21 (37%) patients …