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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 (e.g. 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. The most common adverse events (all grades) were: vomiting (n=26, 46%), nausea (n=23, 40%), increased aspartate aminotransferase (n=22, 39%). There were four deaths, none treatment-related. Interpretation: Savolitinib 600 mg plus gefitinib 250 mg once daily had an acceptable safety profile and demonstrated promising antitumour activity in EGFR-mutated, MET- amplified advanced NSCLC patients who had progressed on EGFR-TKIs. Trial Registration: NCT02374645. Funding Statement: The study was funded by AstraZeneca, Cambridge, UK, the manufacturer of savolitinib and gefitinib. Hutchison MediPharma authorised AstraZeneca to conduct this study. Declaration of Interests: MF, RH, GFA, CE, SM, RBV and AM are AstraZeneca employees and shareholders. RH also owns shares in Foundation medicine, and has a patent pending for Foundation Medicine. MF is also a patent holder for AstraZeneca. Y-LW has received personal fees from AstraZeneca, Roche, Boehringer Ingeiheim, Pfizer, Bristol-Myers Squibb, Merck Sharp & Dohme, and Sanofi; and grants from AstraZeneca, Roche, and Boehringer Ingelheim. J-JY, JF, Y-QS, J-HC, G-YC, J-XH, WL, X-QL, NY, CZ, J-AH and LY declare no conflicts of interest. Ethics Approval Statement: The study was approved by Institutional Review Boards/Independent Ethics Committees at each study centre, and by the Human Genetics Resources Administration of China. The trial was conducted in accordance with the International Conference on Harmonisation Good Clinical Practice guidelines, the provisions of the Declaration of Helsinki, applicable regulatory requirements, and the AstraZeneca policy on Bioethics and Human Biological Samples. All patients provided written informed consent before study procedures. |
