A phase Ib study of the highly selective MET-TKI savolitinib plus gefitinib in patients with EGFR-mutated, MET-amplified advanced non-small-cell lung cancer.
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are recommended first-line treatments in EGFR-mutated (EGFRm) non-small-cell lung cancer (NSCLC). However, acquired resistance (e.g. MET amplification) is frequently observed. Savolitinib (volitinib, HMPL-504, AZD6094) is an oral, potent, and highly selective MET-TKI. In this phase Ib, open-label, multicenter study, we enrolled Chinese patients with EGFRm advanced NSCLC, whose disease progressed following prior EGFR-TKI treatment. 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 endpoint was safety/tolerability. Secondary endpoints included antitumor activity. Thirteen patients were enrolled in the safety phase (median age 52 years, 46% female) and 51 enrolled in the expansion phase (median age 61 years, 67% female). No dose-limiting toxicities were reported in either dose group during the safety run-in. Adverse events of grade ≥ 3 in the safety run-in and expansion phases (n = 57) were reported in 21 (37%) patients. The most frequently reported adverse events (all grades) were: vomiting (n = 26, 46%), nausea (n = 23, 40%), increased aspartate aminotransferase (n = 22, 39%). Of four deaths, none were treatment-related. The objective response rates in EGFR T790M-negative, -positive, and -unknown patients were 52% (12/23), 9% (2/23), and 40% (2/5), respectively. Savolitinib 600 mg plus gefitinib 250 mg once daily had an acceptable safety profile and demonstrated promising antitumor activity in EGFRm, MET-amplified advanced NSCLC patients who had disease progression on EGFR-TKIs. NCT02374645, Date of registration: March 2nd 2015.
['Yang|Jin-Ji|JJ|', 'Fang|Jian|J|', 'Shu|Yong-Qian|YQ|', 'Chang|Jian-Hua|JH|', 'Chen|Gong-Yan|GY|', 'He|Jian Xing|JX|', 'Li|Wei|W|', 'Liu|Xiao-Qing|XQ|', 'Yang|Nong|N|', 'Zhou|Caicun|C|', 'Huang|Jian An|JA|', 'Frigault|Melanie M|MM|', 'Hartmaier|Ryan|R|', 'Ahmed|Ghada F|GF|', 'Egile|Coumaran|C|', 'Morgan|Shethah|S|', 'Verheijen|Remy B|RB|', 'Mellemgaard|Anders|A|', 'Yang|Liu|L|', 'Wu|Yi-Long|YL|https://orcid.org/0000-0002-3611-0258']
Savolitinib Gefitinib EGFR-TKI EGFRm NSCLC MET