A phase Ib study of the highly selective MET-TKI savolitinib plus gefitinib in patients with EGFR -mutated, MET -amplifi
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PHASE I STUDIES
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 Jin-Ji Yang 1 & Jian Fang 2 & Yong-Qian Shu 3 & Jian-Hua Chang 4 & Gong-Yan Chen 5 & Jian Xing He 6 & Wei Li 7 & Xiao-Qing Liu 8 & Nong Yang 9 & Caicun Zhou 10 & Jian An Huang 11 & Melanie M. Frigault 12 & Ryan Hartmaier 12 & Ghada F. Ahmed 13 & Coumaran Egile 14 & Shethah Morgan 15 & Remy B. Verheijen 16 & Anders Mellemgaard 15 & Liu Yang 17 & Yi-Long Wu 1 Received: 13 August 2020 / Accepted: 21 September 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Summary Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are recommended first-line treatments in EGFRmutated (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, openlabel, 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. Keywords Savolitinib . Gefitinib . EGFR-TKI . NSCLC . MET . EGFRm
Introduction Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are recommended first-line treatments for patients with EGFR-mutated (EGFRm) non-small-cell lung cancer (NSCLC) [1, 2]. However, despite high initial response rates in this setting [3–5], most patients eventually develop Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10637-020-01010-4) contains supplementary material, which is available to authorized users. * Yi-Long Wu
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