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
| Autor: | Remy B. Verheijen, Yongqian Shu, Wei Li, Nong Yang, Caicun Zhou, Anders Mellemgaard, Coumaran Egile, Jian Fang, Ryan J. Hartmaier, Yi-Long Wu, Xiao-Qing Liu, Jianxing He, Liu Yang, Melanie M. Frigault, Jian-An Huang, Jianhua Chang, Shethah Morgan, Jin-Ji Yang, Gongyan Chen, Ghada F. Ahmed |
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| Rok vydání: | 2020 |
| Předmět: |
Oncology
Adult Male medicine.medical_specialty Lung Neoplasms Nausea Gefitinib Internal medicine Carcinoma Non-Small-Cell Lung Antineoplastic Combined Chemotherapy Protocols Clinical endpoint Medicine Humans Pharmacology (medical) Lung cancer Adverse effect Aged Pharmacology Dose-Response Relationship Drug business.industry Triazines Middle Aged Protein-Tyrosine Kinases Proto-Oncogene Proteins c-met medicine.disease respiratory tract diseases ErbB Receptors Savolitinib Tolerability Pyrazines Vomiting Female medicine.symptom business medicine.drug |
| Zdroj: | Investigational new drugs. 39(2) |
| ISSN: | 1573-0646 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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