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.

Abstract

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.

• Authors: Jin-Ji Yang, Jian Fang, Yong-Qian Shu, Jian-Hua Chang, Gong-Yan Chen, Jian Xing He, Wei Li, Xiao-Qing Liu, Nong Yang, Caicun Zhou, Jian An Huang, Melanie M Frigault, Ryan Hartmaier, Ghada F Ahmed, Coumaran Egile, Shethah Morgan, Remy B Verheijen, Anders Mellemgaard, Liu Yang, Yi-Long Wu
• Journal: Investigational new drugs (Invest New Drugs) Vol. 39 Issue 2 Pg. 477-487 (04 2021) ISSN: 1573-0646 [Electronic] United States
• PMID: 33052556 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• Pyrazines
• Triazines
• 1-(1-(imidazo(1,2-a)pyridin-6-yl)ethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-(1,2,3)triazolo(4,5-b)pyrazine
• EGFR protein, human
• ErbB Receptors
• Protein-Tyrosine Kinases
• Proto-Oncogene Proteins c-met
• Gefitinib

Topics

• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics)
• Dose-Response Relationship, Drug
• ErbB Receptors (genetics)
• Female
• Gefitinib (administration & dosage, adverse effects, therapeutic use)
• Humans
• Lung Neoplasms (drug therapy, genetics)
• Male
• Middle Aged
• Protein-Tyrosine Kinases (antagonists & inhibitors)
• Proto-Oncogene Proteins c-met (biosynthesis)
• Pyrazines (administration & dosage, adverse effects, therapeutic use)
• Triazines (administration & dosage, adverse effects, therapeutic use)