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Ref Type Journal Article
PMID (32537847)
Authors Saleh M, Cassier PA, Eberst L, Naik G, Morris VK, Pant S, Terret C, Gao L, Long A, Mao H, McNeely S, Wagner EK, Carlesi RM, Fu S
Title Phase I Study of Ramucirumab Plus Merestinib in Previously Treated Metastatic Colorectal Cancer: Safety, Preliminary Efficacy, and Pharmacokinetic Findings.
Journal The oncologist
Vol
Issue
Date 2020 Jun 14
URL
Abstract Text The combination of the antivascular endothelial growth factor receptor 2 monoclonal antibody, ramucirumab, and the type II MET kinase inhibitor, merestinib, is tolerable. Preliminary efficacy data suggest that the combination may provide clinical benefit to patients with metastatic colorectal cancer (mCRC). Further development of this combination would likely necessitate the identification of subsets of patients with mCRC where the clinical benefit is of clinical relevance.This study evaluated safety, preliminary efficacy, and pharmacokinetics of ramucirumab plus merestinib in patients with MCR previously treated with oxaliplatin and/or irinotecan.Open-label phase Ia/b study comprising 3+3 dose-limiting toxicity (DLT) observation and expansion parts. Treatment was ramucirumab 8 mg/kg on days 1 and 15 and merestinib 80 mg once daily (QD; 28-day cycle). Primary objective was safety and tolerability. Secondary objectives were pharmacokinetics and preliminary antitumor activity. Exploratory objective was biomarker associations.Safety findings: DLT (proteinuria) of 7 phase Ia patients (the expansion part started at the initial recommended dose level); 16 patients (70%) with grade ≥3 treatment-emergent adverse events (TEAEs); 10 patients (43%) with grade ≥3 treatment-related TEAEs. The most common grade ≥3 treatment-related TEAEs were fatigue (4 patients [17%]) and increased blood alkaline phosphatase, diarrhea, and hypertension (2 patients each [9%]). One patient discontinued treatment because of cholestatic hepatitis. Geometric mean trough concentrations at cycle 1, day 15, were ramucirumab, 24.8 μg/mL; merestinib, 130 ng/mL. No complete or partial response was seen; 12 patients (52%) achieved stable disease. Median progression-free survival was 3.3 months (95% confidence interval [CI]: 1.6-4.4). Median overall survival was 8.9 months (95% CI: 3.5-12.7). There were no associations between genetic alterations and efficacy.Ramucirumab plus merestinib is tolerable and may have clinical benefit in biomarker-unselected, heavily pretreated patients with mCRC.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Merestinib LY2801653|LY-2801653 AXL Inhibitor 27 DDR1 Inhibitor 8 DDR2 inhibitor 7 FLT3 Inhibitor 55 MET Inhibitor 51 RON Inhibitor 10 ROS1 Inhibitor 14 Trk Receptor Inhibitor (Pan) 23 TYRO3 Inhibitor 8 Merestinib (LY2801653) inhibits several receptor tyrosine kinases including MET, MST1R (RON), AXL, MERTK, TYRO3, ROS1 fusions, PDGFRA, FLT3, TEK, DDR1/2, MKNK1/2, and NTRK1/2/3 with greatest activity against NTRK1, and may result in decreased tumor growth (PMID: 23275061, PMID: 24305878, PMID: 29568395, PMID: 32537847).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown colorectal cancer not applicable Merestinib + Ramucirumab Phase I Actionable In a Phase I trial, the combination of Merestinib (LY2801653) and Cyramza (ramucirumab) demonstrated tolerability and resulted in a median overall survival of 8.9 months, median progression-free survival of 3.3 months, and stable disease in 52% (12/23) of patients with previously treated metastatic colorectal cancer (PMID: 32537847; NCT02745769). 32537847