Phase I Study of Ramucirumab Plus Merestinib in Previously Treated Metastatic Colorectal Cancer: Safety, Preliminary Efficacy, and Pharmacokinetic Findings.
Journal
The oncologist
ISSN: 1549-490X
Titre abrégé: Oncologist
Pays: England
ID NLM: 9607837
Informations de publication
Date de publication:
11 2020
11 2020
Historique:
received:
09
04
2020
accepted:
30
05
2020
pubmed:
17
6
2020
medline:
22
5
2021
entrez:
16
6
2020
Statut:
ppublish
Résumé
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.
Sections du résumé
LESSONS LEARNED
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.
BACKGROUND
This study evaluated safety, preliminary efficacy, and pharmacokinetics of ramucirumab plus merestinib in patients with MCR previously treated with oxaliplatin and/or irinotecan.
METHODS
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.
RESULTS
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.
CONCLUSION
Ramucirumab plus merestinib is tolerable and may have clinical benefit in biomarker-unselected, heavily pretreated patients with mCRC.
Identifiants
pubmed: 32537847
doi: 10.1634/theoncologist.2020-0520
pmc: PMC7648328
doi:
Substances chimiques
Antibodies, Monoclonal
0
Antibodies, Monoclonal, Humanized
0
Banques de données
ClinicalTrials.gov
['NCT02745769']
Types de publication
Clinical Trial, Phase I
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1628-e1639Informations de copyright
© AlphaMed Press; the data published online to support this summary are the property of the authors.
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