TY - JOUR
T1 - Phase I Study of Ramucirumab Plus Merestinib in Previously Treated Metastatic Colorectal Cancer
T2 - Safety, Preliminary Efficacy, and Pharmacokinetic Findings
AU - Saleh, Mansoor
AU - Cassier, Philippe A.
AU - Eberst, Lauriane
AU - Naik, Gurudatta
AU - Morris, Van K.
AU - Pant, Shubham
AU - Terret, Catherine
AU - Gao, Ling
AU - Long, Amanda
AU - Mao, Huzhang
AU - McNeely, Samuel
AU - Wagner, Erin K.
AU - Carlesi, Roberto M.
AU - Fu, Siqing
N1 - Funding Information:
These findings were presented in part at the ESMO World Congress on Gastrointestinal Cancer, Barcelona, Spain, 3–6 July 2019. Medical writing assistance was provided by Luke Carey, PhD, CMPP, of ProScribe – Envision Pharma Group, and was funded by Eli Lilly and Company. ProScribe's services complied with international guidelines for Good Publication Practice (GPP3). The authors would like to thank all study participants and Sylwia Szymczak (Eli Lilly and Company) for support with data collection.
Funding Information:
These findings were presented in part at the ESMO World Congress on Gastrointestinal Cancer, Barcelona, Spain, 3–6 July 2019. Medical writing assistance was provided by Luke Carey, PhD, CMPP, of ProScribe – Envision Pharma Group, and was funded by Eli Lilly and Company. ProScribe's services complied with international guidelines for Good Publication Practice (GPP3). The authors would like to thank all study participants and Sylwia Szymczak (Eli Lilly and Company) for support with data collection. Data sharing statement: Lilly provides access to all individual participant data collected during the trial, after anonymization, with the exception of pharmacokinetic or genetic data. Data are available to request 6 months after the indication studied has been approved in the U.S. and E.U. and after primary publication acceptance, whichever is later. No expiration date of data requests is currently set once data are made available. Access is provided after a proposal has been approved by an independent review committee identified for this purpose and after receipt of a signed data sharing agreement. Data and documents, including the study protocol, statistical analysis plan, clinical study report, blank or annotated case report forms, will be provided in a secure data sharing environment. For details on submitting a request, see the instructions provided at www.vivli.org.
Publisher Copyright:
© AlphaMed Press; the data published online to support this summary are the property of the authors.
PY - 2020/11/1
Y1 - 2020/11/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85088092184&partnerID=8YFLogxK
U2 - 10.1634/theoncologist.2020-0520
DO - 10.1634/theoncologist.2020-0520
M3 - Article
C2 - 32537847
AN - SCOPUS:85088092184
SN - 1083-7159
VL - 25
SP - e1628-e1639
JO - Oncologist
JF - Oncologist
IS - 11
ER -
