Summary
Purpose Macrophage-stimulating 1-receptor (RON) is expressed on macrophages, epithelial cells, and a variety of tumors. Narnatumab (IMC-RON8; LY3012219) is a neutralizing monoclonal antibody that blocks RON binding to its ligand, macrophage-stimulating protein (MSP). This study assessed safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and efficacy of narnatumab in patients with advanced solid tumors. Methods Narnatumab was administered intravenously weekly at 5, 10, 15, or 20 mg/kg or every 2 weeks at 15, 20, 30, or 40 mg/kg in 4-week cycles. Results Thirty-nine patients were treated, and 1 dose-limiting toxicity (DLT) (grade 3 hyponatremia, 5 mg/kg) was reported. The most common narnatumab-related adverse events (AEs) were fatigue (20.5%) and decreased appetite, diarrhea, nausea, and vomiting (10.3% each). Except for 2 treatment-related grade 3 AEs (hyponatremia, hypokalemia), all treatment-related AEs were grade 1 or 2. Narnatumab had a short half-life (<7 days). After Cycle 2, no patients had concentrations above 140 μg/mL (concentration that demonstrated antitumor activity in animal models), except for 1 patient receiving 30 mg/kg biweekly. Eleven patients had a best response of stable disease, ranging from 6 weeks to 11 months. Despite only 1 DLT, due to suboptimal drug exposure, the dose was not escalated beyond 40 mg/kg biweekly. This decision was based on published data reporting that mRNA splice variants of RON are highly prevalent in tumors, accumulate in cytoplasm, and are not accessible by large-molecule monoclonal antibodies. Conclusions Narnatumab was well tolerated and showed limited antitumor activity with this dosing regimen.
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Acknowledgments
The authors wish to acknowledge Dale L. Ludwig (Eli Lilly and Company), David Surguladze (Eli Lilly and Company), and Erik Corcoran (formerly at Eli Lilly but now at Editas Medicine) for assistance with preclinical studies and analyses and Jude Richard (INC Research, Austin, TX) for medical writing assistance.
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P. M. LoRusso, M. Gounder, S. I. Jalal, and E. G. Chiorean disclosed no potential conflicts of interest. V. André, S. R. P. Kambhampati, N. Loizos, T. R. Holzer, A. Nasir, and J. Kauh are employees of Eli Lilly and Company. J. Cosaert and J. Hall were employed by Eli Lilly and Company during the conduct of the study but are now employed by Merck KGaA (Darmstadt, Germany) and Boehringer Ingelheim (Ridgefield, CT), respectively.
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This research was supported with funds from Eli Lilly and Company.
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This study was conducted in accordance with applicable laws and regulations, Good Clinical Practices, and the Declaration of Helsinki and with approval by the local Institutional Review Boards of participating institutions.
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Patients provided written informed consent before participating in the study.
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LoRusso, P.M., Gounder, M., Jalal, S.I. et al. Phase 1 study of narnatumab, an anti-RON receptor monoclonal antibody, in patients with advanced solid tumors. Invest New Drugs 35, 442–450 (2017). https://doi.org/10.1007/s10637-016-0413-0
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DOI: https://doi.org/10.1007/s10637-016-0413-0