Phase 1 study of narnatumab, an anti-RON receptor monoclonal antibody, in patients with advanced solid tumors

Abstract

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.

Therapeutic anti-cancer activity of antibodies targeting sulfhydryl bond constrained epitopes on unglycosylated RON receptor tyrosine kinase

“…Several monoclonal antibodies have been developed by different groups and a few advanced to clinical development. However, recently, the fully human RON targeting antibody Narnatumab, reported a lack of efficacy in its phase I clinical trial study due to poor pharmacokinetics properties even though the antibody was well tolerated [18]. To date, there is still an unmet need for a RON targeting therapeutic antibody.…”

“…Clinical testing of the leading monoclonal antibody Narnatumab (IMC-RON8) was abandoned following a report of lack of efficacy in Phase I trials on the investigated dosing regimen. Narnatumab had a short half-life of less than 7 days leading to suboptimal drug exposures for the patients [18].…”

mTORC1 is a key mediator of RON-dependent breast cancer metastasis with therapeutic potential

“…This is important because everolimus is already approved in advanced ER+ breast cancer, and because several RON kinase inhibitors have been tested in Phase I clinical trials. So far, RON inhibitors have been well tolerated in healthy subjects (NCT02779738), and in patients with various types of cancer (reference 57 and NCT01721148), so this hypothesis could be tested clinically in the near future.…”

The Receptor Tyrosine Kinase RON and Its Isoforms as Therapeutic Targets in Ewing Sarcoma

“…To explore RON as a therapeutic target, we utilized the monoclonal antibody IMC-RON8 (narnatumab) that had reached phase I clinical investigation [33]. IMC-RON8 blocks MSP-RON binding and thus ligand-induced receptor activation and signaling.…”