Phase 1 study of narnatumab, an anti-RON receptor monoclonal antibody, in patients with advanced solid tumors.
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.
Barbara Ann Karmanos Cancer Institute, Detroit, MI, USA. patricia.lorusso@yale.edu.|Yale Cancer Center, New Haven, CT, USA. patricia.lorusso@yale.edu.
Patricia M
PM
LoRusso
Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Mrinal
M
Gounder
Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, USA.
Shadia I
SI
Jalal
Eli Lilly and Company, Indianapolis, IN, USA.
Valérie
V
André
Eli Lilly and Company, Indianapolis, IN, USA.
Siva Rama Prasad
SRP
Kambhampati
Eli Lilly and Company, Indianapolis, IN, USA.
Nick
N
Loizos
Eli Lilly and Company, Indianapolis, IN, USA.|Boehringer Ingelheim, Ridgefield, CT, USA.
Jennifer
J
Hall
Eli Lilly and Company, Indianapolis, IN, USA.
Timothy R
TR
Holzer
Eli Lilly and Company, Indianapolis, IN, USA.
Aejaz
A
Nasir
Eli Lilly and Company, Indianapolis, IN, USA.|Merck KGaA, Darmstadt, Germany.
Jan
J
Cosaert
Eli Lilly and Company, Indianapolis, IN, USA.
John
J
Kauh
Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, USA.|Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA, USA.
E Gabriela
EG
Chiorean
D061605:Administration, Intravenous; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D016207:Cytokines / Q000097:blood; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome; D055815:Young Adult
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D016207:Cytokines; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases
IMC-RON8; Macrophage-stimulating protein receptor; Narnatumab; Phase 1; RON; Solid tumors