First-in-human phase I trial of anti-hepatocyte growth factor antibody (YYB101) in refractory solid tumor patients

Abstract

Background: YYB101, a humanized monoclonal antibody against hepatocyte growth factor (HGF), has shown safety and efficacy in vitro and in vivo. This is a first-in-human trial of this antibody.

Materials and methods: YYB101 was administered intravenously to refractory cancer patients once every 4 weeks for 1 month, and then once every 2 weeks until disease progression or intolerable toxicity, at doses of 0.3, 1, 3, 5, 10, 20, 30 mg/kg, according to a 3+3 dose escalation design. Maximum tolerated dose, safety, pharmacokinetics, and pharmacodynamics were studied. HGF, MET, PD-L1, and ERK expression was evaluated for 9 of 17 patients of the expansion cohort (20 mg/kg).

Results: In 39 patients enrolled, no dose-limiting toxicity was observed at 0.3 mg/kg, and the most commonly detected toxicity was generalized edema (n = 7, 18.9%) followed by pruritis and nausea (n = 5, 13.5%, each), fatigue, anemia, and decreased appetite (n = 4, 10.8%, each). No patient discontinued treatment because of adverse events. YYB101 showed dose-proportional pharmacokinetics up to 30 mg/kg. Partial response in 1 (2.5%) and stable disease in 17 (43.5%) were observed. HGF, MET, PD-L1, and ERK proteins were not significant predictors for treatment response. However, serum HGF level was significantly lowered in responders upon drug administration. RNA sequencing revealed a mesenchymal signature in two long-term responders.

Conclusion: YYB101 showed favorable safety and efficacy in patients with refractory solid tumors. Based on this phase I trial, a phase II study on the YYB101 + irinotecan combination in refractory metastatic colorectal cancer patients is planned.

Conclusion: ClinicalTrials.gov Identifier: NCT02499224.

Keywords: hepatocyte growth factor; pharmacodynamics; pharmacokinetics; phase I; refractory cancer.

Conflict of interest statement

Conflict of interest statement: S-J L and S-W S are employees of CellabMED Inc., Korea. The remaining authors declare no conflicts of interest.

© The Author(s), 2020.

Figures

Figure 1.

a) Swimmer plot for patients in the dose-escalation cohort; b) Swimmer plot for patients in the expansion cohort; and c) Waterfall plot for all enrolled patients.

Figure 2.

a) Pre- and on-treatment biopsy immunohistochemistry (IHC) assay result. RB010 was a CRC patient who had disease progression after 4 weeks. RB010 IHC profile: baseline ERK 60%/ hepatocyte growth factor (HGF) 0/MET 90%/PD-L1 2% and D29 biopsy with ERK 95%/HGF 0/MET 0%/PD-L1 CPS 0. RB012 was a melanoma patient who achieved stable disease for 23 weeks. RB012 IHC profile: baseline ERK 90% HGF 40% MET 90% PD-L1 2% and D29 biopsy with ERK 90%/HGF 90%/MET 0%/PD-L1 1%. RB013 was a CRC patient who had stable disease for 15.7 weeks. RB013 IHC profile: baseline ERK 0%/HGF 0%/MET 90%/PD-L1 11% and D29 biopsy ERK 0%/HGF 0%/MET 40%/PD-L1 8%. RB017 was a sebaceous carcinoma patient who had stable disease for 15.6 weeks. RB017 IHC profile: ERK 100%/HGF 0/MET 0/PD-L1 0% and D29 biopsy had ERK 70%/HGF 0/MET 0/PD-L1 0%; b) Genomic landscape of enrolled patients. None of the MET overexpressed tumor specimens harbored MET amplification in NGS; and c) Change in blood HGF level before and after YYB101 treatment. YYB101 efficiently decreased serum HGF level. CRC, Colorectal cancer; D, Day; NGS, Next generation sequencing.