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

Focal adhesion kinase priming in pancreatic cancer, altering biomechanics to improve chemotherapy

“…Similarly, disruption of tumour-stroma interactions via the hepatocyte growth factor (HGF)/c-MET pathway using a triple therapy combining the humanised monoclonal anti-HGF antibody AMG102, a c-MET inhibitor and gemcitabine chemotherapy led to significant inhibition of cell proliferation in vitro and reduced tumour burden and metastasis in vivo [ 105 ]. These findings led to a first-in-human phase I trial of the clinically relevant anti-HGF antibody, YYB101 in refractory solid tumours, revealing favourable safety and efficacy [ 106 ], and presenting a new therapeutic drug candidate for the treatment of PDAC patients (NCT02499224, Table 1 ).…”

Dependence receptors: new targets for cancer therapy

“…Migration and invasion of cancer cells were also inhibited by another monoclonal antibody targeting c‐MET, YYB‐001 (Kim et al , 2019). A phase I clinical trial with this antibody has just been completed for colorectal cancer (NCT04368507) (Kim et al , 2020), reflecting the potential of therapies targeting DRs for preventing metastatic spread.…”

Therapeutic Strategies for Ovarian Cancer in Point of HGF/c-MET Targeting

“…In the preclinical model of ovarian cancer, YYB-101 blocked HGF, leading to the inhibition of the progression of ovarian cancer cells through downstream signaling of the c-MET axis [ 102 , 103 ]. However, in the phase I trial of YYB-101 in ovarian cancer, administering YYB-101 to patients who had failed at least four previous regimens resulted in none of the patients with ovarian cancer responding to single-agent treatment [ 104 ].…”