454PD - First in human, a phase I study of ISU104, a novel ErbB3 monoclonal antibody, in patients with advanced solid tumours

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BackgroundErbB3, a heterodimeric partner of EGFR or ErbB2, is activated by heregulin binding in various cancers. ISU104, blocking ErbB3 activation and dimerization, showed anti-tumor effects in various preclinical models as mono- or combination-therapy. MethodsIn the part 1, we enrolled the patients with advanced solid tumor who were refractory to standard treatments. Study was conducted with a standard 3+3 dose escalation scheme at 5 different doses (1, 3, 5, 10, 20mg/kg/day). Dose-limiting toxicities (DLTs) were evaluated during the 1st Cycle of 28 days. Thereafter, ISU104 was given weekly, and tumor response was assessed every 8 weeks. Blood samples for pharmacokinetics (PK) and immunogenicity studies were performed. ResultsIn the part 1, 15 patients (13 males, 2 females) were enrolled. Median age was 54 (range 36–96). No DLT was observed even at the maximum dose (20mg/kg/day). The most common drug-related adverse events (AEs) were oral mucositis (n=3), pruritus (n=2), diarrhea (n=2), and fatigue (n=2), but of which were grade 1. Only two grade 3 AEs were noted; asthenia (n=1) and anemia (n=1). Thirteen subjects were assessable; 7 stable diseases and 1 partial response (table). One responder lasted up to 40 weeks. Drug clearances tend to decrease (0.77±0.41ml/h/kg at 1mg/kg; 0.20±0.03ml/h/kg at 20mg/kg) and half-lives to increase (44.50±5.74h at 1mg/kg; 269.86±19.08h at 20mg/kg) as dose is increased. PK analysis and modeling suggested target-mediated clearance of ISU104 and saturation of target binding at 3mg/kg, and the dosing regimen for the part 2 of the current study, which would be 20mg/kg tri-weekly.Table454PDTableCancer typeHypopharynxHypopharynx*RectalBreastPalateRectalSubmandibularParotidColonNSCLCEsophagusTonsilEsophagusBest responsePRSDSDSDSDSDSDSDPDPDPDPDPDMaximum change in tumor size (target lesion) (%)-60.5-21.9-21.4-8.10.52.83.66.913.213.517.428.173.7*Double primary with esophagus ConclusionsIntravenous administrations of ISU104 were well tolerated up to 20mg/kg/day without DLT, and showed disease control rate of 60.0%. Safety and efficacy of ISU104 as mono- or combination-therapy and potential biomarkers will be further explored in head and neck, colorectal and breast cancers. Clinical trial identificationNCT03552406. Legal entity responsible for the studyISU Abxis. FundingKDDF: Korea Drug Development Fund. DisclosureB. Keam: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: MSD; Advisory / Consultancy: Genexin; Research grant / Funding (self): ONO; Research grant / Funding (self): MSD; Research grant / Funding (institution): AstraZeneca. T.M. Kim: Research grant / Funding (institution): AstraZeneca. K. Park: Advisory / Consultancy: Astellas Pharma; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim; Advisory / Consultancy: Clovis Oncology; Advisory / Consultancy: Lilly; Advisory / Consultancy: Hanmi; Advisory / Consultancy: Kyowa Hakko Kirin; Advisory / Consultancy: Norvatis; Advisory / Consultancy: Ono Pharmaceutical; Advisory / Consultancy: Roche; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: GlaxoSmithKline; Advisory / Consultancy: MSD; Speaker Bureau / Expert testimony: AZD. J.S. Ahn: Advisory / Consultancy: Samsung Bioepis; Honoraria (institution): Menarini; Honoraria (institution): Amgen; Honoraria (institution): Pfizer; Honoraria (institution): AstraZeneca; Honoraria (institution): Roche; Honoraria (institution): Janssen; Honoraria (institution): MSD; Honoraria (institution): Bristol-Myers Squibb-Ono Pharmaceutical; Honoraria (institution): Eisai; Honoraria (institution): Boehringer Ingelheim. J. Juhn: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: ISU Abxis. S. Kim: Full / Part-time employment: ISU Abxis. S. Hong: Shareholder / Stockholder / Stock options, Full / Part-time employment: ISU ABXIS. M. Ahn: Honoraria (institution), Advisory / Consultancy: AstraZeneca; Honoraria (institution), Advisory / Consultancy: BMS; Honoraria (institution), Advisory / Consultancy: MSD; Honoraria (institution): ONO; Honoraria (institution), Advisory / Consultancy: Roche; Advisory / Consultancy: TAKEDA; Advisory / Consultancy: Novartis; Advisory / Consultancy: Alpha pharmaceutical. All other authors have declared no conflicts of interest.