S-Space College of Medicine/School of Medicine (의과대학/대학원) Internal Medicine (내과학전공) Journal Papers (저널논문_내과학전공)
A phase I open-label dose-escalation study of the anti-HER3 monoclonal antibody LJM716 in patients with advanced squamous cell carcinoma of the esophagus or head and neck and HER2-overexpressing breast or gastric cancer
- Reynolds, Kerry Lynn; Bedard, Philippe L.; Lee, Se-Hoon; Lin, Chia-Chi; Tabernero, Josep; Alsina, Maria; Cohen, Ezra; Baselga, Jose; Blumenschein, George, Jr.; Graham, Donna M.; Garrido-Laguna, Ignacio; Juric, Dejan; Sharma, Sunil; Salgia, Ravi; Seroutou, Abdelkader; Tian, Xianbin; Fernandez, Rose; Morozov, Alex; Sheng, Qing; Ramkumar, Thiruvamoor; Zubel, Angela; Bang, Yung-Jue
- Issue Date
- BMC Cancer, Vol.17, p. 646
- ADA: anti-drug antibodies; AE: adverse event; ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase; AUC: area under curve; BLRM: Bayesian logistic regression model; CEER: Collaborative Enzyme Enhanced Reactive; CI: confidence interval; CT: computed tomography; DLT: dose-limiting toxicities; ECOG: Eastern Cooperative Oncology Group; EGFR: epidermal growth factor receptor; ErbB: v-erb-b2 erythroblastic leukemia viral oncogene homolog; ESCC: esophageal squamous cell carcinoma; EWOC: escalation with overdose control; EX: expansion phase; FAS: full analysis set; HER2: human epidermal growth factor receptor 2; HER3: human epidermal growth factor receptor; IgG1: immunoglobulin G1; IHC: immunohistochemistry; IRR: infusion-related reactions; IV: intravenously; MRI: magnetic resonance imaging; MTD: maximum tolerated dose; ND: not determined; NGS: nextgeneration sequencing; NRG1: neuregulin 1; ORR: overall response rate; p-AKT: phosphor-AKT; PD: progressive disease; PFS: progression-free survival; p-HER3: phospho-human epidermal growth factor receptor 3; PI3K: phosphoinositide 3-kinase; PIK3CA amp: PIK3CA amplified; PIK3CA: phosphoinositide 3-kinase, catalytic subunit alpha; PR: partial response; PS: performance status; PTEN: phosphatase and tensin homolog; Q2W: once every two weeks; QW: once weekly; RDE: recommended dose for expansion; RECIST: Response Evaluation Criteria in Solid Tumors; RTK: receptor tyrosine kinase; RT-PCR: reverse transcription polymerase chain reaction; SAE: serious adverse event; SCCHN: squamous cell carcinoma of the head and neck; SD: stable disease; t-AKT: total AKT; t-HER3: total human epidermal growth factor receptor 3; UNK: unknown
- Background: Human epidermal growth factor receptor 3 (HER3) is important in maintaining epidermal growth factor receptor-driven cancers and mediating resistance to targeted therapy. A phase I study of anti-HER3 monoclonal antibody LJM716 was conducted with the primary objective to identify the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE), and dosing schedule. Secondary objectives were to characterize safety/tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity. Methods: This open-label, dose-finding study comprised dose escalation, followed by expansion in patients with squamous cell carcinoma of the head and neck or esophagus, and HER2-overexpressing metastatic breast cancer or gastric cancer. During dose escalation, patients received LJM716 intravenous once weekly (QW) or every two weeks (Q2W), in 28-day cycles. An adaptive Bayesian logistic regression model was used to guide dose escalation and establish the RDE. Exploratory pharmacodynamic tumor studies evaluated modulation of HER3 signaling. Results: Patients received LJM716 3-40 mg/kg QW and 20 mg/kg Q2W (54 patients; 36 patients at 40 mg/kg QW). No dose-limiting toxicities (DLTs) were reported during dose-escalation. One patient experienced two DLTs (diarrhea, hypokalemia [ both grade 3]) in the expansion phase. The RDE was 40 mg/kg QW, providing drug levels above the preclinical minimum effective concentration. One patient with gastric cancer had an unconfirmed partial response; 17/54 patients had stable disease, two lasting > 30 weeks. Down-modulation of phospho-HER3 was observed in paired tumor samples. Conclusions: LJM716 was well tolerated; the MTD was not reached, and the RDE was 40 mg/kg QW. Further development of LJM716 is ongoing.