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12-09-2017 | Treatment | Article

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

BMC Cancer

Authors: Kerry Lynn Reynolds, Philippe L. Bedard, Se-Hoon Lee, Chia-Chi Lin, Josep Tabernero, Maria Alsina, Ezra Cohen, José Baselga, George Blumenschein Jr, Donna M. Graham, Ignacio Garrido-Laguna, Dejan Juric, Sunil Sharma, Ravi Salgia, Abdelkader Seroutou, Xianbin Tian, Rose Fernandez, Alex Morozov, Qing Sheng, Thiruvamoor Ramkumar, Angela Zubel, Yung-Jue Bang

Publisher: BioMed Central



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.


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.


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.


LJM716 was well tolerated; the MTD was not reached, and the RDE was 40 mg/kg QW. Further development of LJM716 is ongoing.

Trial registration

Clinicaltrials.​gov registry number NCT01598077 (registered on 4 May, 2012).

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