Background: Human epidermal growth factor receptor 3 (HER3) is implicated in tumor growth, proliferation, drug resistance, and metastasis. LJM716 is a fully humanized anti-HER3 IgG1 monoclonal antibody with single-agent and combination anti-tumor activity in HER2-amplified and neuregulin-expressing xenografts. This open-label dose escalation Phase I study evaluated the safety and tolerability of single-agent LJM716 in Japanese patients (pts) with HER2+ advanced/metastatic breast (BC) or gastric cancer (GC), and recurrent/metastatic esophageal squamous cell carcinoma (ESCC) or squamous cell carcinoma of the head and neck (SCCHN) regardless of HER2 status.

Methods: Pts (aged ≥18 years, ECOG PS 0‒2) received intravenous (IV) once-weekly (QW) LJM716 in 28 day cycles. The primary objective was to determine the maximum tolerated dose (MTD) and/or recommended dose (RD). Secondary objectives included safety and tolerability, preliminary anti-tumor activity, and pharmacokinetics. Dose escalation decisions were made based on a synthesis of all relevant data, guided by an adaptive Bayesian logistic regression model (BLRM) on dose limiting toxicities (DLTs).

Results: At the data cutoff date of Jun 3, 2015, 12 pts (SCCHN [n = 2], ESCC [n = 2], and HER2+ BC [n = 6] or GC [n = 2]) were enrolled (median age 58 years, 50% male, 58% ECOG PS 0). Pts were treated in 3 dose cohorts of 10‒40 mg/kg QW; the median duration of exposure to LJM716 was 14.0 weeks (range 4.0‒48.1). No DLT was reported during Cycle 1; at 40 mg/kg QW 1 pt experienced a DLT of Grade (Gr) 3 pneumonia aspiration during Cycle 2. The BLRM with overdose control supported the tolerability of LJM716 up to 40 mg/kg QW based on DLTs occurring during Cycle 1. However, DLTs occurring after Cycle 1 were also clinically considered, and 40 mg/kg QW was declared as the RD in Japanese pts; the MTD was not reached. One or more adverse event (AE) suspected as drug related were experienced by 10 (83%) pts; most commonly (≥25%) diarrhea (6 pts [50%]), stomatitis, paronychia, fatigue, and pyrexia (3 pts [25%] each). Four pts (33%) experienced ≥1 Gr 3/4 drug-related AEs (all at 40 mg/kg QW): pneumonia aspiration and neutropenia (1 pt [8%] each) and lymphocyte count decreased (2 pts [17%]). Serious AEs were experienced by 2 pts (17%); Gr 2 nausea and Gr 1 vomiting (not suspected as drug related) and Gr 3 pneumonia aspiration (suspected as drug related). One pt died within the follow up period after the last dose of study drug due to disease progression. LJM716 plasma concentration increased with dose, and mean AUClast and Cmax were similar to those found in Western pts. There were no complete or partial responses; stable disease was reported in 6 (50%) pts.

Conclusion: LJM716 was well tolerated with a manageable safety profile, and the RD of LJM716 was established at 40 mg/kg QW IV in Japanese pts - the same RD as determined in Western pts in a separate clinical trial. Clinical trials identifier: NCT01911936.

Citation Format: TAITO ESAKI, HISANOBU ODA, TATSUHIRO KAJITANI, TAKAYUKI KOBAYASHI, JUNICHI TOMOMATSU, TOMOYUKI KAKIZUME, TAKAHIRO WATANABE, HIROMI TAKEUCHI, KOICHI FUKINO, SHUNJI TAKAHASHI. Phase I study of the safety and tolerability of LJM716 in Japanese patients with advanced solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C120.