Abstract
HER3 is a key dimerization partner for other HER family members, and its expression is associated with poor prognosis. This first-in-human study of U3-1287 (NCT00730470), a fully human anti-HER3 monoclonal antibody, evaluated its safety, tolerability, and pharmacokinetics in patients with advanced solid tumor. The study was conducted in 2 parts: part 1--sequential cohorts received escalating doses (0.3-20 mg/kg) of U3-1287 every 2 weeks, starting 3 weeks after the first dose; part 2--additional patients received 9, 14, or 20 mg/kg U3-1287 every 2 weeks, based on observed tolerability and pharmacokinetics from part 1. Recommended phase II dose, adverse event rates, pharmacokinetics, and tumor response were determined. Fifty-seven patients (part 1: 26; part 2: 31) received U3-1287. As no dose-limiting toxicities were reported, the maximum-tolerated dose was not reached. The maximum-administered dose was 20 mg/kg every 2 weeks. The most frequent adverse events related to U3-1287 were fatigue (21.1%), diarrhea (12.3%), nausea (10.5%), decreased appetite (7.0%), and dysgeusia (5.3%). No patient developed anti-U3-1287 antibodies. In these heavily pretreated patients, stable disease was maintained 9 weeks or more in 19.2% in part 1 and 10 weeks or more in 25.8% in part 2. U3-1287 treatment was well tolerated, and some evidence of disease stabilization was observed. Pharmacokinetic data support U3-1287 dosing of 9 to 20 mg/kg every 2 to 3 weeks. Combination studies of U3-1287 are ongoing.
Highlights
The EGF receptor (EGFR)/HER family of receptor tyrosine kinases, consisting of HER1 (EGFR), HER2, HER3, and HER4, plays an important role in oncogenesis
Recent studies suggest that HER3 upregulation or reactivation is important to the development of resistance to EGFR- and HER2-targeted treatments [8,9,10,11]
We present results from the first-in-human study of U3-1287, a first-in-class HER3-targeting monoclonal antibody
Summary
The EGF receptor (EGFR)/HER family of receptor tyrosine kinases, consisting of HER1 (EGFR), HER2, HER3, and HER4, plays an important role in oncogenesis. A number of tumor types require EGFR or HER2 signaling for growth and survival [5,6,7], prompting the development of various therapeutic agents that target the EGFR and HER2 receptors. Current anti-EGFR and anti-HER2 agents, have proven to be effective only in a subset of patients, and initial response is frequently followed by relapse and the development of therapeutic resistance. Recent studies suggest that HER3 upregulation or reactivation is important to the development of resistance to EGFR- and HER2-targeted treatments [8,9,10,11]. Elevated HER3 expression has been detected in many tumor types and is associated with negative clinical prognosis, including shorter relapse-free survival time in breast
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