Abstract A187: A phase 1b/2 trial of U3–1287, a HER3 inhibitor, in combination with erlotinib in patients (pts) with advanced NSCLC.
Authors: Tseng Jennifer , Ebrahimi Ben , Johnson Tirrell , Copigneaux Catherine , Beckman Robert A. , Gordon Michael 
Published: June 2012

Abstract
Background: EGFR is frequently overexpressed in NSCLC, particularly in adenocarcinomas. Many advanced NSCLCs initially respond to EGFR tyrosine kinase inhibitors (TKIs) but subsequently develop resistance. HER3 is a key dimerization partner of HER family members, including EGFR, and activates oncogenic signaling pathways. Overexpression of HER3 occurs in many solid tumors and is associated with poor prognosis in lung cancer pts. Data suggest that HER3 expression may play a role in EGFR TKI resistance, suggesting that simultaneous inhibition of HER3 and EGFR may offer therapeutic benefit. U3–1287 is a fully human anti-HER3 monoclonal antibody with synergistic anticancer activity in combination with anti-EGFR inhibitors in preclinical models. A phase 1b/2 trial was initiated to investigate the combination of U3–1287 with the EGFR TKI erlotinib in the treatment of advanced NSCLC pts. We report here the results of the phase 1b portion as of June 13, 2011.
Materials and Methods: To be eligible, pts had to have stage IIIB/IV NSCLC that had progressed on ≥1 prior chemotherapy treatments and were EGFR treatment-naive. In the open-label, phase 1b portion of the study, pts received erlotinib 150 mg/day orally and U3–1287 18 mg/kg intravenously every 3 weeks (Q3W). The U3–1287 dose was selected on the basis of results from the first-in-human phase 1 study (ENA 2010, abstract 234) in which no dose-limiting toxicities (DLTs) were observed up to the maximum administered dose of 20 mg/kg Q2W. In the event that 18 mg/kg was not tolerated based on DLT assessment, sequential cohorts were to receive de-escalating doses of U3–1287. DLTs included any treatment-related grade ≥3 toxicity except for anorexia, grade 3 fatigue persistent ≥7 days, nausea/vomiting in the absence of standard anti-emetic therapy, and lymphopenia. Phase 1b study end points included adverse event (AE) incidence, pharmacokinetics, and tumor response.
Results: Seven pts (4 male) enrolled in the phase 1b portion of the trial, with a median age of 68 years (range, 48–78). Five pts had adenocarcinoma, and 2 pts had squamous carcinoma. Pts had 1, 2, or 3 prior NSCLC therapies (n=4, 2, and 1, respectively). There were no reported DLTs. Erlotinib-related AEs reported in ≥2 pts were rash (6 pts), diarrhea (4), dry skin (3), decreased appetite, dehydration, dermatitis acneiform, dysgeusia, mucosal inflammation, nausea, skin exfoliation, and stomatitis (2 each). No U3–1287-related AEs were reported in &gt;1 pt; those that occurred in 1 pt each were increases in blood creatinine and urea, decreased appetite, diarrhea, dysgeusia, mucosal inflammation, nausea, proteinuria, rash, ventricular extrasystoles, and vomiting. AEs grade ≥3 occurred in 2 pts, and included a grade 3 case each of pain, fatigue, headache, dehydration, diarrhea, and increase in blood creatinine; none were related to U3–1287. One pt had grade 3 diarrhea and a serious AE of grade 3 dehydration requiring hospitalization after the DLT observation period (cycle 1); both AEs were erlotinib-related. All other treatment-related AEs were grades 1 or 2. At the week-6 visit, 4 pts had stable disease, and 3 had progressive disease.
Conclusions: Results to date indicate that the combination of U3–1287 with erlotinib is generally well tolerated. As no DLTs were reported, the recommended phase 2 dose is 18 mg/kg Q3W for U3–1287 in combination with 150 mg/day erlotinib.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A187.