Abstract
This study evaluated the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), pharmacokinetic profile, and preliminary antitumor activity of QLNC120, an inhibitor of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2), in HER2 overexpressing advanced breast cancer patients. In addition, the prognostic biomarkers of QLNC120 were investigated. QLNC120 was administered as a single dose, followed by 7 days observation, and then once daily consecutively. Scheduled dose escalation was 450mg, 750mg, 1000mg and 1250mg. For pharmacokinetic analysis, blood samples were collected after the single dose and after the first 7 days of continuous administration. Tissue samples were collected for biomarker analysis. Twenty-four heavily treated HER2 overexpressing advanced breast cancer patients were enrolled. No DLT was observed. MTD was not found. QLNC120 and its active metabolite-lapatinib exposure did not increase in a dose-dependent manner ranging from 450 to 1250mg QLNC120. From 450 to 1250mg QLNC120, the exposure of combination of QLNC120 and its active metabolite-lapatinib was equal to or greater than the exposure of 1250mg lapatinib. Common QLNC120-related toxicities included rash, diarrhea, oral mucositis, hematuria and white blood cell decrease. Seven of twenty-two evaluable patients achieved partial response (PR) or stable disease (SD)≥24 weeks. In biomarker analysis, nine of fifteen patients (60%) had a mutation in HRAS exon 1. Patients with HRAS mutation achieved longer progression free survival(PFS) (24.9 vs 12.9 weeks, p=0.023, HR=0.291). QLNC120 is well-tolerated and safe with encouraging antitumor activity in HER2 overexpressing advanced breast cancer. HRAS mutation was associated with the anti-tumor activity of QLNC120. (Trial registration: NCT01931943, http://ClinicalTrials.gov/show/NCT01931943)
Highlights
The epidermal growth factor (ErbB) family of membrane receptor tyrosine kinases comprises epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), HER3 and HER4 [1]
This study evaluated the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), pharmacokinetic profile, and preliminary antitumor activity of QLNC120, an inhibitor of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2), in HER2 overexpressing advanced breast cancer patients
In this phase I study, QLNC120 was well tolerated at doses up to 1250 mg daily with clinical activity at doses ranging from 450 mg to 1000 mg in heavily pretreated patients with HER2 overexpressing advanced breast cancer
Summary
The epidermal growth factor (ErbB) family of membrane receptor tyrosine kinases comprises EGFR, HER2, HER3 and HER4 [1]. Some smallmolecule tyrosine kinase inhibitors (TKIs) (e.g., lapatinib, neratinib) and antibodies (e.g., trastuzumab, trastuzumabDM1, pertuzumab) targeting the erbB family have been developed to treat HER2 positive breast cancer. Despite these new therapeutic options, disease progression of HER2-directed therapy is experienced by most patients, and new strategies are needed to delay or overcome the onset of tumor progression. The results of in vivo research demonstrated that the anti-tumor activity of QLNC120 was dose-dependent. When compared to the anti-tumor activity of Lapatinib in vivo, QLNC120 efficacy was superior with less toxicity. The maximum concentration of QLNC120 and lapatinib was observed at approximately 2.5-9 hours post dose in our in vivo model. After a single oral dose of 60 mg/ kg QLNC120 in SD rats, the excretion of the parent drug and its metabolites in feces, bile and urine was 58.4%, 6.55% and 0.1% of the dose, respectively
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