title: Phase I study of QLNC120, a novel EGFR and HER2 kinase inhibitor, in pre-treated patients with HER2-overexpressing advanced breast cancer.
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).
authors.affiliation: Department of Medical Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
authors.forename: Tongtong
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Medical Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Medical Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Medical Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Department of Medical Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Department of Medical Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
authors.forename: Binghe
authors.initials: B
authors.lastname: Xu
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D015870:Gene Expression; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009367:Neoplasm Staging; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics*; D019233:Retreatment; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D066246:ErbB Receptors; D047428:Protein Kinase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human
keywords: HRAS; Phase I; QLNC120; tyrosine kinase inhibitor