Cancer Res Treat.  2018 Jul;50(3):835-842. 10.4143/crt.2017.303.

Phase 1 Studies of Poziotinib, an Irreversible Pan-HER Tyrosine Kinase Inhibitor in Patients with Advanced Solid Tumors

Affiliations
  • 1Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea. bangyj@snu.ac.kr
  • 2Seoul National University Cancer Research Institute, Seoul, Korea.
  • 3Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.
  • 4Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.
  • 5Hanmi Pharm. Co., Ltd., Seoul, Korea.
  • 6Department of Pathology, Seoul National University College of Medicine, Seoul, Korea.

Abstract

PURPOSE
Poziotinib, a pan-human epidermal growth factor receptor 2 (HER) tyrosine kinase inhibitor, has shown potent activity againstwild type of epidermal growth factorreceptor(EGFR) family kinases including EGFR, HER2, and HER4 and EGFR-mutant cells in vitro. Two phase I studies were conducted to determine the maximum tolerated dose (MTD), pharmacokinetics, safety, and antitumor activity against advanced solid tumors.
MATERIALS AND METHODS
Standard 3+3 dose escalation scheme using two different dosing schedules were studied: once daily, 14-day on, and 7-day off (intermittent schedule); and once daily continuous dosing with food effect. Additional patients were enrolled in an expansion cohort.
RESULTS
A total of 75 patients were enrolled in the two studies. The most common drug-related treatment-emergent adverse eventswere diarrhea,rash, stomatitis, pruritus, and anorexia. Dose-limiting toxicities were grade 3 diarrhea in the intermittent schedule and grade 3 anorexia and diarrhea in the continuous dosing schedule. The MTDs were determined as 24 mg/day in the intermittent dosing schedule and 18 mg/day in the continuous dosing schedule. Eight (16%) and 24 (47%) of 51 evaluable patients in the intermittent schedule achieved partial response (PR) and stable disease (SD), respectively. Four (21%) and six (32%) of 19 evaluable patients in continuous dosing schedule achieved PR and SD, respectively. Patients with PR (n=7) or SD ≥ 12 weeks (n=7) had HER2 amplification (n=7; breast cancer, 5; and stomach cancer, 2) and EGFR amplification (n=1, squamous cell lung cancer).
CONCLUSION
Poziotinib was safe and well tolerated in patients with advanced solid tumors. It showed an encouraging activity against EGFR-mutant and HER2-amplified cancers.

Keyword

EGFR mutation; HER2 amplification; Poziotinib; Non-small-cell lung carcinoma

MeSH Terms

Anorexia
Appointments and Schedules
Breast Neoplasms
Carcinoma, Non-Small-Cell Lung
Cohort Studies
Diarrhea
Epithelial Cells
Humans
In Vitro Techniques
Lung
Maximum Tolerated Dose
Pharmacokinetics
Phosphotransferases
Protein-Tyrosine Kinases*
Pruritus
Receptor, Epidermal Growth Factor
Stomach Neoplasms
Stomatitis
Tyrosine*
Phosphotransferases
Protein-Tyrosine Kinases
Receptor, Epidermal Growth Factor
Tyrosine
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