Cancer Chemotherapy and Pharmacology

, Volume 69, Issue 4, pp 891–899

Phase I study of continuous afatinib (BIBW 2992) in patients with advanced non-small cell lung cancer after prior chemotherapy/erlotinib/gefitinib (LUX-Lung 4)

  • H. Murakami
  • T. Tamura
  • T. Takahashi
  • H. Nokihara
  • T. Naito
  • Y. Nakamura
  • K. Nishio
  • Y. Seki
  • A. Sarashina
  • M. Shahidi
  • N. Yamamoto
Original Article

DOI: 10.1007/s00280-011-1738-1

Cite this article as:
Murakami, H., Tamura, T., Takahashi, T. et al. Cancer Chemother Pharmacol (2012) 69: 891. doi:10.1007/s00280-011-1738-1

Abstract

Purpose

This Phase I study determined the maximum-tolerated dose (MTD) of afatinib (Afatinib is an investigational compound and its safety and efficacy have not yet been established) (BIBW 2992; trade name not yet approved by FDA), an irreversible inhibitor of epidermal growth factor receptor (EGFR)/human epidermal growth factor receptor (HER)1 and 2, up to a dose of 50 mg/day in advanced non-small cell lung cancer (NSCLC), to establish the recommended dose for Phase II.

Methods

Patients with advanced NSCLC who had received prior platinum-doublet chemotherapy and/or erlotinib/gefitinib therapy, or who were ineligible for, or not amenable to, treatment with established therapies, received oral afatinib once daily. The MTD was determined based on dose-limiting toxicities (DLTs); other assessments included safety, pharmacokinetic profile, antitumour activity according to response evaluation criteria in solid tumours and EGFR/HER1 mutation analysis where possible.

Results

Twelve evaluable patients were treated at doses of 20–50 mg/day. One DLT was observed at 50 mg/day in Course 1 (Grade 3 mucositis). The most frequent drug-related adverse events were diarrhoea, dry skin, stomatitis, rash, paronychia and anorexia; most were Grade 1 or 2. Six out of 12 patients had tumour size reductions; durable stable disease was achieved in three patients including one with EGFR/HER1 exon 19 and T790 M mutations. Peak plasma concentrations of afatinib were reached 3–4 h after administration and declined with a half-life of 30–40 h. Afatinib 50 mg/day was well tolerated with an acceptable safety profile during Phase I.

Conclusion

Recommended dose for Phase II was defined as 50 mg/day for Japanese patients; the same as for non-Japanese patients.

Keywords

Phase IAfatinibBIBW 2992Epidermal growth factor receptorTyrosine kinase inhibitorNon-small cell lung cancer

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • H. Murakami
    • 1
  • T. Tamura
    • 2
  • T. Takahashi
    • 1
  • H. Nokihara
    • 2
  • T. Naito
    • 1
  • Y. Nakamura
    • 1
  • K. Nishio
    • 3
  • Y. Seki
    • 4
  • A. Sarashina
    • 5
  • M. Shahidi
    • 6
  • N. Yamamoto
    • 1
  1. 1.Division of Thoracic OncologyShizuoka Cancer CenterShizuokaJapan
  2. 2.National Cancer Center HospitalTokyoJapan
  3. 3.Kinki University School of MedicineOsakaJapan
  4. 4.Nippon Boehringer IngelheimTokyoJapan
  5. 5.Nippon Boehringer IngelheimKobeJapan
  6. 6.Boehringer IngelheimBracknellUK