, 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)

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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.


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.


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.


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

All authors have contributed equally to the development of the manuscript, and all authors are in agreement with the content of the manuscript.
Clinical trial registration: NCT00711594 (http://clinicaltrials.gov).