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.
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)/humanepidermal 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.
Authors: Martin Schuler; Jürgen R Fischer; Christian Grohé; Sylvia Gütz; Michael Thomas; Martin Kimmich; Claus-Peter Schneider; Eckart Laack; Angela Märten Journal: Oncologist Date: 2014-09-17
Authors: Natalie R Young; Christian Soneru; Jing Liu; Tatyana A Grushko; Ashley Hardeman; Olufunmilayo I Olopade; Anke Baum; Flavio Solca; Ezra E W Cohen Journal: Target Oncol Date: 2015-01-06 Impact factor: 4.493