138PD - Impact of dose adjustment on the safety and efficacy of afatinib in patients (pts) with advanced EGFR mutation-positive non-small cell lung cancer...

Date 14 April 2016
Event European Lung Cancer Conference 2016 (ELCC) 2016
Session Targeting EGFR and ALK driven tumours
Topics Cytotoxic agents
Non-small-cell lung cancer
Biological therapy
Presenter Martin Schuler
Citation Journal of Thoracic Oncology (2016) 11 (supplement 4): S57-S166. S1556-0864(16)X0004-4
Authors M. Schuler1, J.C. Yang2, L.V. Sequist3, N. Yamamoto4, C. Zhou5, K. O'Byrne6, V. Hirsh7, T.S.K. Mok8, R. Shah9, Y. Wu10
  • 1West German Cancer Center, University Hospital Essen, University Duisburg-Essen, 45147 - Essen/DE
  • 2Department Of Oncology, National Taiwan University Hospital and National Taiwan University, Taipei/TW
  • 3Department Of Thoracic Oncology, Massachusetts General Hospital and Harvard Medical School, Boston/US
  • 4Third Department Of Internal Medicine, Wakayama Medical University, Wakayama/JP
  • 5Shanghai Pulmonary Hospital, Tongji University, Shanghai/CN
  • 6Translational Research Institute, Princess Alexandra Hospital and Queensland University of Technology, Brisbane/AU
  • 7Department Of Oncology, McGill University, Montreal/CA
  • 8State Key Laboratory Of South China, Hong Kong Cancer Institute, The Chinese University of Hong Kong, Hong Kong/CN
  • 9Kent Oncology Centre, Maidstone Hospital, Kent/GB
  • 10Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou/CN



Afatinib 40 mg/day is approved for the first-line treatment of pts with EGFR mutation-positive NSCLC. The dose can be adjusted based on individual tolerability. Post-hoc analyses assessed the impact of afatinib dose adjustment on adverse events (AEs), pharmacokinetics (PK) and progression-free survival (PFS) in LL3 and LL6.


All afatinib-treated pts in LL3 (n = 229) and LL6 (n = 239) were included. In case of drug-related grade 3 or selected prolonged grade 2 AEs with afatinib 40 mg, the dose could be reduced by 10 mg decrements to a minimum of 20 mg. We analysed the incidence and severity of common AEs before and after dose reduction and compared PK data collected as part of the standard visit schedule on Day 43 in pts who reduced to 30 mg vs those remaining at 40 mg. PFS in pts who dose reduced within the first 6 months of treatment was compared with those who remained on afatinib 40 mg/day.


Dose reductions occurred in 53% (122/229) and 28% (67/239) of pts in LL3 and LL6, respectively; the majority (86% and 82%, respectively) within the first 6 months of treatment. Dose reduction led to decreases in the incidence and severity of EGFR-mediated drug-related AEs (table). Combined PK analysis of LL3 and LL6 suggested that dose reduction was more likely in pts with higher plasma concentrations of afatinib. On Day 43, pts who had dose reduced to 30 mg (n = 59) had geometric mean plasma afatinib concentrations of 23.3 ng/mL, vs 22.8 ng/mL in pts who remained on the 40 mg dose (n = 284). Median PFS was similar in pts who dose reduced during the first 6 months of treatment vs those who did not in LL3 (11.3 vs 11.0 months [HR = 1.25; 95% CI, 0.91–1.72]) and LL6 (12.3 vs 11.0 months [HR = 1.00; 95% CI, 0.69–1.46]). 138PDT1

Adverse eventPercentage of patients
 Pre-dose reduction (n = 122)Post-dose reduction (n = 122)Pre-dose reduction (n = 67)Post-dose reduction (n = 67)
 AllG ≥3AllG ≥3AllG ≥3AllG ≥3
Nail effect44.316.436.94.919.4013.40


Tolerability-guided dose adjustment of afatinib reduced treatment-related AEs without adversely affecting efficacy.

Clinical trial identification

NCT00949650 and NCT01121393

Legal entity responsible for the study

Boehringer Ingelheim


Boehringer Ingelheim


M. Schuler: Employment/leadership at Universität Duisburg-Essen, Universitätsklinikum Essen and Ruhrlandklinik; consultant for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG), Lilly and Novartis; honoraries for CME presentations from Alexion, Boehringer Ingelheim, Celgene, GlaxoSmithKline, Lilly and Novartis; research funding to his institution from Boehringer Ingelheim, Bristol Myers-Squibb and Novartis; and patents for Universität Duisburg-Essen. J. Yang: Advisory board participation for and honoraria from Boehringer Ingelheim, Eli Lilly, Bayer, Roche/Genentech, AstraZeneca, Astellas, Bayer, MSD, Merck Serono, Pfizer, Novartis, Clovis Oncology and Celgene. L.V. Sequist: Advisory board participation for Boehringer Ingelheim, Clovis, AstraZeneca, Novartis, Merrimack, Genentech, Ariad and Taiho. N. Yamamoto: Honoraria from Boehringer Ingelheim. C. Zhou: Advisory board participation for Boehringer Ingelheim and AstraZeneca, and corporate-sponsored research for Boehringer Ingelheim. K. O'Byrne: Consultation fees from Pfizer, Roche, AZD, Boehringer Ingelheim, BMS, MSD, Lilly Oncology and Novartis; honoraria for speaker's bureaus from Pfizer, Roche, AZD, Lilly Oncology, Boehringer Ingelheim; owner of stock in CARP Pharmaceuticals and Bluesky Biosciences; organiser of the annual Brisbane Cancer Conference hosted by the Princess Alexandra Hospital Research Foundation which raises money from sponsors including AZD, Roche, MSD, BMS, Astellas, Boehringer Ingelheim, Celgene, Ipsen, Janssen, Lilly Oncology, Merck, Novartis, Pfizer, Takeda, Illumina and Thermofisher. V. Hirsh: Honoraria from Boehringer Ingelheim. T. Mok: Stock or other ownership from Sanomics LTD.; honoraria from AstraZeneca, Roche/Genentech, Pfizer, Eli Lilly, BI, Merck Serono, MSD, Janssen, Clovis Oncology, BioMarin, GSK, Amgen, Novartis, SFJ Pharmaceutical, ACEA Biosciences, Vertex Pharmaceuticals, BMS, AVEO & Biodesix, Prime Oncology; advisory board participation for AstraZeneca, Roche/Genentech, Pfizer, Eli Lilly, BI, Merck Serono, MSD, Janssen, Clovis Oncology, BioMarin, GSK, Novartis, SFJ Pharmaceutical, ACEA Biosciences, Vertex Pharmaceuticals, AVEO & Biodesix, BMS, geneDecode Co., Ltd.; speakers bureau for AstraZeneca, Roche/Genentech, Pfizer, Eli Lilly, BI, MSD, Amgen, Janssen, Clovis Oncology, GSK, Novartis, BMS, Prime Oncology. R. Shah: Advisory board participation and honoraria for Boehringer Ingelheim. Y.-L. Wu: Speaker fees from Roche, AstraZeneca, Eli Lilly, Sanofi and Pfizer.