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Original Investigation
June 13, 2019

Afatinib vs Placebo as Adjuvant Therapy After Chemoradiotherapy in Squamous Cell Carcinoma of the Head and Neck: A Randomized Clinical Trial

Author Affiliations
  • 1Department of Medicine and Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut
  • 2Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
  • 3Instituto Português de Oncologia, Porto, Portugal
  • 4Department of Medical Oncology, Hospital Virgen de la Victoria, IBIMA, Malaga, Spain
  • 5Division of Gastrointestinal Oncology, Shizuoka Cancer Centre, Shizuoka, Japan
  • 6Department of Medical Oncology, Hospital Marcio Cunha, Ipatinga, Brazil
  • 7Russian Oncological Research Centre, Moscow, Russia
  • 8Department of Medical Oncology, Antwerp University Hospital, Edegem, Belgium
  • 9Department of Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
  • 10Department of Head and Neck Medical Oncology, National Cancer Centre Hospital East, Kashiwa, Japan
  • 11Department of Clinical Oncology, Hospital Amaral Carvalho, Jau, Brazil
  • 12Department of Internal Medicine, National Kapodistrian University of Athens, Attikon University Hospital, Athens, Greece
  • 13Oncology Centre of Moskovskiy, St Petersburg, Russia
  • 14Comprehensive Cancer Centre, University of California at Irvine, Orange
  • 15Department of Oncology, Hospital Virgen del Rocio, Sevilla, Spain
  • 16Department of Medical Oncology and Hematology, Kobe University Hospital Cancer Center, Kobe, Japan
  • 17Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
  • 18Department of Oncology and Radiotherapy, Hospital Na Bulovce and 1st Medical Faculty of Charles University, Prague, Czech Republic
  • 19Department of Oncology, Vall d’Hebron University Hospital, Barcelona, Spain
  • 20Shree Krishna Hospital and Medical Research Centre, Gujarat, India
  • 21Department of Clinical Oncology, AC Camargo Cancer Center, São Paulo, Brazil
  • 22Inselspital, University Hospital Bern, Bern, Switzerland
  • 23Department of Head and Neck Cancer, Gustave Roussy, Villejuif, France
  • 24Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, Connecticut
  • 25Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany
  • 26Boehringer Ingelheim, Danmark A/S, Denmark
  • 27Division of Radiotherapy and Imaging, The Royal Marsden Hospital/The Institute of Cancer Research, National Institute for Health Research Biomedical Research Centre, London, United Kingdom
  • 28Department of Translational Science, Moores Cancer Centre, University of California at San Diego, La Jolla
JAMA Oncol. 2019;5(8):1170-1180. doi:10.1001/jamaoncol.2019.1146
Key Points

Question  Does afatinib as adjuvant therapy after definitive chemoradiotherapy improve disease-free survival in head and neck cancer?

Findings  This randomized clinical trial of 617 patients found that afatinib therapy after definitive chemoradiotherapy in patients with intermediate- to high-risk unresected head and neck cancer did not improve disease-free survival vs placebo. In addition, afatinib therapy did not confer any health-related quality-of-life benefit, and changes over time in global health status and pain scores favored placebo.

Meaning  These study findings indicate that use of adjuvant afatinib therapy after concurrent chemoradiotherapy is not recommended in head and neck cancer.


Importance  Locoregionally advanced head and neck squamous cell cancer (HNSCC) is treated curatively; however, risk of recurrence remains high among some patients. The ERBB family blocker afatinib has shown efficacy in recurrent or metastatic HNSCC.

Objective  To assess whether afatinib therapy after definitive chemoradiotherapy (CRT) improves disease-free survival (DFS) in patients with HNSCC.

Design, Setting, and Participants  This multicenter, phase 3, double-blind randomized clinical trial (LUX-Head & Neck 2) studied 617 patients from November 2, 2011, to July 4, 2016. Patients who had complete response after CRT, comprising radiotherapy with cisplatin or carboplatin, with or without resection of residual disease, for locoregionally advanced high- or intermediate-risk HNSCC of the oral cavity, hypopharynx, larynx, or oropharynx were included in the study. Data analysis was of the intention-to-treat population.

Interventions  Patients were randomized (2:1) to treatment with afatinib (40 mg/d) or placebo, stratified by nodal status (N0-2a or N2b-3) and Eastern Cooperative Oncology Group performance status (0 or 1). Treatment continued for 18 months or until disease recurrence, unacceptable adverse events, or patient withdrawal.

Main Outcomes and Measures  The primary end point was DFS, defined as time from the date of randomization to the date of tumor recurrence or secondary primary tumor or death from any cause. Secondary end points were DFS at 2 years, overall survival (defined as time from the date of randomization to death), and health-related quality of life.

Results  A total of 617 patients were studied (mean [SD] age, 58 [8.4] years; 528 male [85.6%]). Recruitment was stopped after a preplanned interim futility analysis on July 4, 2016, on recommendation from an independent data monitoring committee. Treatment was discontinued. Median DFS was 43.4 months (95% CI, 37.4 months to not estimable) in the afatinib group and not estimable (95% CI, 40.1 months to not estimable) in the placebo group (hazard ratio, 1.13; 95% CI, 0.81-1.57; stratified log-rank test P = .48). The most common grade 3 and 4 drug-related adverse effects were acneiform rash (61 [14.8%] of 411 patients in the afatinib group vs 1 [0.5%] of 206 patients in the placebo group), stomatitis (55 [13.4%] in the afatinib group vs 1 [0.5%] in the placebo group), and diarrhea (32 [7.8%] in the afatinib group vs 1 [0.5%] in the placebo group).

Conclusions and Relevance  This study’s findings indicate that treatment with afatinib after CRT did not improve DFS and was associated with more adverse events than placebo in patients with primary, unresected, clinically high- to intermediate-risk HNSCC. The use of adjuvant afatinib after CRT is not recommended.

Trial Registration  ClinicalTrials.gov identifier: NCT01345669