314O_PR - Second-line afatinib vs methotrexate (MTX) in patients (pts) with recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC): su...

Date 18 December 2015
Event ESMO Asia 2015 Congress
Session Head and neck cancer
Topics Anticancer Agents
Head and Neck Cancers
Biological Therapy
Presenter Makoto Tahara
Citation Annals of Oncology (2015) 26 (suppl_9): 93-102. 10.1093/annonc/mdv527
Authors M. Tahara1, E.E.W. Cohen2, R. Haddad3, J. Fayette4, L. Licitra5, P. Clement6, J.B. Vermorken7, T.C. Gauler8, D. Cupissol9, J.J. Grau10, J. Guigay11, J.M. del Campo12, K. Okami13, S. Takahashi14, B. Burtness15, X.J. Cong16, N. Gibson17, F. Solca18, E. Ehrnrooth19, J. Machiels20
  • 1Department Of Head And Neck Medical Oncology, National Cancer Center Hospital East, Chiba 277-8577 - Kashiwa/JP
  • 2Department Of Medicine, University of California San Diego Moores Cancer Center, La Jolla/US
  • 3Department Of Medical Oncology, Dana-farber Cancer Institute, Harvard Medical School And, Department of Medicine, Brigham and Women’s Hospital, Boston/US
  • 4Léon Bérard Center And Hospices Civils De Lyon, University of Lyon, Lyon/FR
  • 5Department Of Medical Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milano/IT
  • 6Department Of Oncology, KU Leuven, Leuven/BE
  • 7Department Of Medical Oncology, Antwerp University Hospital, Edegem/BE
  • 8West German Cancer Center, University Hospital Essen, Essen/DE
  • 9Medical Oncology, Institut du Cancer de Montpellier Val d’Aurelle, Montpellier/FR
  • 10Hospital Clínic De Barcelona, University of Barcelona, Barcelona/ES
  • 11Gustave Roussy, Villejuif and Centre Antoine Lacassagne, Nice/FR
  • 12Medical Oncology Department, Hospital Universitario Vall D’Hebron, Barcelona/ES
  • 13Department Of Otolaryngology, Tokai University Hospital, Kanagawa/JP
  • 14Department Of Medical Oncology, Japanese Foundation for Cancer Research, Tokyo/JP
  • 15Department Of Medical Oncology, Fox Chase Cancer Center, Philadelphia/US
  • 16Statistics, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield/US
  • 17Drug Metabolism & Pharmacokinetics, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach/DE
  • 18Pharmacology And Translational Research, Boehringer Ingelheim RCV GmbH & Co. KG, Vienna/AT
  • 19Ta Oncology, Boehringer Ingelheim, Danmark A/S/DK
  • 20Institut Roi Albert Ii, Service D’oncologie Médicale, Cliniques Universitaires Saint-luc And Institut De Recherche Clinique Et Expérimentale (pole Miro), Université Catholique de Louvain, Brussels/BE



In the Phase III LUX-H&N1 trial, afatinib, an irreversible ErbB family blocker, significantly improved progression-free survival (PFS) vs MTX (median 2.6 vs 1.7 mos; HR 0.80; p = 0.03) in pts with second-line R/M HNSCC (Machiels, Lancet Oncol 2015). Here we report PFS and response rates (RR) in the pre-defined subgroups and biomarker-defined populations.


R/M HNSCC pts progressing on/after platinum therapy were randomized 2:1 to 40 mg/d oral afatinib (n = 322) or 40 mg/m2/wk IV MTX (n = 161), stratified by ECOG PS (0/1) and prior use of anti-EGFR monoclonal antibody (mAb) therapy (Yes/No) in the R/M setting. The primary endpoint was PFS by independent review. Optional tumor biomarker assessments, including human papillomavirus status assessed by p16, EGFR amplification, HER3 and PTEN, were conducted in a central laboratory.


Improvements in PFS and RR with afatinib vs MTX in subgroups based on geographical region (Asia, Europe, or North/Latin America) and age (<65 or ≥65 yrs) were consistent with the overall study population (Table). Afatinib demonstrated a more pronounced effect in pts not previously treated with anti-EGFR mAb therapy. In the biomarker subgroups, improvements in PFS were observed with afatinib vs MTX in pts with p16-negative, HER3-low, and PTEN-high disease; a trend towards prolonged PFS was observed in pts with EGFR-amplified tumors (Table). Higher RRs with afatinib vs MTX were observed in all biomarker subgroups, with the exception of p16-positive disease.

Efficacy outcomes according to subgroups/biomarkers (all comparisons are afatinib vs MTX)

Subgroup/biomarker Median PFS, mos PFS HR (95% CI) RR, % RR odds ratio (95% CI)*
Prior anti-EGFR mAb
Yes (n = 287) 1.6 vs 1.6 0.91 (0.70–1.19) 3.7 vs 4.1 0.90 (0.26–3.17)
No (n = 196) 2.8 vs 2.0 0.63 (0.45–0.88) 19.6 vs 7.9 2.82 (1.03–7.73)
Asia (n = 43) 2.7 vs 1.5 0.62 (0.32–1.20) 23.1 vs 11.8 2.25 (0.40–12.75)
Europe (n = 369) 2.6 vs 1.9 0.82 (0.64–1.04) 8.4 vs 5.8 1.49 (0.61–3.60)
North/Latin America (n = 60) 2.9 vs 1.6 0.41 (0.21–0.79) 12.8 vs 0 NE
Age, yrs
<65 (n = 355) 2.6 vs 1.6 0.79 (0.62–1.01) 10.0 vs 5.2 2.05 (0.81–5.15)
≥65 (n = 128) 2.8 vs 2.3 0.68 (0.45–1.03) 10.8 vs 6.7 1.70 (0.44–6.64)
p16-neg† (H-score <210; n = 199) 2.7 vs 1.6 0.70 (0.50–0.97) 14.1 vs 1.6 10.32 (1.35–78.90)
p16-pos (H-score ≥210; n = 35) 2.0 vs 2.3 0.81 (0.39–1.69) 0 vs 8.3 NE
EGFR-amplified‡ (n = 66) 2.8 vs 1.6 0.66 (0.35–1.24) 14.0 vs 0 NE
EGFR not amplified (n = 80) 1.7 vs 2.4 1.13 (0.68–1.86) 3.8 vs 0 NE
HER3-low (H-score ≤50; n = 66) 2.9 vs 2.0 0.47 (0.25–0.86) 12.2 vs 0 NE
HER3-high (H-score >50; n = 90) 1.7 vs 2.4 1.33 (0.79–2.24) 9.4 vs 0 NE
PTEN-high (H-score >150; n = 42) 2.9 vs 1.4 0.36 (0.16–0.81) 6.7 vs 0 NE
PTEN-low (H-score ≤150; n = 115) 2.6 vs 2.7 1.01 (0.65–1.58) 12.2 vs 0 NE

*Odds ratios are not available for comparisons of subgroups with no responders;

†p16 staining was analyzed in tumors from all subsites;

‡ ≥50% of cells with ≥4 copies, or ≥1 cell with ≥8 copies.

CI, confidence interval; HR, hazard ratio; H-score, histology score; NE, not estimable


More pronounced anti-tumor effects were observed with afatinib vs MTX in subgroups of R/M HNSCC pts with p16-negative, EGFR-amplified, HER3-low, and PTEN-high disease. Future prospective studies based on these subgroups and biomarkers are needed to provide a more robust readout of clinical outcomes.

Clinical trial identification



M. Tahara: advisory board participation for Merck Sharp & Dohme; honoraria from Merck Serono, Bristol-Myers Squibb, Eisai, Otsuka and Bayer; and research funding from Eisai, Merck Sharp & Dohme, Boehringer Ingelheim and AstraZeneca. E.E.W. Cohen: advisory board participation for Merck and Pfizer; and honoraria from Eisai and Bayer. R.I. Haddad: advisory board participation for BMS, Merck and Bayer; and corporate-sponsored research from Merck, BMS, Celgene and Boehringer Ingelheim. L.F. Licitra: advisory board participation for EISAI, BMS, GlaxoSmithKline, Lilly, Merk – Serono, Amgen, Boehringer Ingelheim, DEBIOPHARM, VentiRX, SOBI, Novartis, AstraZeneca, Bayer, MSD, Celgene, and Roche; corporate-sponsored research for EISAI, Exelixis, Lilly, Merk – Serono, Amgen, Boehringer Ingelheim, Pfizer, Novartis, AstraZeneca, Roche, and MSD; and travel coverage for medical meetings from Merk – Serono. J.B. Vermorken: advisory board participation for Boehringer Ingelheim and being on the steering committee of the LUX H&N trials. T. Gauler: stock ownership or options from Bayer AG since 1984; advisory board participation for Boehringer Ingelheim, Merck Serono, Novartis and MSD; honoraria from Novartis, Merck Serono, Boehringer Ingelheim and Roche. J. Guigay: advisory board participation from BMS and Merck Serono; and research grants from BMS, Boehringer Ingelheim, Chugai, GSK, MSD, Merck Serono and Sanofi. K. Okami: honoraria from Merck Serono and Bristol-Myers Squibb. S. Takahashi: corporate-sponsored research from Boehringer Ingelheim. B. Burtness: advisory board participation for VentiRX, Medimmune, Amgen, Bayer and Boehringer Ingelheim; corporate-sponsored research for Merck; and expert testimony for Johnson & Johnson. X.J. Cong, N. Gibson, F. Solca, E. Ehrnrooth: employment by Boehringer Ingelheim. J.-P.H. Machiels: advisory board participation for Boehringer Ingelheim (without compensation). All other authors have declared no conflicts of interest.