Second-line afatinib vs methotrexate (MTX) in patients (pts) with recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC): subgroup/biomarker analysis of LUX-head and neck 1 (LUX-H&N1)

Date

18 Dec 2015

Session

Head and neck cancer

Presenters

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

Author affiliations

¹ Department Of Head And Neck Medical Oncology, National Cancer Center Hospital East, Chiba 277-8577 - Kashiwa/JP
² Department Of Medicine, University of California San Diego Moores Cancer Center, La Jolla/US
³ Department Of Medical Oncology, Dana-farber Cancer Institute, Harvard Medical School And, Department of Medicine, Brigham and WomenÃ¢â‚¬â„¢s Hospital, Boston/US
⁴ LÃƒÂ©on BÃƒÂ©rard Center And Hospices Civils De Lyon, University of Lyon, Lyon/FR
⁵ Department Of Medical Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milano/IT
⁶ Department Of Oncology, KU Leuven, Leuven/BE
⁷ Department Of Medical Oncology, Antwerp University Hospital, Edegem/BE
⁸ West German Cancer Center, University Hospital Essen, Essen/DE
⁹ Medical Oncology, Institut du Cancer de Montpellier Val dÃ¢â‚¬â„¢Aurelle, Montpellier/FR
¹⁰ Hospital ClÃƒÂnic De Barcelona, University of Barcelona, Barcelona/ES
¹¹ Gustave Roussy, Villejuif and Centre Antoine Lacassagne, Nice/FR
¹² Medical Oncology Department, Hospital Universitario Vall DÃ¢â‚¬â„¢Hebron, Barcelona/ES
¹³ Department Of Otolaryngology, Tokai University Hospital, Kanagawa/JP
¹⁴ Department Of Medical Oncology, Japanese Foundation for Cancer Research, Tokyo/JP
¹⁵ Department Of Medical Oncology, Fox Chase Cancer Center, Philadelphia/US
¹⁶ Statistics, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield/US
¹⁷ Drug Metabolism & Pharmacokinetics, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach/DE
¹⁸ Pharmacology And Translational Research, Boehringer Ingelheim RCV GmbH & Co. KG, Vienna/AT
¹⁹ Ta Oncology, Boehringer Ingelheim, Danmark A/S/DK
²⁰ Institut Roi Albert Ii, Service DÃ¢â‚¬â„¢oncologie MÃƒÂ©dicale, Cliniques Universitaires Saint-luc And Institut De Recherche Clinique Et ExpÃƒÂ©rimentale (pole Miro), UniversitÃƒÂ© Catholique de Louvain, Brussels/BE

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Abstract 693

Aim/Background

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.

Methods

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.

Results

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)
Region
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^â (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^â¡ (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;

^âp16 staining was analyzed in tumors from all subsites;

^â¡ ≥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

Conclusions

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

NCT01345682

Disclosure

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.