Afatinib maintenance therapy following post-operative radiochemotherapy in head and neck squamous cell carcinoma: Results from the phase III randomised double-blind placebo-controlled study BIB2992ORL (GORTEC 2010–02)

Published:November 23, 2022DOI:


      • The study planned one-year afatinib maintenance therapy (N = 67) or placebo (N = 67).
      • Afatinib after post-operative RCT showed no improved 2y-DFS in patients with HNSCC.
      • Afatinib should not be recommended in this setting outside clinical trials.



      We investigated the efficacy and safety of afatinib maintenance therapy in patients with head and neck squamous cell carcinoma (HNSCC) with macroscopically complete resection and adjuvant radiochemotherapy (RCT).


      This French multicentric randomised phase III double-blind placebo-controlled study included adult patients with ECOG-PS≤2, normal haematological, hepatic and renal functions, and non-metastatic, histologically confirmed HNSCC of the oral cavity, oropharynx, larynx or hypopharynx, with macroscopically complete resection and adjuvant RCT (≥2 cycles of cisplatin 100 mg/m2 J1, J22, J43 and 66Gy (2Gy/fraction, 5 fractions/week, conventional or intensity modulated radiotherapy ≥60Gy). Randomised patients were planned to receive either afatinib (afa arm) or placebo (control arm (C)) as maintenance therapy for one year. Primary endpoint was disease free survival (DFS). A 15% improvement in DFS was expected at 2 years with afatinib (from 55 to 70%).


      Among the 167 patients with resected HNSCC included in 19 cancer centres and hospitals from Dec 2011, 134 patients were randomised to receive one-year maintenance afatinib or placebo (afa:67; C:67). Benefit/risk ratio was below assumptions and independent advisory committee recommended to stop the study in Feb 2017, the sponsor decided premature study discontinuation, with a 2-year follow-up for the last randomised patient. 2y-DFS was 61% (95% CI 0.48–0.72) in the afatinib group and 64% (95% CI 0.51–0.74) in the placebo group (HR 1.12, 95% CI 0.70–1.80).


      Maintenance therapy with afatinib compared with placebo following post-operative RCT in patients with HNSCC did not significantly improve 2y-DFS and should not be recommended in this setting outside clinical trials. identifier NCT01427478.


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        • Sung H.
        • Ferlay J.
        • Siegel R.L.
        • Laversanne M.
        • Soerjomataram I.
        • Jemal A.
        • et al.
        Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
        CA A Cancer J Clin. 2021; 71: 209-249
        • Ang K.K.
        • Harris J.
        • Wheeler R.
        • Weber R.
        • Rosenthal D.I.
        • Nguyen-Tân P.F.
        • et al.
        Human papillomavirus and survival of patients with oropharyngeal cancer.
        N Engl J Med. 2010; 363: 24-35
        • Taberna M.
        • Mena M.
        • Pavón M.A.
        • Alemany L.
        • Gillison M.L.
        • Mesía R.
        Human papillomavirus-related oropharyngeal cancer.
        Ann Oncol. 2017; 28: 2386-2398
        • Brierley J.D.
        • Gospodarowicz M.K.
        • Wittekind C.
        TNM classification of malignant tumours.
        8th ed. Wiley & Sons, 2017: 20171-20272
        • Leeman J.E.
        • Lee N.
        • Riaz N.
        Patterns of failure in head and neck cancer patients treated with intensity modulated radiation therapy: editorial response.
        Transl Cancer Res. 2017; 6: S1299-S1300
        • Bernier J.
        • Cooper J.S.
        • Pajak T.F.
        • van Glabbeke M.
        • Bourhis J.
        • Forastiere A.
        • et al.
        Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (#9501).
        Head Neck. 2005; 27: 843-850
        • Cooper J.S.
        • Pajak T.F.
        • Forastiere A.A.
        • Jacobs J.
        • Campbell B.H.
        • Saxman S.B.
        • et al.
        Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck.
        N Engl J Med. 2004; 350: 1937-1944
        • Bernier J.
        • Domenge C.
        • Ozsahin M.
        • Matuszewska K.
        • Lefebvre J.L.
        • Greiner R.H.
        • et al.
        Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer.
        Cancer Radiother. 2005; 9: 203-204
        • Borel C.
        • Sun X.
        • Coutte A.
        • Bera G.
        • Zanetta S.
        • Alfonsi M.
        • et al.
        Standard versus fractionated high dose cisplatin concomitant with radiotherapy in locally advanced head & neck squamous cell cancer (LA-HNSCC): results of the GORTEC 2015-02 CisFRad randomized trial.
        Ann Oncol. 2020; 31: S660
        • Strojan P.
        • Vermorken J.B.
        • Beitler J.J.
        • Saba N.F.
        • Haigentz M.
        • Bossi P.
        • et al.
        Cumulative cisplatin dose in concurrent chemoradiotherapy for head and neck cancer: a systematic review.
        Head Neck. 2016; 38 (John Wiley & Sons): E2151-E2158
        • Bonner J.A.
        • Harari P.M.
        • Giralt J.
        • Azarnia N.
        • Shin D.M.
        • Cohen R.B.
        • et al.
        Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck.
        N Engl J Med. 2006 9; 354: 567-578
        • Bonner J.A.
        • Harari P.M.
        • Giralt J.
        • Cohen R.B.
        • Jones C.U.
        • Sur R.K.
        • et al.
        Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival.
        Lancet Oncol. 2010; 11: 21-28
        • Seiwert T.Y.
        • Jagadeeswaran R.
        • Faoro L.
        • Janamanchi V.
        • Nallasura V.
        • Dinali M.
        • et al.
        The MET receptor tyrosine kinase is a potential novel therapeutic target for head and neck squamous cell carcinoma.
        Cancer Res. 2009; 69: 3021-3031
        • Seiwert T.Y.
        • Fayette J.
        • Cupissol D.
        • del Campo J.M.
        • Clement P.M.
        • Hitt R.
        • et al.
        A randomized, phase II study of afatinib versus cetuximab in metastatic or recurrent squamous cell carcinoma of the head and neck.
        Ann Oncol. 2014; 25: 1813-1820
        • Thariat J.
        • Bensadoun R.J.
        • Etienne-Grimaldi M.C.
        • Grall D.
        • Penault-Llorca F.
        • Dassonville O.
        • et al.
        Contrasted outcomes to gefitinib on tumoral IGF1R expression in head and neck cancer patients receiving postoperative chemoradiation (GORTEC trial 2004-02).
        Clin Cancer Res. 2012; 18: 5123-5133
        • Harrington K.
        • Temam S.
        • Mehanna H.
        • D'Cruz A.
        • Jain M.
        • D'Onofrio I.
        • et al.
        Postoperative adjuvant lapatinib and concurrent chemoradiotherapy followed by maintenance lapatinib monotherapy in high-risk patients with resected squamous cell carcinoma of the head and neck: a phase III, randomized, double-blind, placebo-controlled study.
        J Clin Oncol. 2015; 33: 4202-4209
        • Colevas A.D.
        • Yom S.S.
        • Pfister D.G.
        • Spencer S.
        • Adelstein D.
        • Adkins D.
        • et al.
        NCCN guidelines ® insights: head and neck cancers, version 1.2018 featured updates to the NCCN guidelines.
        JNCCN Journal of the National Comprehensive Cancer Network. 2018; 16: 479-490
        • Novello S.
        • Barlesi F.
        • Califano R.
        • Cufer T.
        • Ekman S.
        • Levra M.G.
        • et al.
        Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
        Ann Oncol. 2016; 27 (V1–27)
        • Liberatoscioli C.
        • Langendijk J.A.
        • van Herpen C.
        • Collette L.
        • Ozsahin E.M.
        • Karra Gurunath R.
        • et al.
        EORTC 22071-24071: randomized, phase III trial of EGFR-antibody combined with adjuvant chemoradiation for patients with head and neck squamous cell carcinoma (HNSCC) at high risk of recurrence.
        J Clin Oncol. 2011; 29 (TPS197–TPS197. /doi/10.1200/jco.2011.29.15_suppl.tps197)
        • Zhang L.
        Efficacy and safety of afatinib in advanced non-small cell lung cancer with EGFR mutations: a real-world study based meta-analysis.
        J Clin Oncol. 2021; 39 (e21134–e21134)
        • Deeks E.D.
        • Keating G.M.
        Afatinib in advanced NSCLC: a profile of its use.
        Drugs Ther Perspect. 2018; 34: 89-98
      1. ICRU Report 62.

        • Aaronson N.K.
        • Ahmedzai S.
        • Bergman B.
        • Bullinger M.
        • Cull A.
        • Duez N.J.
        • et al.
        The European organization for research and treatment of cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology.
        J Natl Cancer Inst. 1993; 85: 365-376
        • Bjordal K.
        • Hammerlid E.
        • Ahlner-Elmqvist M.
        • de Graeff A.
        • Boysen M.
        • Evensen J.F.
        • et al.
        Quality of life in head and neck cancer patients: validation of the European organization for research and treatment of cancer quality of life questionnaire-H&N35.
        J Clin Oncol. 1999; 17 (1999(3):1008-1008
        • Fayers P.
        • Aaronson N.K.
        • Bjordal K.
        • Groenvold M.
        • Curran A.B.
        The EORTC QLQ-C30 scoring manual.
        3rd ed. EORTC Quality of Life Group, 2001
        • Burtness B.
        • Haddad R.
        • Dinis J.
        • Trigo J.
        • Yokota T.
        • de Souza Viana L.
        • et al.
        Afatinib vs placebo as adjuvant therapy after chemoradiotherapy in squamous cell carcinoma of the head and neck: a randomized clinical trial.
        JAMA Oncol. 2019; 5: 1170-1180
        • Clement P.M.
        • Gauler T.
        • Machiels J.P.
        • Haddad R.I.
        • Fayette J.
        • Licitra L.F.
        • et al.
        Afatinib versus methotrexate in older patients with second-line recurrent and/or metastatic head and neck squamous cell carcinoma: subgroup analysis of the LUX-Head & Neck 1 trial.
        Ann Oncol. 2016; 27: 1585-1593
        • Machiels J.P.H.
        • Haddad R.I.
        • Fayette J.
        • Licitra L.F.
        • Tahara M.
        • Vermorken J.B.
        • et al.
        Afatinib versus methotrexate as second-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 1): an open-label, randomised phase 3 trial.
        Lancet Oncol. 2015; 16: 583-594
        • Margalit D.N.
        • Haddad R.I.
        • Tishler R.B.
        • Chau N.G.
        • Schoenfeld J.D.
        • Bakst R.L.
        • et al.
        A phase 1 study of afatinib in combination with postoperative radiation therapy with and without weekly docetaxel in intermediate- and high-risk patients with resected squamous cell carcinoma of the head and neck.
        Int J Radiat Oncol Biol Phys. 2019; 105: 132-139
        • Ferris R.L.
        • Blumenschein G.
        • Fayette J.
        • Guigay J.
        • Colevas A.D.
        • Licitra L.
        • et al.
        Nivolumab vs investigator's choice in recurrent or metastatic squamous cell carcinoma of the head and neck: 2-year long-term survival update of CheckMate 141 with analyses by tumor PD-L1 expression.
        Oral Oncol. 2018; 81: 45-51
        • Shaverdian N.
        • Lisberg A.E.
        • Bornazyan K.
        • Veruttipong D.
        • Goldman J.W.
        • Formenti S.C.
        • Garon E.B.
        • Lee P.
        Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial.
        Lancet Oncol. 2017; 18: 895-903