Original Research| Volume 109, P28-35, March 2019

Download started.


Afatinib in patients with metastatic or recurrent HER2-mutant lung cancers: a retrospective international multicentre study

Published:January 24, 2019DOI:


      • The response rate of advanced HER2-mutant lung cancers treated with afatinib was 13%.
      • All responses were seen in patients with HER2 exon 20 insertion mutations.
      • Responses were observed even in patients treated with prior HER2-targeted therapies.
      • Afatinib led to durable disease control in a subset of patients (up to 30 months).
      • Afatinib was well tolerated in most patients.



      HER2 mutations occur in 1–3% of lung adenocarcinomas. With increasing use of next-generation sequencing at diagnosis, more patients with HER2-mutant tumours present for treatment. Few data are available to describe the clinical course and outcomes of these patients when treated with afatinib, a pan-HER inhibitor.


      We identified patients with metastatic or recurrent HER2-mutant lung adenocarcinomas treated with afatinib among seven institutions across Europe, Australia, and North America between 2009 and 2017. We determined the partial response rate to afatinib, types of HER2 mutations, duration of response, time on treatment, and survival.


      We collected information on 27 patients with stage IV or recurrent HER2-mutant lung adenocarcinomas treated with afatinib. Of 23 patients evaluable for response, three partial responses were noted (13%, 95% confidence interval [CI] 4–33%). In addition, 57% of patients (13/23) had stable disease, and 30% (7/23) had progressive disease. We documented partial responses in patients with HER2 exon 20 insertions, including two with YVMA insertion and one with VAG insertion. Two patients with partial responses were previously treated with trastuzumab and pertuzumab. Median duration of response to afatinib was 6 months (range 5–10); median time on treatment was 3 months (range 1–30) and median overall survival from the date of diagnosis of metastatic or recurrent disease was 23 months (95% CI 18–53 months).


      Afatinib is modestly active in patients with HER2-mutant lung adenocarcinomas, including responses after progression on prior HER2-targeted therapies. However, investigations into the biology of HER2-mutant lung adenocarcinomas and development of better HER2-directed therapies are warranted.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to European Journal of Cancer
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Pao W.
        • Hutchinson K.E.
        Chipping away at the lung cancer genome.
        Nat Med. 2012; 18: 349-351
        • Kris M.G.
        • Johnson B.E.
        • Berry L.D.
        • Kwiatkowski D.J.
        • Iafrate A.J.
        • Wistuba I.I.
        • et al.
        Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs.
        J Am Med Assoc. 2014; 311: 1998-2006
        • Pillai R.N.
        • Behera M.
        • Berry L.D.
        • Rissi M.R.
        • Kris M.G.
        • Johnson B.E.
        • et al.
        HER2 mutations in lung adenocarcinomas: a report from the Lung Cancer Mutation Consortium.
        Cancer. 2017; 123: 4099-4105
        • Barlesi F.
        • Mazieres J.
        • Merlio J.P.
        • Debieuvre D.
        • Mosser J.
        • Lena H.
        • et al.
        Routine molecular profiling of patients with advanced non-small-cell lung cancer: results of a 1-year nationwide programme of the French Cooperative Thoracic Intergroup (IFCT).
        Lancet (London, England). 2016; 387: 1415-1426
        • Spector N.L.
        • Blackwell K.L.
        Understanding the mechanisms behind trastuzumab therapy for human epidermal growth factor receptor 2-positive breast cancer.
        J Clin Oncol. 2009; 27: 5838-5847
        • Arcila M.E.
        • Chaft J.E.
        • Nafa K.
        • Roy-Chowdhuri S.
        • Lau C.
        • Zaidinski M.
        • et al.
        Prevalence, clinicopathologic associations, and molecular spectrum of ERBB2 (HER2) tyrosine kinase mutations in lung adenocarcinomas.
        Clin Canc Res. 2012; 18: 4910-4918
        • Perera S.A.
        • Li D.
        • Shimamura T.
        • Raso M.G.
        • Ji H.
        • Chen L.
        • et al.
        HER2YVMA drives rapid development of adenosquamous lung tumors in mice that are sensitive to BIBW2992 and rapamycin combination therapy.
        Proc Natl Acad Sci USA. 2009; 106: 474-479
        • Shigematsu H.
        • Takahashi T.
        • Nomura M.
        • Majmudar K.
        • Suzuki M.
        • Lee H.
        • et al.
        Somatic mutations of the HER2 kinase domain in lung adenocarcinomas.
        Cancer Res. 2005; 65: 1642-1646
        • Li B.T.
        • Ross D.S.
        • Aisner D.L.
        • Chaft J.E.
        • Hsu M.
        • Kako S.L.
        • et al.
        HER2 amplification and HER2 mutation are distinct molecular targets in lung cancers.
        J Thorac Oncol. 2016; 11: 414-419
        • Mazieres J.
        • Peters S.
        • Lepage B.
        • Cortot A.B.
        • Barlesi F.
        • Beau-Faller M.
        • et al.
        Lung cancer that harbors an HER2 mutation: epidemiologic characteristics and therapeutic perspectives.
        J Clin Oncol. 2013; 31: 1997-2003
        • Kosaka T.
        • Tanizaki J.
        • Paranal R.M.
        • Endoh H.
        • Lydon C.
        • Capelletti M.
        • et al.
        Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors.
        Cancer Res. 2017; 77: 2712-2721
        • Li D.
        • Ambrogio L.
        • Shimamura T.
        • Kubo S.
        • Takahashi M.
        • Chirieac L.R.
        • et al.
        BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models.
        Oncogene. 2008; 27: 4702-4711
        • De Greve J.
        • Teugels E.
        • Geers C.
        • Decoster L.
        • Galdermans D.
        • De May J.
        • et al.
        Clinical activity of afatinib (BIBW 2992) in patients with lung adenocarcinoma with mutations in the kinase domain of HER2/neu.
        Lung Canc. 2012; 76: 123-127
        • Eng J.
        • Hsu M.
        • Chaft J.E.
        • Kris M.G.
        • Arcila M.E.
        • Li B.T.
        Outcomes of chemotherapies and HER2 directed therapies in advanced HER2-mutant lung cancers.
        Lung Canc. 2016; 99: 53-56
        • Kris M.G.
        • Camidge D.R.
        • Giaccone G.
        • Hida T.
        • Li B.T.
        • O'Connell J.
        • et al.
        Targeting HER2 aberrations as actionable drivers in lung cancers: phase II trial of the pan-HER tyrosine kinase inhibitor dacomitinib in patients with HER2-mutant or amplified tumors.
        Ann Oncol. 2015; 26: 1421-1427
        • Li B.T.
        • Lee A.
        • O'Toole S.
        • Cooper W.
        • Yu B.
        • Chaft J.E.
        • et al.
        HER2 insertion YVMA mutant lung cancer: long natural history and response to afatinib.
        Lung Canc. 2015; 90: 617-619
        • Mazieres J.
        • Barlesi F.
        • Filleron T.
        • Besse B.
        • Monnet I.
        • Beau-Faller M.
        • et al.
        Lung cancer patients with HER2 mutations treated with chemotherapy and HER2-targeted drugs: results from the European EUHER2 cohort.
        Ann Oncol. 2016; 27: 281-286
        • Eisenhauer E.A.
        • Therasse P.
        • Bogaerts J.
        • Schwartz L.H.
        • Sargent D.
        • Ford R.
        • et al.
        New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).
        Eur J Cancer. 2009; 45: 228-247
        • Li C.
        • Sun Y.
        • Fang R.
        • Han X.
        • Luo X.
        • Wang R.
        • et al.
        Lung adenocarcinomas with HER2-activating mutations are associated with distinct clinical features and HER2/EGFR copy number gains.
        J Thorac Oncol. 2012; 7: 85-89
        • Peters S.
        • Curioni-Fontecedro A.
        • Nechushtan H.
        • Shih J.Y.
        • Liao W.Y.
        • Gautschi O.
        • et al.
        Activity of afatinib in heavily pretreated patients with HER2 mutation-positive advanced NSCLC: findings from a global named patient use program.
        J Thorac Oncol. 2018; 13: 1897-1905
        • Dahabreh I.J.
        • Murray S.
        Lack of replication for the association between HER2 I655V polymorphism and breast cancer risk: a systematic review and meta-analysis.
        Canc Epidemiol. 2011; 35: 503-509
        • Smit E.F.
        • Peters S.
        • Dziadziuszko R.
        • Dafni U.
        • Wolf J.
        • Wasag B.
        • et al.
        A single-arm phase II trial of afatinib in pretreated patients with advanced NSCLC harboring a HER2 mutation: the ETOP NICHE trial.
        J Clin Oncol. 2017; 35 (S9079-9070)
        • Hyman D.M.
        • Piha-Paul S.A.
        • Won H.
        • Rodon J.
        • Saura C.
        • Shapiro G.I.
        • et al.
        HER kinase inhibition in patients with HER2- and HER3-mutant cancers.
        Nature. 2018; 554: 189-194
        • Gandhi L.
        • Besse B.
        • Mazieres J.
        • Waqar S.
        • Cortot A.
        • Barlesi F.
        • et al.
        MA04.02 neratinib ± temsirolimus in HER2-mutant lung cancers: an international, randomized phase II study.
        J Thorac Oncol. 2017; 12: S358-S359
        • Robichaux J.P.
        • Elamin Y.Y.
        • Tan Z.
        • Carter B.W.
        • Zhang S.
        • Liu S.
        • et al.
        Mechanisms and clinical activity of an EGFR and HER2 exon 20-selective kinase inhibitor in non-small cell lung cancer.
        Nat Med. 2018; 24: 638-646
        • Oh I.J.
        • Hur J.Y.
        • Park C.K.
        • Kim Y.C.
        • Lee M.K.
        • Kim H.J.
        • et al.
        Clinical activity of Pan-HER inhibitors against HER2-mutant lung adenocarcinoma.
        Clin Lung Cancer. 2018; 19: e775-e781
        • Ettinger D.S.
        • Aisner D.L.
        • Wood D.E.
        • Akerley W.
        • Bauman J.
        • Chang J.Y.
        CCN guidelines insights: non-small cell lung cancer, version 5.2018.
        J Natl Compr Canc Netw. 2018; 16: 807-821