HER2: defining a Neu target in non-small-cell lung cancer
Authors: S. Ekman
Journal: Annals of Oncology (2019)

The human epidermal growth factor receptor family of receptor tyrosine kinases consists of four members, HER1–4 (also named ErbB1–4), that function as homo and heterodimers and has been extensively studied in tumor biology due to its general role in signal transduction and oncogenesis. The first evidence for a role of HER2 in cancer came from the connection to its rat ortholog, Neu, a mutated gene isolated from carcinogen-induced neuroblastomas [1.Schechter A.L. Stern D.F. Vaidyanathan L. et al.The neu oncogene: an ERB-B-related gene encoding a 185,000-Mr tumour antigen.Nature. 1984; 312: 513-516Crossref PubMed Scopus (939) Google Scholar]. Furthermore, overexpression of HER2 under the control of a murine mammary tumor virus promoter lead to mammary adenocarcinomas in transgenic mice, which could be treated with a murine form of the anti-HER2 antibody trastuzumab [2.Finkle D. Quan Z.R. Asghari V. et al.HER2-targeted therapy reduces incidence and progression of midlife mammary tumors in female murine mammary tumor virus huHER2-transgenic mice.Clin Cancer Res. 2004; 10: 2499-2511Crossref PubMed Scopus (94) Google Scholar]. In a groundbreaking study, Slamon et al. [3.Slamon D.J. Clark G.M. Wong S.G. et al.Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene.Science. 1987; 235: 177-182Crossref PubMed Scopus (9936) Google Scholar] demonstrated the amplification of HER2 and its prognostic role in ∼30% of breast cancers. Later, improvement of survival was shown in patients with HER2 amplified early-stage breast cancer treated with trastuzumab. In breast cancer, HER2 protein overexpression most often occurs in the context of HER2 amplification and immunohistochemistry (IHC) is routinely used as a prognostic and predictive biomarker test for anti-HER2 therapy. Another type of less frequent genetic aberration leading to activation of HER2 involves somatic activating mutations, most commonly in the extracellular or the kinase domains of HER2, identified in various cancer forms including in lung, bladder, breast and colorectal cancer [4.Mishra R. Hanker A.B. Garrett J.T. Genomic alterations of ERBB receptors in cancer: clinical implications.Oncotarget. 2017; 8: 114371-114392Crossref PubMed Scopus (72) Google Scholar]. In non-small-cell lung cancer (NSCLC) activating mutations in HER2 occur in ∼2%–4% of cases of NSCLC, most commonly in adenocarcinoma histology and never smokers [5.Pillai R.N. Behera M. Berry L.D. et al.HER2 mutations in lung adenocarcinomas: a report from the Lung Cancer Mutation Consortium.Cancer. 2017; 123: 4099-4105Crossref PubMed Scopus (104) Google Scholar]. The most common mutation consists of a 12 basepair insertion in exon 20 resulting in an YVMA insertion. Also in NSCLC, oncogenic amplification of HER2 occurs in around 3% of cases without prior EGFR tyrosine kinase inhibitor (TKI) treatment [6.Li B.T. Ross D.S. Aisner D.L. et al.HER2 amplification and HER2 mutation are distinct molecular targets in lung cancers.J Thorac Oncol. 2016; 11: 414-419Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar] and even higher, around 10% of cases, in EGFR TKI resistance. HER2 amplification and mutations do not usually occur together [6.Li B.T. Ross D.S. Aisner D.L. et al.HER2 amplification and HER2 mutation are distinct molecular targets in lung cancers.J Thorac Oncol. 2016; 11: 414-419Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar]. A third mechanism of HER2 activation in lung cancer is protein overexpression, reported to occur in 2%–20% of cases depending on level of overexpression (IHC 2+ or 3+) and demonstrated to have a poor prognostic role [7.Liu L. Shao X. Gao W. et al.The role of human epidermal growth factor receptor 2 as a prognostic factor in lung cancer: a meta-analysis of published data.J Thorac Oncol. 2010; 5: 1922-1932Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar], but in contrast to breast cancer there are controversies regarding the correlation between IHC overexpression and amplification in lung cancer [8.Nakamura H. Saji H. Ogata A. et al.Correlation between encoded protein overexpression and copy number of the HER2 gene with survival in non-small cell lung cancer.Int J Cancer. 2003; 103: 61-66Crossref PubMed Scopus (66) Google Scholar, 9.Yoshizawa A. Sumiyoshi S. Sonobe M. et al.HER2 status in lung adenocarcinoma: a comparison of immunohistochemistry, fluorescence in situ hybridization (FISH), dual-ISH, and gene mutations.Lung Cancer. 2014; 85: 373-378Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar]. HER2 targeted therapy is not yet standard of care in lung cancer, but several clinical studies have been carried out or are ongoing addressing this issue. There are several ways of treating HER2 alterations, including anti-HER2 antibodies and small molecule TKIs. So far, clinical efficacy in different clinical trials in lung cancer using monotherapy anti-HER2 therapies have been rather modest (Table 1). The European retrospective EUHER2 study including patients with HER2 exon 20 insertions demonstrated an overall response rate (ORR) of 7.4% treating with the TKIs afatinib, lapatinib and neratinib, whereas the antibody trastuzumab and the antibody–drug conjugate T-DM1 (trastuzumab emtansine) were more effective with an ORR of 50.9%, but in most cases combined with chemotherapy making it hard to evaluate the contribution of the anti-HER2 therapy [14.Mazières J. Barlesi F. Filleron T. 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: 281-286Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar]. More recently, improved efficacy was shown in a phase II basket trial with T-DM1 in HER2 mutated lung adenocarcinoma with an ORR of 44% (8/18) and a median PFS of 5 months [12.Li B.T. Shen R. Buonocore D. et al.Ado-trastuzumab emtansine for patients with HER2-mutant lung cancers: results from a Phase II Basket Trial.J Clin Oncol. 2018; 36: 2532-2537Crossref PubMed Scopus (279) Google Scholar]. However, in another study with T-DM1 in patients with HER2 overexpressing tumors, the ORR was only 20% in IHC 3+ (4/20) and 0% in IHC 2+ (0/29) tumors, with three of four responders harboring HER2 amplification [10.Peters S. Stahel R. Bubendorf L. et al.Trastuzumab emtansine (T-DM1) in patients with previously treated HER2-overexpressing metastatic non-small cell lung cancer: efficacy, safety, and biomarkers.Clin Cancer Res. 2019; 25: 64-72Crossref PubMed Scopus (118) Google Scholar].Table 1Clinical studies with anti-HER2 agents in lung cancerAgentTrialHER2 aberrationNClinical efficacyT-DM1aTrastuzumab emtansine.Phase II single arm (NCT02289833) [10.Peters S. Stahel R. Bubendorf L. et al.Trastuzumab emtansine (T-DM1) in patients with previously treated HER2-overexpressing metastatic non-small cell lung cancer: efficacy, safety, and biomarkers.Clin Cancer Res. 2019; 25: 64-72Crossref PubMed Scopus (118) Google Scholar]Protein overexpression49ORRbOverall response rate.: IHCcImmunohistochemistry. 2+: 0%, IHC 3+: 20%T-DM1Phase II basket trial (NCT02675829) [11.Dong Z.Y. Zhang J.T. Liu S.Y. et al.EGFR mutation correlates with uninflamed phenotype and weak immunogenicity, causing impaired response to PD-1 blockade in non-small cell lung cancer.Oncoimmunology. 2017; 6: e1356145.Crossref PubMed Scopus (244) Google Scholar]Mutations18ORR: 44%mPFSdMedian progression-free survival.: 5 monthsT-DM1Phase II basket trial [12.Li B.T. Shen R. Buonocore D. et al.Ado-trastuzumab emtansine for patients with HER2-mutant lung cancers: results from a Phase II Basket Trial.J Clin Oncol. 2018; 36: 2532-2537Crossref PubMed Scopus (279) Google Scholar]Mutations18ORR: 44%mPFS: 5 monthsT-DM1Phase II (terminated early; limited efficacy) [13.Hotta K. Aoe K. Kozuki T. et al.A phase II study of trastuzumab emtansine in HER2-positive non-small cell lung cancer.J Thorac Oncol. 2018; 13: 273-279Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar]IHC 3+, IHC 2+ and FISH+ or exon 20 mutation15ORR: 6.7% (1/15)mPFS: 2.0 mpmOSeMedian overall survival.: 10.9 monthsTrastuzumab (T), Neratinib, afatinib, lapatinib, T-DM1Retrospective [14.Mazières J. Barlesi F. Filleron T. 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: 281-286Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar]Exon 20 insertion65ORR: TKIs 7.4%, T/T-DM1 50.9%Trastuzumab+carboplatin/paclitaxelPhase II [15.Langer C.J. Stephenson P. Thor A. et al.Trastuzumab in the treatment of advanced non-small-cell lung cancer: is there a role? Focus on Eastern Cooperative Oncology Group Study 2598.J Clin Oncol. 2004; 22: 1180-1187Crossref PubMed Scopus (193) Google Scholar]Protein overexpression53ORR: 24.5%mPFS: 3.3 monthsmOS: 10.1 monthsGemcitabine(G)/Cisplatin (C) +/-Trastuzumab (T)Phase II [16.Gatzemeier U. Groth G. Butts C. et al.Randomized phase II trial of gemcitabine–cisplatin with or without trastuzumab in HER2-positive non-small-cell lung cancer.Ann Oncol. 2004; 15: 19-27Abstract Full Text Full Text PDF PubMed Scopus (344) Google Scholar]Protein overexpression/amplification101 (GC+T n=51, GC n=50)ORR: GC+T 36%, GC 41%Trastuzumab, afatinib, lapatinib, masatinibRetrospective [17.Mazières J. Peters S. Lepage B. et al.Lung cancer that harbors an HER2 mutation: epidemiologic characteristics and therapeutic perspectives.J Clin Oncol. 2013; 31: 1997-2003Crossref PubMed Scopus (503) Google Scholar]Mutations22ORR: 50%Trastuzumab+pertuzumabPhase II basket trial (NCT02091141) [18.Hainsworth J.D. Meric-Bernstam F. Swanton C. et al.Targeted therapy for advanced solid tumors on the basis of molecular profiles: results from mypathway, an open-label, phase IIa multiple basket study.J Clin Oncol. 2018; 36: 536-542Crossref PubMed Scopus (273) Google Scholar]Protein overexpression/amplification/mutationsAmplification n=16, mutations n=14ORR (interim results): amplification 13%, mutations 21%Dacomitinib [22]Phase II (NCT00818441) [19.Kris M.G. Camidge D.R. Giaccone G. 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: 1421-1427Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar]Mutations (n=26)/amplification (n=4)30PRfPartial response.: 12% (mutations), 0% (amplification)mOS: 9 months (mutations), 5–22 months (amplification)NeratinibPhase II basket trial (SUMMIT, NCT01953926) [20.Hyman D.M. Piha-Paul S.A. Won H. et al.HER kinase inhibition in patients with HER2- and HER3-mutant cancers.Nature. 2018; 554: 189-194Crossref PubMed Scopus (452) Google Scholar]Mutations26ORR: 3.8% at 8 weeksmPFS 5.5 monthsNeratinib+/-temsirolimusPhase II (NCT01827267) [21.Gandhi L. Besse B. Mazieres J. et al.MA04.02 neratinib ± temsirolimus in HER2-mutant lung cancers: an international, randomized phase II study.J Thoracic Oncol. 2017; 12: S358-S359Abstract Full Text Full Text PDF Google Scholar]Mutations60(neratinib n=17, neratinib+temsirolimus n=43)ORR: 0% neratinib, 14% neratinib+temsirolimusAfatinibPhase II [22.De Grève J. Moran T. Graas M.P. et al.Phase II study of afatinib, an irreversible ErbB family blocker, in demographically and genotypically defined lung adenocarcinoma.Lung Cancer. 2015; 88: 63-69Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar]Mutations7ORR: 0%AfatinibPhase II (NCT02369484) [23.Smit E.F. Peters S. Dziadziuszko R. 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: 9070Crossref Google Scholar]Mutations13ORR: 7.7%AfatinibRetrospective [24.Lai W.-C.V. Lebas L. Milia J. et al.Afatinib in patients with metastatic HER2-mutant lung cancers: an international multicenter study.J Clin Oncol. 2017; 35: 9071Crossref Google Scholar]Mutations27ORR: 15%a Trastuzumab emtansine.b Overall response rate.c Immunohistochemistry.d Median progression-free survival.e Median overall survival.f Partial response. Open table in a new tab In the original article by Wang et al. [25.Wang Y. Jiang T. Qin Z. et al.HER2 exon 20 insertions in non-small-cell lung cancer are sensitive to the irreversible pan-HER receptor tyrosine kinase inhibitor pyrotinib.Ann Oncol. 2019; 30: 447-455Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar] published in this edition of Annals of Oncology, the antitumor effect of an irreversible pan-HER receptor TKI, pyrotinib, is investigated. As model systems, patient-derived organoids and xenografts (PDXs) were established from a HER2-A775_G776YVMA-inserted advanced lung adenocarcinoma patient sample. Furthermore, preliminary safety and efficacy data from a phase II clinical trial with pyrotinib in fifteen HER2-mutant NSCLC patients are also presented. Pyrotinib showed significant growth inhibition of organoids relative to afatinib in vitro (P = 0.0038). In the PDX model, pyrotinib showed an improved antitumor effect compared with afatinib (P = 0.0471) and T-DM1(P = 0.0138) with mice treated with pyrotinib displaying a mean tumor volume reduction of 52.2%, this compared with afatinib (25.4%) and T-DM1 (10.9%) showing no obvious reductions. In the phase II cohort of 15 patients with HER2-mutant NSCLC, pyrotinib 400 mg once daily resulted in an ORR of 53.3% and a median PFS of 6.4 months. For safety, pyrotinib related adverse events were all grade 1–2 occurring in 60% of the patients and no dose reduction or dose discontinuation occurred due to adverse events. The results have encouraged the authors to initiate a phase II trial (NCT02834936) that is currently recruiting. The limited clinical activity of anti-HER2 agents in lung cancer observed so far may have several explanations and implications. The clinical and biological heterogeneity of NSCLC patients with HER2 alterations is significant. First of all, the lack of correlation between HER2 amplification, mutations and protein overexpression leaves the question open of how we define HER2-positive lung cancers and which of them are suitable for treatment with anti-HER2 agents. The variations in clinical efficacy of anti-HER2 agents for different HER2 aberrations suggests distinct molecular entities and therapeutic targets. HER2-positive lung cancer may not be an adequate general term, and patient cohorts for the study of HER2-targeted agents should be defined by the specific HER2 alteration present. Secondly, because of the substantial variation in clinical efficacy and toxicity observed between different anti-HER2 agents there is a need to better understand and compare the pharmacodynamic and pharmacokinetic properties of different anti-HER2 agents. Thirdly, the knowledge about resistance mechanisms for anti-HER2 treatments, both primary and acquired resistance, is limited although some data are emerging [26.de Melo Gagliato D. Jardim D.L. Marchesi M.S. Hortobagyi GN. Mechanisms of resistance and sensitivity to anti-HER2 therapies in HER2+ breast cancer.Oncotarget. 2016; 7: 64431-64446Crossref PubMed Scopus (132) Google Scholar]. For all of these purposes, we need the development of optimal preclinical models for the guidance of precision medicine and to support the design of clinical trials, where the patient-derived in vivo models used in the present article are examples that have been shown to have significant correlation to the clinical situation [27.Pauli C. Hopkins B.D. Prandi D. et al.Personalized.Cancer Discov. 2017; 7: 462-477Crossref PubMed Scopus (549) Google Scholar]. Such models should be paired with extensive biomarker studies as part of the clinical trials carried out in order to validate and complement the biomarker selection. Overall, the study by Wang et al. has demonstrated promising activity of pyrotinib against NSCLC with HER2 exon 20 mutations in both patient-derived in vivo models, as well as in a patient cohort of a phase II trial. This study together with others warrant further investigations of HER2 inhibitor strategies using optimal drugs and drug combinations in patients molecularly selected in a rational way. None declared.