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Optimizing diagnosis and treatment of EGFR exon 20 insertions mutant NSCLC

      Highlights

      • The EGFR ex20ins has become a “druggable target” in NSCLC.
      • Amivantamab and Mobocertinib have been approved in pre-treated EGFR ex20ins NSCLC patients.
      • Novel selective EGFRex20ins inhibitors are being investigated in clinical trials.
      • NGS is the standard approach for the molecular detection of EGFRex20ins.

      Abstract

      The Epidermal growth factor receptor (EGFR) exon (ex) 20 insertions (ins) has been considered as an “undruggable target” for a long time, with platinum-pemetrexed combination recommended as upfront standard treatment for newly diagnosed advanced non-small cell lung cancer (NSCLC) patients. Recent preliminary data from early phase clinical trials have demonstrated that pharmacological inhibition of EGFRex20ins is possible, offering new treatment opportunities to 1–2% of advanced NSCLC patients harboring such hard-to-treat molecular alteration. Among the different drugs under clinical investigation, both amivantamab and mobocertinib have received regulatory approval in the United States, by the Food and Drugs Administration (FDA), while amivantamab has been recently approved also in Europe, for the clinical treatment of advanced NSCLC patients harboring EGFRex20ins who failed at least one prior line of systemic therapy, representing a major breakthrough in lung cancer treatment over the last year. With novel effective targeted options on the horizon, there is a renewed interest on optimizing the molecular screening of advanced NSCLC, and next-generation sequencing (NGS)-based genotyping is currently considered the gold standard approach to profile advanced NSCLC patients, as recommended by international guidelines. Herein we provide an updated overview of the most recent findings and upcoming challenges regarding both molecular detection and therapeutic management of EGFR ex20ins mutant advanced NSCLC patients.

      Keywords

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      References

        • Paez J.G.
        • Jänne P.A.
        • Lee J.C.
        • Tracy S.
        • Greulich H.
        • Gabriel S.
        • et al.
        EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy.
        Science. 2004; 304: 1497-1500
        • Lynch T.J.
        • Bell D.W.
        • Sordella R.
        • Gurubhagavatula S.
        • Okimoto R.A.
        • Brannigan B.W.
        • et al.
        Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib.
        N Engl J Med. 2004; 350: 2129-2139
        • Malapelle U.
        • Pilotto S.
        • Passiglia F.
        • Pepe F.
        • Pisapia P.
        • Righi L.
        • et al.
        Dealing with NSCLC EGFR mutation testing and treatment: A comprehensive review with an Italian real-world perspective.
        Crit Rev Oncol Hematol. 2021; 160: 103300
        • Chouaid C.
        • Filleron T.
        • Debieuvre D.
        • Pérol M.
        • Girard N.
        • Dansin E.
        • et al.
        A real-world study of patients with advanced non-squamous non-small cell lung cancer with EGFR exon 20 insertion: clinical characteristics and outcomes.
        Target Oncol. 2021; 16: 801-811
      1. Choudhury NJ, Schoenfeld AJ, Flynn J, et al. Response to standard therapies and comprehensive genomic analysis for patients with lung adenocarcinoma with EGFR exon 20 insertions. Clin Cancer Res. 2021 May 15;27(10):2920-2927.

        • Oxnard G.R.
        • Lo P.C.
        • Nishino M.
        • et al.
        Natural history and molecular characteristics of lung cancers harboring EGFR exon 20 insertions.
        J Thorac Oncol. 2013; 8: 179-184
        • Cardona A.F.
        • Rojas L.
        • Zatarain-Barrón Z.L.
        • Freitas H.C.
        • Granados S.T.
        • Castillo O.
        • et al.
        EGFR exon 20 insertion in lung adenocarcinomas among Hispanics (geno1.2-CLICaP).
        Lung Cancer. 2018; 125: 265-272
        • Riess J.W.
        • Gandara D.R.
        • Frampton G.M.
        • Madison R.
        • Peled N.
        • Bufill J.A.
        • et al.
        Diverse EGFR Exon 20 insertions and co-occurring molecular alterations identified by comprehensive genomic profiling of NSCLC.
        J Thorac Oncol. 2018; 13: 1560-1568
        • Yang G.
        • Li J.
        • Xu H.
        • Yang Y.
        • Yang L.u.
        • Xu F.
        • et al.
        EGFR exon 20 insertion mutations in Chinese advanced non-small cell lung cancer patients: Molecular heterogeneity and treatment outcome from nationwide real-world study.
        Lung Cancer. 2020; 145: 186-194
        • Yang J.-H.
        • Sequist L.V.
        • Geater S.L.
        • Tsai C.-M.
        • Mok T.S.K.
        • Schuler M.
        • et al.
        Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUXLung 3, and LUX-Lung 6.
        Lancet Oncol. 2015; 16: 830-838
        • Naidoo J.
        • Sima C.S.
        • Rodriguez K.
        • Busby N.
        • Nafa K.
        • Ladanyi M.
        • et al.
        Epidermal growth factor receptor exon 20 insertions in advanced lung adenocarcinomas: clinical outcomes and response to erlotinib.
        Cancer. 2015; 121: 3212-3220
        • Bazhenova L.
        • Minchom A.
        • Viteri S.
        • et al.
        Comparative clinical outcomes for patients with advanced NSCLC harboring EGFR exon 20 insertion mutations and common EGFR mutations.
        Lung Cancer. 2021; 162: 154-161
        • Xu C.-W.
        • Wang W.-X.
        • Wang D.
        • et al.
        Pemetrexed-based chemotherapy for non-small-cell lung cancer patients with EGFR exon 20 insertion mutation: a multicenter study.
        Transl Lung Cancer Res. 2020 Oct; 9: 1853-1861
        • Meador C.B.
        • Sequist L.V.
        • Piotroska Z.
        • et al.
        Targeting EGFR Exon 20 Insertions in Non-Small Cell Lung Cancer: Recent Advances and Clinical Updates.
        Cancer Discov. 2021 Sep; 11: 2145-2157
        • Gazdar A.F.
        Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors.
        Oncogene. 2009; 28: S24-S31
      2. Arcila, Nafa, Chaft, et al. EGFR Exon 20 Insertion Mutations in Lung Adenocarcinomas: Prevalence, Molecular Heterogeneity, and Clinicopathologic Characteristics. Mol Cancer Ther. 2013 Feb; 12(2): 220–229.

        • Yasuda H.
        • Park E.
        • Yun C.-H.
        • Sng N.J.
        • Lucena-Araujo A.R.
        • Yeo W.-L.
        • et al.
        Structural, Biochemical, and Clinical Characterization of Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertion Mutations in Lung Cancer.
        Sci Transl Med. 2013; 5
      3. Voon PJ, Tsui DW, Rosenfeld N, et al. EGFR exon 20 insertion A763-Y764insFQEA and response to erlotinib--Letter. Mol Cancer Ther. 2013 Nov; 12(11):2614-5.

        • Zochbauer-Muller S.
        • Kaserer B.
        • Prosch H.
        • et al.
        Case report: afatinib treatment in a patient with NSCLC harbouring a rare EGFR exon 20 mutation.
        Front Oncol. 2020; 10593852
        • Urbán L.
        • Dóczi R.
        • Vodicska B.
        • Tihanyi D.
        • Horváth M.
        • Kormos D.
        • et al.
        Major clinical response to afatinib monotherapy in lung adenocarcinoma harboring EGFR exon 20 insertion mutation.
        Clin Lung Cancer. 2021; 22: e112-e115
        • Malapelle U.
        • Pilotto S.
        • Reale M.L.
        • Passiglia F.
        • Pisapia P.
        • Pepe F.
        • et al.
        Epidermal growth factor receptor exon 20 insertion variants in non-small cell lung cancer patients.
        Crit Rev Oncol Hematol. 2022; 169: 103536
        • Angulo B.
        • Conde E.
        • Suárez-Gauthier A.
        • Plaza C.
        • Martínez R.
        • Redondo P.
        • et al.
        A comparison of EGFR mutation testing methods in lung carcinoma: direct sequencing, real-time PCR and immunohistochemistry.
        PLoS ONE. 2012; 7: e43842
        • Hwang I.
        • Kim S.
        • Chun S.
        • et al.
        Next-Generation Sequencing for Effective Detection of Various EGFR Exon 20 Insertions (E20ins) in Non-Small Cell Lung Cancer (NSCLC).
        Journal of Thoracic Oncology. 2019; 14: S659
        • Mosele F.
        • Remon J.
        • Mateo J.
        • Westphalen C.B.
        • Barlesi F.
        • Lolkema M.P.
        • et al.
        Recommendations for the use of next-generation sequencing (NGS) for patients with metastatic cancers: a report from the ESMO Precision Medicine Working Group.
        Ann Oncol. 2020; 31: 1491-1505
        • Bauml J.M.
        • Viteri S.
        • Minchom A.
        • Bazhenova L.
        • Ou S.
        • Schaffer M.
        • et al.
        FP07.12 underdiagnosis of EGFR exon 20 insertion mutation variants: estimates from NGS-based real-world datasets.
        J Thorac Oncol. 2021; 16: S208-S209
        • Coleman N.
        • Woolf D.
        • Welsh L.
        • McDonald F.
        • MacMahon S.
        • Yousaf N.
        • et al.
        EGFR Exon 20 insertion (A763_Y764insFQEA) mutant NSCLC is not identified by roche cobas version 2 tissue testing but has durable intracranial and extracranial response to osimertinib.
        J Thorac Oncol. 2020; 15: e162-e165
        • Lin H.M.
        • Yin Y.
        • Crossland V.
        • et al.
        EGFR testing patterns and detection of EGFR exon 20 insertions in the United States.
        JTO Clin Res Rep. 2022; 3100285
        • Viteri S.
        • Bauml J.M.
        • Bazhenova L.
        • et al.
        Real-world frequency of non-small cell lung cancer with epidermal growth factor receptor (EGFR) exon 20 insertion (Exon20ins) mutations by site of insertion.
        J. Thoracic Oncol. 2021; 16: S699-S703
        • Yun J.
        • Lee S.-H.
        • Kim S.-Y.
        • et al.
        Antitumor activity of amivantamab (JNJ-61186372), an EGFR-cMet bispecific antibody, in diverse models of EGFR Exon 20 insertion-driven NSCLC.
        Cancer Discov. 2020; (CD-20-0116)
        • Park K.
        • Haura E.B.
        • Leighl N.B.
        • Mitchell P.
        • Shu C.A.
        • Girard N.
        • et al.
        Amivantamab in EGFR Exon 20 insertion-mutated non–small-cell lung cancer progressing on platinum chemotherapy: initial results from the CHRYSALIS phase I study.
        J Clin Oncol. 2021; 39: 3391-3402
        • Sabari J.K.
        • Shu C.A.
        • Park K.
        • et al.
        Amivantamab in post-platinum EGFR exon 20 insertion mutant nonsmall cell lung cancer.
        J Thorac Oncol. 2021; 16: S108-S109
        • Minchom A.
        • Viteri S.
        • Bazhenova L.
        • Gadgeel S.M.
        • Ou S.-H.
        • Trigo J.
        • et al.
        Amivantamab compared with real-world therapies in patients with advanced non-small cell lung cancer harboring EGFR exon 20 insertion mutations who progressed after platinum-based chemotherapy.
        Lung Cancer. 2022; 168: 74-82
      4. Gonzalvez F, Vincent S, Baker TE, , et al. Mobocertinib (TAK-788): a targeted inhibitor of EGFR exon 20 insertion mutants in non-small cell lung cancer. Cancer Discov 2021.

        • Riely G.J.
        • Neal J.W.
        • Camidge D.R.
        • et al.
        Activity and safety of mobocertinib (TAK-788) in previously treated non-small cell lung cancer with EGFR exon 20 insertion mutations from a phase 1/2 trial.
        Cancer Discov. 2021;
        • Zhou C.
        • Ramalingam S.S.
        • Kim T.M.
        • Kim S.-W.
        • Yang J.-H.
        • Riely G.J.
        • et al.
        Treatment Outcomes and Safety of Mobocertinib in Platinum-Pretreated Patients With EGFR Exon 20 Insertion-Positive Metastatic Non-Small Cell Lung Cancer: A Phase 1/2 Open-label Nonrandomized Clinical Trial.
        JAMA Oncol. 2021; 7: e214761
      5. Spira A, Ramalingam S, Neal J, et al, Mobocertinib in EGFR Exon 20 Insertion–Positive Metastatic NSCLC Patients With Disease Control on Prior EGFR TKI Therap. Journal of Thoracic Oncology. Volume 16, Issue 10, Supplement, October 2021, Pages S873-S874.

      6. Wang M, Yang J C-H, Mitchell PL et al., Sunvozertinib, a selective EGFR inhibitor for previously treated non-small cell lung cancer with EGFR exon 20 insertion mutations. Cancer Discov. 2022 Jul 6;12(7):1676-1689.

        • Janne P.A.
        • Wang M.
        • Camidge D.R.
        • Mitchell P.
        • Fang J.
        • Nian W.
        • et al.
        Antitumor activity of sunvozertinib in NSCLC patients with EGFR Exon20 insertion mutations after platinum and anti-PD(L)1 treatment failures..
        JCO. 2022; 40: 9015
        • Yu H.A.
        • Tan D.-W.
        • Smit E.F.
        • Spira A.I.
        • Soo R.A.
        • Nguyen D.
        • et al.
        Phase (Ph) 1/2a study of CLN-081 in patients (pts) with NSCLC with EGFR exon 20 insertion mutations (Ins20)..
        JCO. 2022; 40: 9007
        • Cha M.Y.
        • Lee K.-O.
        • Kim M.
        • Song J.Y.
        • Lee K.H.
        • Park J.
        • et al.
        Antitumor activity of HM781-36B, a highly effective pan-HER inhibitor in erlotinib- resistant NSCLC and other EGFR-dependent cancer models.
        Int J Cancer. 2012; 130: 2445-2454
        • Heymach J.V.
        • Negrao M.V.
        • Robichaux J.P.
        • et al.
        A phase II trial of poziotinib in EGFR and HER2 exon 20 mutant non-small cell lung cancer (NSCLC).
        J Thorac Oncol. 2018; 13: S323-S324
        • Le X.
        • Goldman J.W.
        • Clarke J.M.
        • et al.
        Poziotinib shows activity and durability of responses in subgroups of previously treated EGFR exon 20 NSCLC patients.
        J Clin Oncol. 2020; 38: 9514
        • Prelaj A.
        • Bottiglieri A.
        • Proto C.
        • et al.
        Poziotinib for EGFR and HER2 exon 20 insertion mutation in advanced NSCLC: Results from the expanded access program.
        Eur J Cancer. 2021 May; 149: 235-248
        • Elamin Y.Y.
        • Robichaux J.P.
        • Carter B.W.
        • et al.
        Poziotinib for EGFR exon 20-mutant NSCLC: Clinical efficacy, resistance mechanisms, and impact of insertion location on drug sensitivity.
        Cancer Cell. 2022; 40: 754-767.e6https://doi.org/10.1016/j.ccell.2022.06.006
      7. Planchard D, Popat S, Kerr K, et al., Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018 Oct 1;29(Suppl 4):iv192-iv237.

        • van Veggel B.
        • Madeira R.S.J.F.V.
        • Hashemi S.M.S.
        • et al.
        Osimertinib treatment for patients with EGFR exon 20 mutation positive non-small cell lung cancer.
        Lung Cancer. 2020; 141: 9-13
        • Kim T.M.
        • Ock C.Y.
        • Kim M.
        • et al.
        1529P - Phase II study of osimertinib in NSCLC patients with EGFR exon 20 insertion mutation: A multicenter trial of the Korean Cancer Study Group (LU17-19).
        Ann Oncol. 2019; 30v628
        • Fang W.
        • Huang Y.
        • Hong S.
        • et al.
        EGFR exon 20 insertion mutations and response to osimertinib in non-small-cell lung cancer.
        BMC Cancer. 2019; 19: 595
        • Piotrowska Z.
        • Wang Y.
        • Sequist L.V.
        • et al.
        ECOG-ACRIN 5162: A phase II study of osimertinib 160 mg in NSCLC with EGFR exon 20 insertions.
        J Clin Oncol. 2020; 38: 9513
        • Zwierenga F.
        • van Veggel B.
        • Hendriks L.E.
        • et al.
        High dose osimertinib in patients with advanced stage EGFR exon 20 mutation-positive NSCLC: Results from the phase 2 multicenter POSITION20 trial.
        Lung Cancer. 2022 Jun; 23: 133-140
        • Robichaux J.P.
        • Elamin Y.
        • Carter B.
        • et al.
        Identification of mechanisms of acquired resistance to poziotinib in EGFR exon 20 mutant non-small cell lung cancer (NSCLC).
        J Thorac Oncol. 2019; 14: S282-S283
        • Reck M.
        • Mok T.S.K.
        • Nishio M.
        • et al.
        Atezolizumab plus bevacizumab and chemotherapy in non-small-cell lung cancer (IMpower150): key subgroup analyses of patients with EGFR mutations or baseline liver metastases in a randomised, open-label phase 3 trial.
        Lancet Respir Med. 2019; 7: 387-401
        • Nogami N.
        • Barlesi F.
        • Socinski M.A.
        • et al.
        IMpower150 final exploratory analyses for atezolizumab plus bevacizumab and chemotherapy in Key NSCLC patient subgroups With EGFR mutations or metastases in the liver or brain.
        J Thorac Oncol. 2022 Feb; 17: 309-323
      8. Mountzios G, Planchard D, Metro G, et al. Real-world management of patients with EGFR exon 20-mutant NSCLC in the precision oncology era: First report from the European EXOTIC registry. Ann Oncol 2022;33(suppl_2):S105–S110.