Non–Small Cell Lung Cancer, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology

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  • 1 The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins;
  • | 2 Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance;
  • | 3 University of Colorado Cancer Center;
  • | 4 Huntsman Cancer Institute at the University of Utah;
  • | 5 Fox Chase Cancer Center;
  • | 6 Robert H. Lurie Comprehensive Cancer Center of Northwestern University;
  • | 7 Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute;
  • | 8 The University of Texas MD Anderson Cancer Center;
  • | 9 Dana-Farber/Brigham and Women’s Cancer Center;
  • | 10 Duke Cancer Institute;
  • | 11 University of Wisconsin Carbone Cancer Center;
  • | 12 Moffitt Cancer Center;
  • | 13 UT Southwestern Simmons Comprehensive Cancer Center;
  • | 14 Yale Cancer Center/Smilow Cancer Hospital;
  • | 15 Mayo Clinic Cancer Center;
  • | 16 UCSF Helen Diller Family Comprehensive Cancer Center;
  • | 17 O'Neal Comprehensive Cancer Center at UAB;
  • | 18 Fred & Pamela Buffett Cancer Center;
  • | 19 Massachusetts General Hospital Cancer Center;
  • | 20 University of Michigan Rogel Cancer Center;
  • | 21 Stanford Cancer Institute;
  • | 22 Vanderbilt-Ingram Cancer Center;
  • | 23 City of Hope National Medical Center;
  • | 24 Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine;
  • | 25 The University of Tennessee Health Science Center;
  • | 26 The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute;
  • | 27 UC San Diego Moores Cancer Center;
  • | 28 Memorial Sloan Kettering Cancer Center;
  • | 29 UC Davis Comprehensive Cancer Center;
  • | 30 Abramson Cancer Center at the University of Pennsylvania;
  • | 31 UCLA Jonsson Comprehensive Cancer Center;
  • | 32 Roswell Park Comprehensive Cancer Center; and
  • | 33 National Comprehensive Cancer Network

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non–Small Cell Lung Cancer (NSCLC) provide recommended management for patients with NSCLC, including diagnosis, primary treatment, surveillance for relapse, and subsequent treatment. Patients with metastatic lung cancer who are eligible for targeted therapies or immunotherapies are now surviving longer. This selection from the NCCN Guidelines for NSCLC focuses on targeted therapies for patients with metastatic NSCLC and actionable mutations.

Individual Disclosures for the NCCN Non–Small Cell Lung Cancer Panel
Individual Disclosures for the NCCN Non–Small Cell Lung Cancer Panel

  • 1.

    Siegel RL, Miller KD, Fuchs HE, et al. Cancer statistics, 2022. CA Cancer J Clin 2022;72:733.

  • 2.

    Torre LA, Siegel RL, Jemal A. Lung Cancer Statistics. Adv Exp Med Biol 2016;893:119.

  • 3.

    Howlader N, Noone AM, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2018, based on November 2020 SEER data submission, posted to the SEER web site, April 2021. National Cancer Institute, Bethesda, MD. 2021. Accessed March 8, 2022. Available at: https://seer.cancer.gov/csr/1975_2018/

    • Search Google Scholar
    • Export Citation
  • 4.

    Howlader N, Noone AM, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2017, based on November 2019 SEER data submission, posted to the SEER web site, April 2020. National Cancer Institute, Bethesda, MD. 2020. Accessed March 8, 2022. Available at https://seer.cancer.gov/csr/1975_2017/

    • Search Google Scholar
    • Export Citation
  • 5.

    Brahmer JR, Govindan R, Anders RA, et al. The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of non-small cell lung cancer (NSCLC). J Immunother Cancer 2018;6:75.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    Johnson DH, Schiller JH, Bunn PA, Jr. Recent clinical advances in lung cancer management. J Clin Oncol 2014;32:973982.

  • 7.

    Reck M, Heigener DF, Mok T, et al. Management of non-small-cell lung cancer: recent developments. Lancet 2013;382:709719.

  • 8.

    Forde PM, Ettinger DS. Targeted therapy for non-small-cell lung cancer: past, present and future. Expert Rev Anticancer Ther 2013;13:745758.

  • 9.

    Ettinger DS. Ten years of progress in non-small cell lung cancer. J Natl Compr Canc Netw 2012;10:292295.

  • 10.

    Reck M, Rodríguez-Abreu D, Robinson AG, et al. Updated analysis of KEYNOTE-024: pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-L1 tumor proportion sore of 50% or greater. J Clin Oncol 2019;37:537546.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Siegel RL, Miller KD, Fuchs HE, et al. Cancer statistics, 2021. CA Cancer J Clin 2021;71:733.

  • 12.

    Mok T, Camidge DR, Gadgeel SM, et al. Updated overall survival and final progression-free survival data for patients with treatment-naive advanced ALK-positive non-small-cell lung cancer in the ALEX study. Ann Oncol 2020;31:10561064.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13.

    Planchard D, Besse B, Groen HJM, et al. Phase 2 study of dabrafenib plus trametinib in patients with BRAF V600E-mutant metastatic NSCLC: updated 5-year survival rates and genomic analysis. J Thorac Oncol 2022;17:103115.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14.

    Faivre-Finn C, Vicente D, Kurata T, et al. Four-year survival with durvalumab after chemoradiotherapy in stage III NSCLC—an update from the PACIFIC trial. J Thorac Oncol 2021;16:860867.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15.

    Borghaei H, Gettinger S, Vokes EE, et al. Five-year outcomes from the randomized, phase III trials CheckMate 017 and 057: nivolumab versus docetaxel in previously treated non-small-cell lung cancer. J Clin Oncol 2021;39:723733.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16.

    Ramalingam SS, Vansteenkiste J, Planchard D, et al. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med 2020;382:4150.

  • 17.

    Garon EB, Hellmann MD, Rizvi NA, et al. Five-year overall survival for patients with advanced non‒small-cell lung cancer treated with pembrolizumab: results from the phase I KEYNOTE-001 study. J Clin Oncol 2019;37:25182527.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18.

    Leighl NB, Hellmann MD, Hui R, et al. Pembrolizumab in patients with advanced non-small-cell lung cancer (KEYNOTE-001): 3-year results from an open-label, phase 1 study. Lancet Respir Med 2019;7:347357.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19.

    Pacheco JM, Gao D, Smith D, et al. Natural history and factors associated with overall survival in stage IV ALK-rearranged non-small cell lung cancer. J Thorac Oncol 2019;14:691700.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20.

    Shaw AT, Riely GJ, Bang YJ, et al. Crizotinib in ROS1-rearranged advanced non-small-cell lung cancer (NSCLC): updated results, including overall survival, from PROFILE 1001. Ann Oncol 2019;30:11211126.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21.

    Lin JJ, Cardarella S, Lydon CA, et al. Five-year survival in EGFR-mutant metastatic lung adenocarcinoma treated with EGFR-TKIs. J Thorac Oncol 2016;11:556565.

  • 22.

    Singhi EK, Horn L, Sequist LV, et al. Advanced non-small cell lung cancer: sequencing agents in the EGFR-mutated/ALK-rearranged populations. Am Soc Clin Oncol Educ Book 2019;39:e187e197.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23.

    Antonia SJ, Borghaei H, Ramalingam SS, et al. Four-year survival with nivolumab in patients with previously treated advanced non-small-cell lung cancer: a pooled analysis. Lancet Oncol 2019;20:13951408.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24.

    Zhao D, Chen X, Qin N, et al. The prognostic role of EGFR-TKIs for patients with advanced non-small cell lung cancer. Sci Rep 2017;7:40374.

  • 25.

    Johung KL, Yeh N, Desai NB, et al. Extended survival and prognostic factors for patients with ALK-rearranged non-small-cell lung cancer and brain metastasis. J Clin Oncol 2016;34:123129.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26.

    Simoff MJ, Lally B, Slade MG, et al. Symptom management in patients with lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013;143:e455Se497S.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27.

    Ettinger DS, Cox JD, Ginsberg RJ, et al. NCCN Non-Small-Cell Lung Cancer Practice Guidelines. Oncology (Williston Park) 1996; 10(11, Suppl)81111.

    • Search Google Scholar
    • Export Citation
  • 28.

    Ettinger DS, Wood DE, Aisner DL, et al. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer (Version 1.2022). To view the most recent and complete version of the NCCN Guidelines®, go online to NCCN.org.

    • Search Google Scholar
    • Export Citation
  • 29.

    Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 2008;26:35433551.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30.

    Masters GA, Temin S, Azzoli CG, et al. Systemic therapy for stage IV non-small-cell lung cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 2015;33:34883515.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 31.

    Le X, Paz-Ares LG, Van Meerbeeck J, et al. Tepotinib in patients (pts) with advanced non-small cell lung cancer (NSCLC) with MET amplification (METamp). J Clin Oncol 2021;39(15_suppl):90219021.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 32.

    Li BT, Smit EF, Goto Y, et al. Trastuzumab deruxtecan in HER2-mutant non-small-cell lung cancer. N Engl J Med 2022;386:241251.

  • 33.

    Li BT, 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;36:25322537.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34.

    Wolf J, Seto T, Han JY, et al. Capmatinib in MET exon 14-mutated or MET-amplified non-small-cell lung cancer. N Engl J Med 2020;383: 944957.

  • 35.

    Tsurutani J, Iwata H, Krop I, et al. Targeting HER2 with trastuzumab deruxtecan: a dose-expansion, phase I study in multiple advanced solid tumors. Cancer Discov 2020;10:688701.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36.

    Smit EF, Nakagawa K, Nagasaka M, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-mutated metastatic non-small cell lung cancer (NSCLC): interim results of DESTINY-Lung01. J Clin Oncol 2020;38(15_suppl):95049504.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 37.

    Ettinger DS, Wood DE, Aisner DL, et al. NCCN Guidelines Insights: Non-Small Cell Lung Cancer, Version 2.2021. J Natl Compr Canc Netw 2021;19:254266.

  • 38.

    Lam VK, Tran HT, Banks KC, et al. Targeted tissue and cell-free tumor DNA sequencing of advanced lung squamous-cell carcinoma reveals clinically significant prevalence of actionable alterations. Clin Lung Cancer 2019;20:3036.e3.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39.

    Sands JM, Nguyen T, Shivdasani P, et al. Next-generation sequencing informs diagnosis and identifies unexpected therapeutic targets in lung squamous cell carcinomas. Lung Cancer 2020;140:3541.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 40.

    Mazieres J, Drilon A, Lusque A, et al. Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry. Ann Oncol 2019;30: 13211328.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 41.

    Sholl LM, Aisner DL, Varella-Garcia M, et al. Multi-institutional oncogenic driver mutation analysis in lung adenocarcinoma: the Lung Cancer Mutation Consortium experience. J Thorac Oncol 2015;10:768777.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42.

    Hanna NH, Robinson AG, Temin S, et al. Therapy for stage IV non-small-cell lung cancer with driver alterations: ASCO and OH (CCO) joint guideline update. J Clin Oncol 2021;39:10401091.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43.

    Hanna NH, Schneider BJ, Temin S, et al. Therapy for stage IV non-small-cell lung cancer without driver alterations: ASCO and OH (CCO) joint guideline update. J Clin Oncol 2020;38:16081632.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 44.

    Kerr KM, Bubendorf L, Edelman MJ, et al. Second ESMO consensus conference on lung cancer: pathology and molecular biomarkers for non-small-cell lung cancer. Ann Oncol 2014;25:16811690.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 45.

    Roberts PJ, Stinchcombe TE. KRAS mutation: should we test for it, and does it matter? J Clin Oncol 2013;31:11121121.

  • 46.

    Jennings LJ, Arcila ME, Corless C, et al. Guidelines for validation of next-generation sequencing-based oncology panels: a joint consensus recommendation of the Association for Molecular Pathology and College of American Pathologists. J Mol Diagn 2017;19:341365.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 47.

    Aziz N, Zhao Q, Bry L, et al. College of American Pathologists’ laboratory standards for next-generation sequencing clinical tests. Arch Pathol Lab Med 2015;139:481493.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 48.

    Luthra R, Chen H, Roy-Chowdhuri S, et al. Next-generation sequencing in clinical molecular diagnostics of cancer: advantages and challenges. Cancers (Basel) 2015;7:20232036.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 49.

    Drilon A, Wang L, Arcila ME, et al. Broad, hybrid capture-based next-generation sequencing identifies actionable genomic alterations in lung adenocarcinomas otherwise negative for such alterations by other genomic testing approaches. Clin Cancer Res 2015;21:36313639.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 50.

    Robson ME, Bradbury AR, Arun B, et al. American Society of Clinical Oncology Policy Statement Update: genetic and genomic testing for cancer susceptibility. J Clin Oncol 2015;33:36603667.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 51.

    Yu PP, Vose JM, Hayes DF. Genetic cancer susceptibility testing: increased technology, increased complexity. J Clin Oncol 2015;33:35333534.

  • 52.

    Cardarella S, Ortiz TM, Joshi VA, et al. The introduction of systematic genomic testing for patients with non-small-cell lung cancer. J Thorac Oncol 2012;7:17671774.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 53.

    Li T, Kung HJ, Mack PC, et al. Genotyping and genomic profiling of non-small-cell lung cancer: implications for current and future therapies. J Clin Oncol 2013;31:10391049.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 54.

    Planchard D. Identification of driver mutations in lung cancer: first step in personalized cancer. Target Oncol 2013;8:314.

  • 55.

    Li MM, Datto M, Duncavage EJ, et al. Standards and guidelines for the interpretation and reporting of sequence variants in cancer: a joint consensus recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists. J Mol Diagn 2017;19:423.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 56.

    Plon SE, Eccles DM, Easton D, et al. Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results. Hum Mutat 2008;29:12821291.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 57.

    Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17:405424.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 58.

    Besse B, Adjei A, Baas P, et al. 2nd ESMO Consensus Conference on Lung Cancer: non-small-cell lung cancer first-line/second and further lines of treatment in advanced disease. Ann Oncol 2014;25:14751484.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 59.

    Sandler AB, Johnson DH, Herbst RS. Anti-vascular endothelial growth factor monoclonals in non-small cell lung cancer. Clin Cancer Res 2004;10:4258s4262s.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 60.

    Giaccone G. Epidermal growth factor receptor inhibitors in the treatment of non-small-cell lung cancer. J Clin Oncol 2005;23:32353242.

  • 61.

    Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 2012;13:239246.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 62.

    Lin JJ, Kennedy E, Sequist LV, et al. Clinical activity of alectinib in advanced RET-rearranged non-small cell lung cancer. J Thorac Oncol 2016;11:20272032.

  • 63.

    Sabari JK, Santini FC, Schram AM, et al. The activity, safety, and evolving role of brigatinib in patients with ALK-rearranged non-small cell lung cancers. OncoTargets Ther 2017;10:19831992.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 64.

    Solomon BJ, Besse B, Bauer TM, et al. Lorlatinib in patients with ALK-positive non-small-cell lung cancer: results from a global phase 2 study. Lancet Oncol 2018;19:16541667.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 65.

    Besse B, Solomon BJ, Felip E, et al. Lorlatinib in patients (Pts) with previously treated ALK+ advanced non-small cell lung cancer (NSCLC): Updated efficacy and safety. [abstract] J Clin Oncol 2018; 36(15_suppl)9032. (Abstract 9032)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 66.

    Doebele RC, Paz-Ares L, Farago AF, et al. Entrectinib in NTRK fusion-positive non-small cell lung cancer (NSCLC): integrated analysis of patients enrolled in three trials (STARTRK-2, STARTRK-1 and ALKA-372-001) [abstract]. AACR Annual Meeting. Atlanta, GA:Abstract CT131. Available at: https://cancerres.aacrjournals.org/content/79/13_Supplement/CT131

    • Search Google Scholar
    • Export Citation
  • 67.

    Shaw AT, Solomon BJ, Besse B, et al. ALK resistance mutations and efficacy of lorlatinib in advanced anaplastic lymphoma kinase-positive non-small-cell lung cancer. J Clin Oncol 2019;37:13701379.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 68.

    Planchard D, Besse B, Groen HJM, et al. Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial. Lancet Oncol 2016;17:984993.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 69.

    Gautschi O, Milia J, Cabarrou B, et al. Targeted therapy for patients with BRAF-mutant lung cancer: results from the European EURAF Cohort. J Thorac Oncol 2015;10:14511457.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 70.

    Doebele RC, Drilon A, Paz-Ares L, et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials. Lancet Oncol 2020;21:271282.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 71.

    Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med 2018;378:731739.

  • 72.

    Lassen U, Albert CM, Kummar S, et al. Larotrectinib efficacy and safety in TRK fusion cancer: an expanded clinical dataset showing consistency in an age and tumor agnostic approach [abstract]. Presented at the ESMO Congress; October 19-23; Munich, Germany. Abstract 409O.

    • Search Google Scholar
    • Export Citation
  • 73.

    Paik PK, Felip E, Veillon R, et al. Tepotinib in non-small-cell lung cancer with MET exon 14 skipping mutations. N Engl J Med 2020;383:931943.

  • 74.

    Wolf J, Setons T, Han J-Y, et al. Capmatinib (INC280) in METΔex14-mutated advanced non-small cell lung cancer (NSCLC): efficacy data from the phase II GEOMETRY mono-1 study [abstract]. J Clin Oncol 2019;37(15_suppl):9004. (Abstract 9004)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 75.

    Gainor JF, Curigliano G, Kim DW, et al. Pralsetinib for RET fusion-positive non-small-cell lung cancer (ARROW): a multi-cohort, open-label, phase 1/2 study. Lancet Oncol 2021;22:959969.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 76.

    Drilon A, Oxnard GR, Tan DSW, et al. Efficacy of selpercatinib in RET fusion-positive non-small-cell lung cancer. N Engl J Med 2020;383:813824.

  • 77.

    Drilon A, Rekhtman N, Arcila M, et al. Cabozantinib in patients with advanced RET-rearranged non-small-cell lung cancer: an open-label, single-centre, phase 2, single-arm trial. Lancet Oncol 2016;17: 16531660.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 78.

    Drilon A, Wang L, Hasanovic A, et al. Response to cabozantinib in patients with RET fusion-positive lung adenocarcinomas. Cancer Discov 2013;3:630635.

  • 79.

    Riely GJ, Kris MG, Zhao B, et al. Prospective assessment of discontinuation and reinitiation of erlotinib or gefitinib in patients with acquired resistance to erlotinib or gefitinib followed by the addition of everolimus. Clin Cancer Res 2007;13:51505155.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 80.

    Kuriyama Y, Kim YH, Nagai H, et al. Disease flare after discontinuation of crizotinib in anaplastic lymphoma kinase-positive lung cancer. Case Rep Oncol 2013;6:430433.

  • 81.

    Chaft JE, Oxnard GR, Sima CS, et al. Disease flare after tyrosine kinase inhibitor discontinuation in patients with EGFR-mutant lung cancer and acquired resistance to erlotinib or gefitinib: implications for clinical trial design. Clin Cancer Res 2011;17:62986303.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 82.

    Pop O, Pirvu A, Toffart AC, et al. Disease flare after treatment discontinuation in a patient with EML4-ALK lung cancer and acquired resistance to crizotinib. J Thorac Oncol 2012;7:e1e2.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 83.

    Lisberg A, Cummings A, Goldman JW, et al. A phase II study of pembrolizumab in EGFR-mutant, PD-L1+, tyrosine kinase inhibitor naïve patients with advanced NSCLC. J Thorac Oncol 2018;13:11381145.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 84.

    Gainor JF, Shaw AT, Sequist LV, et al. EGFR mutations and ALK rearrangements are associated with low response rates to PD-1 pathway blockade in non-small cell lung cancer: a retrospective analysis. Clin Cancer Res 2016;22:45854593.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 85.

    Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med 2018;378:113125.

  • 86.

    Camidge DR, Dziadziuszko R, Peters S, et al. Updated efficacy and safety data and impact of the EML4-ALK fusion variant on the efficacy of alectinib in untreated ALK-positive advanced non-small cell lung cancer in the global phase III ALEX study. J Thorac Oncol 2019;14:12331243.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 87.

    Peters S, Camidge DR, Shaw AT, et al. Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. N Engl J Med 2017;377:829838.

  • 88.

    Hida T, Nokihara H, Kondo M, et al. Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial. Lancet 2017;390:2939.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 89.

    Larkins E, Blumenthal GM, Chen H, et al. FDA approval: alectinib for the treatment of metastatic, ALK-positive non-small cell lung cancer following crizotinib. Clin Cancer Res 2016;22:51715176.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 90.

    Shaw AT, Gandhi L, Gadgeel S, et al. Alectinib in ALK-positive, crizotinib-resistant, non-small-cell lung cancer: a single-group, multicentre, phase 2 trial. Lancet Oncol 2016;17:234242.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 91.

    Ou SH, Ahn JS, De Petris L, et al. Alectinib in crizotinib-refractory ALK-rearranged non-small-cell lung cancer: a phase II global study. J Clin Oncol 2016;34:661668.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 92.

    Camidge DR, Kim HR, Ahn MJ, et al. Brigatinib versus crizotinib in ALK-positive non-small-cell lung cancer. N Engl J Med 2018;379:20272039.

  • 93.

    Camidge DR, Kim HR, Ahn MJ, et al. Brigatinib versus crizotinib in advanced ALK inhibitor-naive ALK-positive non-small cell lung cancer: second interim analysis of the phase III ALTA-1L trial. J Clin Oncol 2020;38:35923603.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 94.

    Kim DW, Tiseo M, Ahn MJ, et al. Brigatinib in patients with crizotinib-refractory anaplastic lymphoma kinase-positive non-small-cell lung cancer: a randomized, multicenter phase II trial. J Clin Oncol 2017;35:24902498.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 95.

    Camidge DR, Tiseo M, Ahn M-J, et al. P3.02a-013 Brigatinib in crizotinib-refractory ALK+ NSCLC: central assessment and updates from ALTA, a pivotal randomized phase 2 trial [abstract]. J Thorac Oncol 2017;12:S1167S1169.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 96.

    Lim SM, Kim HR, Lee JS, et al. Open-label, multicenter, phase II study of ceritinib in patients with non-small-cell lung cancer harboring ROS1 rearrangement. J Clin Oncol 2017;35:26132618.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 97.

    Soria JC, Tan DSW, Chiari R, et al. First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study. Lancet 2017;389:917929.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 98.

    Shaw AT, Kim TM, Crinò L, et al. Ceritinib versus chemotherapy in patients with ALK-rearranged non-small-cell lung cancer previously given chemotherapy and crizotinib (ASCEND-5): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol 2017;18: 874886.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 99.

    Crinò L, Ahn MJ, De Marinis F, et al. Multicenter phase II study of whole-body and intracranial activity with ceritinib in patients with ALK-rearranged non-small-cell lung cancer previously treated with chemotherapy and crizotinib: results from ASCEND-2. J Clin Oncol 2016;34:28662873.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 100.

    Kazandjian D, Blumenthal GM, Chen HY, et al. FDA approval summary: crizotinib for the treatment of metastatic non-small cell lung cancer with anaplastic lymphoma kinase rearrangements. Oncologist 2014;19:e5e11.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 101.

    Awad MM, Oxnard GR, Jackman DM, et al. MET exon 14 mutations in non-small-cell lung cancer are associated with advanced age and stage-dependent MET genomic amplification and c-Met overexpression. J Clin Oncol 2016;34:721730.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 102.

    Mazières J, Zalcman G, Crinò L, et al. Crizotinib therapy for advanced lung adenocarcinoma and a ROS1 rearrangement: results from the EUROS1 cohort. J Clin Oncol 2015;33:992999.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 103.

    Solomon BJ, Mok T, Kim DW, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med 2014;371:21672177.

  • 104.

    Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 2013;368:23852394.

  • 105.

    Crino L, Kim D, Riely GJ, et al. Initial phase II results with crizotinib in advanced ALK-positive non-small cell lung cancer (NSCLC): PROFILE 1005 [abstract]. J Clin Oncol 2011;29 (Suppl 15):7514.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 106.

    Camidge DR, Bang Y, Kwak EL, et al. Progression-free survival (PFS) from a phase I study of crizotinib (PF-02341066) in patients with ALK-positive non-small cell lung cancer (NSCLC) [abstract]. J Clin Oncol 2011;29(Suppl 15): 2501.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 107.

    Rodig SJ, Shapiro GI. Crizotinib, a small-molecule dual inhibitor of the c-Met and ALK receptor tyrosine kinases. Curr Opin Investig Drugs 2010;11:14771490.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 108.

    Frampton JE. Crizotinib: a review of its use in the treatment of anaplastic lymphoma kinase-positive, advanced non-small cell lung cancer. Drugs 2013;73:20312051.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 109.

    Costa DB, Shaw AT, Ou SH, et al. Clinical experience with crizotinib in patients with advanced ALK-rearranged non-small-cell lung cancer and brain metastases. J Clin Oncol 2015;33:18811888.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 110.

    Camidge DR, Bang YJ, Kwak EL, et al. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. Lancet Oncol 2012;13:10111019.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 111.

    Shaw AT, Yeap BY, Solomon BJ, et al. Impact of crizotinib on survival in patients with advanced, ALK-positive NSCLC compared with historical controls [abstract]. J Clin Oncol 2011;29(Suppl 15):75077507.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 112.

    Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 2010;363:16931703.

  • 113.

    Bang YJ. Treatment of ALK-positive non-small cell lung cancer. Arch Pathol Lab Med 2012;136:12011204.

  • 114.

    Choi YL, Soda M, Yamashita Y, et al. EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors. N Engl J Med 2010;363:17341739.

  • 115.

    Rothenstein JM, Letarte N. Managing treatment-related adverse events associated with Alk inhibitors. Curr Oncol 2014;21:1926.

  • 116.

    Brosnan EM, Weickhardt AJ, Lu X, et al. Drug-induced reduction in estimated glomerular filtration rate in patients with ALK-positive non-small cell lung cancer treated with the ALK inhibitor crizotinib. Cancer 2014;120:664674.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 117.

    Shaw AT, Bauer TM, de Marinis F, et al. First-line lorlatinib or crizotinib in advanced ALK-positive lung cancer. N Engl J Med 2020;383:20182029.

  • 118.

    Planchard D, Smit EF, Groen HJM, et al. Dabrafenib plus trametinib in patients with previously untreated BRAFV600E-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial. Lancet Oncol 2017;18:13071316.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 119.

    Planchard D, Besse B, Kim TM. Updated survival of patients (pts) with previously treated BRAF V600E-mutant advanced non-small cell lung cancer (NSCLC) who received dabrafenib (D) or D + trametinib (T) in the phase II BRF113928 study [abstract]. J Clin Oncol 2017;35(15_suppl):9705.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 120.

    Planchard D, Groen HJM, Kim TM, et al. Interim results of a phase II study of the BRAF inhibitor (BRAFi) dabrafenib (D) in combination with the MEK inhibitor trametinib (T) in patients (pts) with BRAF V600E mutated (mut) metastatic non-small cell lung cancer (NSCLC) [abstract]. J Clin Oncol 2015;33(15_suppl):8006.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 121.

    Odogwu L, Mathieu L, Blumenthal G, et al. FDA approval summary: dabrafenib and trametinib for the treatment of metastatic non-small cell lung cancers harboring BRAF V600E mutations. Oncologist 2018;23:740745.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 122.

    Planchard D, Kim TM, Mazieres J, et al. Dabrafenib in patients with BRAF(V600E)-positive advanced non-small-cell lung cancer: a single-arm, multicentre, open-label, phase 2 trial. Lancet Oncol 2016;17:642650.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 123.

    Chalmers A, Cannon L, Akerley W. Adverse event management in patients with BRAF V600E-mutant non-small cell lung cancer treated with dabrafenib plus trametinib. Oncologist 2019;24:963972.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 124.

    Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;361:947957.

  • 125.

    Nelson V, Ziehr J, Agulnik M, et al. Afatinib: emerging next-generation tyrosine kinase inhibitor for NSCLC. OncoTargets Ther 2013;6:135143.

    • Search Google Scholar
    • Export Citation
  • 126.

    De Grève J, Teugels E, Geers C, et al. Clinical activity of afatinib (BIBW 2992) in patients with lung adenocarcinoma with mutations in the kinase domain of HER2/neu. Lung Cancer 2012;76:123127.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 127.

    Sequist LV, Yang JC, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 2013;31:33273334.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 128.

    FDA approves afatinib for advanced lung cancer. Oncology (Williston Park) 2013;27:813814.

  • 129.

    Dungo RT, Keating GM. Afatinib: first global approval. Drugs 2013;73:15031515.

  • 130.

    West H, Oxnard GR, Doebele RC. Acquired resistance to targeted therapies in advanced non-small cell lung cancer: new strategies and new agents. Am Soc Clin Oncol Educ Book 2013;33:272278.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 131.

    Langer CJ. Epidermal growth factor receptor inhibition in mutation-positive non-small-cell lung cancer: is afatinib better or simply newer? J Clin Oncol 2013;31:33033306.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 132.

    Soria JC, Felip E, Cobo M, et al. Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial. Lancet Oncol 2015;16:897907.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 133.

    Yang JC, Sequist LV, Geater SL, 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, LUX-Lung 3, and LUX-Lung 6. Lancet Oncol 2015;16:830838.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 134.

    Park K, Tan EH, O’Byrne K, et al. Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial. Lancet Oncol 2016;17:577589.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 135.

    Paz-Ares L, Tan EH, O’Byrne K, et al. Afatinib versus gefitinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: overall survival data from the phase IIb LUX-Lung 7 trial. Ann Oncol 2017;28:270277.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 136.

    Urata Y, Katakami N, Morita S, et al. Randomized phase III study comparing gefitinib with erlotinib in patients with previously treated advanced lung adenocarcinoma: WJOG 5108L. J Clin Oncol 2016;34:32483257.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 137.

    Burotto M, Manasanch EE, Wilkerson J, et al. Gefitinib and erlotinib in metastatic non-small cell lung cancer: a meta-analysis of toxicity and efficacy of randomized clinical trials. Oncologist 2015;20:400410.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 138.

    Haspinger ER, Agustoni F, Torri V, et al. Is there evidence for different effects among EGFR-TKIs? Systematic review and meta-analysis of EGFR tyrosine kinase inhibitors (TKIs) versus chemotherapy as first-line treatment for patients harboring EGFR mutations. Crit Rev Oncol Hematol 2015;94:213227.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 139.

    Fukuoka M, Wu YL, Thongprasert S, et al. Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol 2011;29:28662874.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 140.

    Khozin S, Blumenthal GM, Jiang X, et al. U.S. Food and Drug Administration approval summary: Erlotinib for the first-line treatment of metastatic non-small cell lung cancer with epidermal growth factor receptor exon 19 deletions or exon 21 (L858R) substitution mutations. Oncologist 2014;19:774779.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 141.

    Kazandjian D, Blumenthal GM, Yuan W, et al. FDA Approval of gefitinib for the treatment of patients with metastatic EGFR mutation-positive non-small cell lung cancer. Clin Cancer Res 2016;22:13071312.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 142.

    Douillard JY, Ostoros G, Cobo M, et al. First-line gefitinib in Caucasian EGFR mutation-positive NSCLC patients: a phase-IV, open-label, single-arm study. Br J Cancer 2014;110:5562.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 143.

    Jänne PA, Wang X, Socinski MA, et al. Randomized phase II trial of erlotinib alone or with carboplatin and paclitaxel in patients who were never or light former smokers with advanced lung adenocarcinoma: CALGB 30406 trial. J Clin Oncol 2012;30:20632069.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 144.

    Jackman DM, Miller VA, Cioffredi LA, et al. Impact of epidermal growth factor receptor and KRAS mutations on clinical outcomes in previously untreated non-small cell lung cancer patients: results of an online tumor registry of clinical trials. Clin Cancer Res 2009;15:52675273.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 145.

    Gridelli C, Ciardiello F, Gallo C, et al. First-line erlotinib followed by second-line cisplatin-gemcitabine chemotherapy in advanced non-small-cell lung cancer: the TORCH randomized trial. J Clin Oncol 2012;30:30023011.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 146.

    Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 2011;12:735742.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 147.

    Zhou C, Wu YL, Chen G, et al. Updated efficacy and quality-of-life (QoL) analyses in OPTIMAL, a phase III, randomized, open-label study of first-line erlotinib versus gemcitabine/carboplatin in patients with EGFR-activating mutation-positive (EGFR Act Mut+) advanced non-small cell lung cancer (NSCLC) [abstract]. J Clin Oncol 2011;29(Suppl 15): 75207520.

    • Search Google Scholar
    • Export Citation
  • 148.

    Nakagawa K, Garon EB, Seto T, et al. Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2019;20:16551669.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 149.

    Kawashima Y, Fukuhara T, Saito H, et al. Bevacizumab plus erlotinib versus erlotinib alone in Japanese patients with advanced, metastatic, EGFR-mutant non-small-cell lung cancer (NEJ026): overall survival analysis of an open-label, randomised, multicentre, phase 3 trial. Lancet Respir Med 2022;10:7282.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 150.

    Saito H, Fukuhara T, Furuya N, et al. Erlotinib plus bevacizumab versus erlotinib alone in patients with EGFR-positive advanced non-squamous non-small-cell lung cancer (NEJ026): interim analysis of an open-label, randomised, multicentre, phase 3 trial. Lancet Oncol 2019;20:625635.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 151.

    Eberhard DA, Johnson BE, Amler LC, et al. Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J Clin Oncol 2005;23:59005909.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 152.

    Sequist LV, Joshi VA, Jänne PA, et al. Response to treatment and survival of patients with non-small cell lung cancer undergoing somatic EGFR mutation testing. Oncologist 2007;12:9098.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 153.

    Inoue A, Kobayashi K, Usui K, et al. First-line gefitinib for patients with advanced non-small-cell lung cancer harboring epidermal growth factor receptor mutations without indication for chemotherapy. J Clin Oncol 2009;27:13941400.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 154.

    Thatcher N, Goldschmidt JH, Thomas M, et al. Efficacy and safety of the biosimilar ABP 215 compared with bevacizumab in patients with advanced nonsquamous non-small cell lung cancer (MAPLE): a randomized, double-blind, phase III study. Clin Cancer Res 2019;25:20882095.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 155.

    Reinmuth N, Bryl M, Bondarenko I, et al. PF-06439535 (a bevacizumab biosimilar) compared with reference bevacizumab (Avastin®), both plus paclitaxel and carboplatin, as first-line treatment for advanced non-squamous non-small-cell lung cancer: a randomized, double-blind study. BioDrugs 2019;33:555570.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 156.

    Melosky B, Reardon DA, Nixon AB, et al. Bevacizumab biosimilars: scientific justification for extrapolation of indications. Future Oncol 2018;14:25072520.

  • 157.

    Weise M, Kurki P, Wolff-Holz E, et al. Biosimilars: the science of extrapolation. Blood 2014;124:31913196.

  • 158.

    Weise M, Bielsky MC, De Smet K, et al. Biosimilars: what clinicians should know. Blood 2012;120:51115117.

  • 159.

    Mok TS, Cheng Y, Zhou X, et al. Improvement in overall survival in a randomized study that compared dacomitinib with gefitinib in patients with advanced non-small-cell lung cancer and EGFR-activating mutations. J Clin Oncol 2018;36:22442250.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 160.

    Wu YL, Cheng Y, Zhou X, et al. Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial. Lancet Oncol 2017;18:14541466.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 161.

    Mok TS, Cheng Y, Zhou X, et al. Updated overall survival in a randomized study comparing dacomitinib with gefitinib as first-line treatment in patients with advanced non-small-cell lung cancer and EGFR-activating mutations. Drugs 2021;81:257266.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 162.

    Ricciuti B, Chiari R, Chiarini P, et al. Osimertinib (AZD9291) and CNS response in two radiotherapy-naïve patients with EGFR-mutant and T790M-positive advanced non-small cell lung cancer. Clin Drug Investig 2016;36:683686.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 163.

    Riely GJ, Yu HA. EGFR: the paradigm of an oncogene-driven lung cancer. Clin Cancer Res 2015;21:22212226.

  • 164.

    Yu HA, Arcila ME, Rekhtman N, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res 2013;19:22402247.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 165.

    Finlay MR, Anderton M, Ashton S, et al. Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistance mutations that spares the wild type form of the receptor. J Med Chem 2014;57:82498267.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 166.

    Gainor JF, Shaw AT. Emerging paradigms in the development of resistance to tyrosine kinase inhibitors in lung cancer. J Clin Oncol 2013;31:39873996.

  • 167.

    Pao W, Miller VA, Politi KA, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2005;2:e73.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 168.

    Kosaka T, Yatabe Y, Endoh H, et al. Analysis of epidermal growth factor receptor gene mutation in patients with non-small cell lung cancer and acquired resistance to gefitinib. Clin Cancer Res 2006;12:57645769.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 169.

    Onitsuka T, Uramoto H, Nose N, et al. Acquired resistance to gefitinib: the contribution of mechanisms other than the T790M, MET, and HGF status. Lung Cancer 2010;68:198203.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 170.

    Mok TS, Wu YL, Ahn MJ, et al. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med 2017;376:629640.

  • 171.

    Ramalingam SS, Reungwetwattana T, Chewaskulyong B, et al. Osimertinib versus standard-of-care EGFR-TKI as first-line treatment in patients with EGFRm advanced NSCLC: FLAURA [abstract] [abstract]. Presented at the ESMO Congress; Madrid. Abstract LBA2_PR.

    • Search Google Scholar
    • Export Citation
  • 172.

    Ramalingam SS, Yang JC, Lee CK, et al. Osimertinib as first-line treatment of EGFR mutation-positive advanced non-small-cell lung cancer. J Clin Oncol 2018;36:841849.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 173.

    Schoenfeld AJ, Arbour KC, Rizvi H, et al. Severe immune-related adverse events are common with sequential PD-(L)1 blockade and osimertinib. Ann Oncol 2019;30:839844.

  • 174.

    Oshima Y, Tanimoto T, Yuji K, et al. EGFR-TKI-associated interstitial pneumonitis in nivolumab-treated patients with non-small cell lung cancer. JAMA Oncol 2018;4:11121115.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 175.

    Wu YL, Tsuboi M, He J, et al. Osimertinib in resected EGFR-mutated non-small-cell lung cancer. N Engl J Med 2020;383:17111723.

  • 176.

    Cho JH, Lim SH, An HJ, et al. Osimertinib for patients with non-small-cell lung cancer harboring uncommon EGFR mutations: a multicenter, open-label, phase II trial (KCSG-LU15-09). J Clin Oncol 2020;38:488495.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 177.

    Merker JD, Oxnard GR, Compton C, et al. Circulating tumor DNA analysis in patients wth cancer: American Society of Clinical Oncology and College of American Pathologists Joint Review. J Clin Oncol 2018;36:16311641.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 178.

    Oxnard GR, Thress KS, Alden RS, et al. Association between plasma genotyping and outcomes of treatment with osimertinib (AZD9291) in advanced non-small-cell lung cancer. J Clin Oncol 2016;34:33753382.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 179.

    Sacher AG, Paweletz C, Dahlberg SE, et al. Prospective validation of rapid plasma genotyping for the detection of EGFR and KRAS mutations in advanced lung cancer. JAMA Oncol 2016;2:10141022.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 180.

    Hochmair MJ, Holzer S, Filipits M, et al. EGFR T790M resistance mutation in NSCLC: real-life data of patients treated with osimertinib [abstract]. J Clin Oncol 2016;34(15_suppl):e20572.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 181.

    Reichegger H, Jochum W, Förbs D, et al. Rapid intracranial response to osimertinib in a patient with epidermal growth factor receptor T790M-positive adenocarcinoma of the lung. Oncol Res Treat 2016;39:461463.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 182.

    Ballard P, Yates JW, Yang Z, et al. Preclinical comparison of osimertinib with other EGFR-TKIs in EGFR-mutant NSCLC brain metastases models, and early evidence of clinical brain metastases activity. Clin Cancer Res 2016;22:51305140.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 183.

    Yang JC-H, Cho BC, Kim D-W, et al. Osimertinib for patients (pts) with leptomeningeal metastases (LM) from EGFR-mutant non-small cell lung cancer (NSCLC): updated results from the BLOOM study [abstract]. J Clin Oncol 2017;35(15_suppl):2020.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 184.

    Otsuka T, Mori M, Yano Y, et al. Effectiveness of tyrosine kinase inhibitors in Japanese patients with non-small cell lung cancer harboring minor epidermal growth factor receptor mutations: results from a multicenter retrospective study (HANSHIN Oncology Group 0212). Anticancer Res 2015;35:38853891.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 185.

    Tu HY, Ke EE, Yang JJ, et al. A comprehensive review of uncommon EGFR mutations in patients with non-small cell lung cancer. Lung Cancer 2017;114:96102.

  • 186.

    Riely GJ, Politi KA, Miller VA, et al. Update on epidermal growth factor receptor mutations in non-small cell lung cancer. Clin Cancer Res 2006;12:72327241.

  • 187.

    O’Kane GM, Bradbury PA, Feld R, et al. Uncommon EGFR mutations in advanced non-small cell lung cancer. Lung Cancer 2017;109:137144.

  • 188.

    Vasconcelos P, Gergis C, Viray H, et al. EGFR-A763_Y764insFQEA is a unique exon 20 insertion mutation that displays sensitivity to approved and in-development lung cancer EGFR tyrosine kinase inhibitors. JTO Clin Res Rep 2020;1:16.

    • Search Google Scholar
    • Export Citation
  • 189.

    Chelabi S, Mignard X, Leroy K, et al. EGFR exon 20 insertion in metastatic non-small-cell lung cancer: survival and clinical efficacy of EGFR tyrosine-kinase inhibitor and chemotherapy. Cancers (Basel) 2021;13:13.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 190.

    Naidoo J, Sima CS, Rodriguez K, et al. Epidermal growth factor receptor exon 20 insertions in advanced lung adenocarcinomas: clinical outcomes and response to erlotinib. Cancer 2015;121:32123220.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 191.

    Zhou C, Ramalingam SS, Kim TM, 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.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 192.

    Ou S-HI, Lin HM, Hong J-L, et al. Real-world response and outcomes in NSCLC patients with EGFR exon 20 insertion mutations. J Clin Oncol 2021;39(15_suppl):90989098.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 193.

    Park K, Haura EB, Leighl NB, 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;39:33913402.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 194.

    Riely GJ, Neal JW, Camidge DR, 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 I/II trial. Cancer Discov 2021;11:16881699.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 195.

    Janjigian YY, Smit EF, Groen HJ, et al. Dual inhibition of EGFR with afatinib and cetuximab in kinase inhibitor-resistant EGFR-mutant lung cancer with and without T790M mutations. Cancer Discov 2014;4:10361045.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 196.

    Pirker R, Pereira JR, Szczesna A, et al. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet 2009;373:15251531.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 197.

    Socinski MA, Evans T, Gettinger S, et al. Treatment of stage IV non-small cell lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013;143:e341Se368S.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 198.

    Kreuter M, Vansteenkiste J, Fischer JR, et al. Randomized phase 2 trial on refinement of early-stage NSCLC adjuvant chemotherapy with cisplatin and pemetrexed versus cisplatin and vinorelbine: the TREAT study. Ann Oncol 2013;24:986992.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 199.

    Sequist LV, Heist RS, Shaw AT, et al. Implementing multiplexed genotyping of non-small-cell lung cancers into routine clinical practice. Ann Oncol 2011;22:26162624.

  • 200.

    Miller VA, Riely GJ, Zakowski MF, et al. Molecular characteristics of bronchioloalveolar carcinoma and adenocarcinoma, bronchioloalveolar carcinoma subtype, predict response to erlotinib. J Clin Oncol 2008;26:14721478.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 201.

    Tsao MS, Aviel-Ronen S, Ding K, et al. Prognostic and predictive importance of p53 and RAS for adjuvant chemotherapy in non small-cell lung cancer. J Clin Oncol 2007;25:52405247.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 202.

    Slebos RJ, Hruban RH, Dalesio O, et al. Relationship between K-ras oncogene activation and smoking in adenocarcinoma of the human lung. J Natl Cancer Inst 1991;83:10241027.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 203.

    Skoulidis F, Goldberg ME, Greenawalt DM, et al. STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma. Cancer Discov 2018;8:822835.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 204.

    Skoulidis F, Li BT, Dy GK, et al. Sotorasib for lung cancers with KRAS p.G12C mutation. N Engl J Med 2021;384:23712381.

  • 205.

    Frampton GM, Ali SM, Rosenzweig M, et al. Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors. Cancer Discov 2015;5:850859.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 206.

    Paik PK, Drilon A, Fan PD, et al. Response to MET inhibitors in patients with stage IV lung adenocarcinomas harboring MET mutations causing exon 14 skipping. Cancer Discov 2015;5:842849.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 207.

    Drilon A, Clark JW, Weiss J, et al. Antitumor activity of crizotinib in lung cancers harboring a MET exon 14 alteration. Nat Med 2020;26:4751.

  • 208.

    Garon EB, Heist RS, Seto T, et al. CT082 - Capmatinib in METex14-mutated (mut) advanced non-small cell lung cancer (NSCLC): Results from the phase II GEOMETRY mono-1 study, including efficacy in patients (pts) with brain metastases (BM) [abstract]. Presented at the ACCR Annual Meeting 2020 (virtual). Abstract CT082.

    • Search Google Scholar
    • Export Citation
  • 209.

    Schuler MH, Berardi R, Lim W-T, et al. Phase (Ph) I study of the safety and efficacy of the cMET inhibitor capmatinib (INC280) in patients (pts) with advanced cMET+ non-small cell lung cancer (NSCLC). J Clin Oncol 2016;34(15_suppl):90679067.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 210.

    Ou SH, Kwak EL, Siwak-Tapp C, et al. Activity of crizotinib (PF02341066), a dual mesenchymal-epithelial transition (MET) and anaplastic lymphoma kinase (ALK) inhibitor, in a non-small cell lung cancer patient with de novo MET amplification. J Thorac Oncol 2011;6:942946.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 211.

    Camidge DR, Ou S-HI, Shapiro G, et al. Efficacy and safety of crizotinib in patients with advanced c-MET-amplified non-small cell lung cancer (NSCLC) [abstract]. J Clin Oncol 2014;32(Suppl 5):80018001.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 212.

    Drilon A, Barlesi F, De Braud F, et al. Entrectinib in locally advanced or metastatic ROS1 fusion positive non-small cell lung cancer (NSCLC): integrated analysis of STARTRK-2, STARTRK-1, and ALKA-372-001 [abstract]. Cancer Res 2019 79:CT192.

    • Search Google Scholar
    • Export Citation
  • 213.

    Doebele RC, Ahn M-J, Siena S, et al. OA02.01: Efficacy and safety of entrectinib in locally advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC) [abstract]. J Thorac Oncol 2018;13:S321S322.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 214.

    Gautschi O, Milia J, Filleron T, et al. Targeting RET in patients with RET-rearranged lung cancers: results from the global, multicenter RET registry. J Clin Oncol 2017;35:14031410.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 215.

    Ferrara R, Auger N, Auclin E, et al. Clinical and translational implications of RET rearrangements in non-small cell lung cancer. J Thorac Oncol 2018;13:2745.

  • 216.

    Michels S, Scheel AH, Scheffler M, et al. Clinicopathological characteristics of RET rearranged lung cancer in European patients. J Thorac Oncol 2016;11:122127.

  • 217.

    Takeuchi K, Soda M, Togashi Y, et al. RET, ROS1 and ALK fusions in lung cancer. Nat Med 2012;18:378381.

  • 218.

    Tsuta K,