Overall survival in stage IV EGFR mutation‑positive NSCLC: Comparing first‑, second‑ and third‑generation EGFR‑TKIs (Review)

Vaid,Ashok  K.; Gupta,Alok; Momi,Gagandeep

doi:10.3892/ijo.2021.5168

February-2021 Volume 58 Issue 2

Full Size Image

Cover Legend PDF

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

An International Open Access Journal Devoted to General Medicine.

February-2021 Volume 58 Issue 2

Full Size Image

Cover Legend PDF

Review

Overall survival in stage IV EGFR mutation‑positive NSCLC: Comparing first‑, second‑ and third‑generation EGFR‑TKIs (Review)

Authors:
- Ashok K. Vaid
- Alok Gupta
- Gagandeep Momi
View Affiliations / Copyright

Affiliations: Department of Medical Oncology, Medanta Cancer Institute, Gurugram, Haryana 122001, India, Department of Medical Oncology, Medanta Cancer Institute, Lucknow, Uttar Pradesh 226030, India, Department of Medical Affairs, Oncology, AstraZeneca Pharma India Ltd., Bangalore, Karnataka 560045, India
Pages: 171-184
|
Published online on: January 7, 2021

https://doi.org/10.3892/ijo.2021.5168
Expand metrics +

Abstract

A substantial (40‑60%) proportion of patients with non‑small cell lung carcinoma (NSCLC) have epidermal growth factor receptor (EGFR) mutations, a crucial therapeutic target in NSCLC. Treatment strategies for patients with advanced‑stage NSCLC have markedly changed, from the empirical use of cytotoxic agents to targeted regimens. EGFR tyrosine kinase inhibitors (TKIs), the first‑line therapy for advanced NSCLC, are reported to be the most effective. Although progression‑free survival (PFS) and objective response rates have long been used as endpoints, meeting these endpoints may not necessarily coincide with an increase in overall survival (OS) among patients with advanced lung cancer. Recently, the FLAURA study with the third‑generation, irreversible, oral EGFR‑TKI, osimertinib, demonstrated an extended median OS by 6.8 months compared with standard EGFR‑TKIs, with a 20% reduction in the risk of mortality [osimertinib, 38.6; EGFR‑TKIs, 31.8; hazard ratio (HR), 0.80; 95% confidence interval (CI), 0.641‑0.997; P=0.046]; this was in addition to meeting the primary endpoint of clinically and statistically significant PFS. Osimertinib was also shown to lead to a statistically significant reduction in the risk of central nervous system disease progression (HR, 0.48; 95% CI, 0.26‑0.86; P=0.014). Notably, 28% of patients remained on osimertinib treatment for 3 years, considerably longer than those in the comparator group (9%). The duration of first subsequent treatment with osimertinib was 25.5 months compared with 13.7 months with standard EGFR‑TKIs (HR, 0.478; 95% CI, 0.393‑0.581; P<0.0001). Thus, the long‑term OS benefit with first‑line osimertinib highlights a promising option in the management of stage IV NSCLC. The present narrative review compares the OS benefit of first‑, second‑ and third‑generation EGFR‑TKIs for patients with stage IV EGFR mutation‑positive NSCLC and discusses their role in disease management.

View Figures

View References

1	Zhang YL, Yuan JQ, Wang KF, Fu XH, Han XR, Threapleton D, Yang ZY, Mao C and Tang JL: The prevalence of EGFR mutation in patients with non-small cell lung cancer: A systematic review and meta-analysis. Oncotarget. 7:78985–78993. 2016. View Article : Google Scholar : PubMed/NCBI
2	Midha A, Dearden S and McCormack R: EGFR mutation incidence in non-small-cell lung cancer of adenocarcinoma histology: A systematic review and global map by ethnicity (mutMapII). Am J Cancer Res. 5:2892–2911. 2015.PubMed/NCBI
3	Chantharasamee J, Poungvarin N, Danchaivijitr P and Techawatanawanna S: Clinical outcome of treatment of meta-static non-small cell lung cancer in patients harboring uncommon EGFR mutation. BMC Cancer. 19:7012019. View Article : Google Scholar
4	Seshacharyulu P, Ponnusamy MP, Haridas D, Jain M, Ganti AK and Batra SK: Targeting the EGFR signaling pathway in cancer therapy. Expert Opin Ther Targets. 16:15–31. 2012. View Article : Google Scholar : PubMed/NCBI
5	Morgillo F, Della Corte CM, Fasano M and Ciardiello F: Mechanisms of resistance to EGFR-targeted drugs: Lung cancer. ESMO Open. 1:e0000602016. View Article : Google Scholar : PubMed/NCBI
6	Barnes TA, O'Kane GM, Vincent MD and Leighl NB: Third-generation tyrosine kinase inhibitors targeting epidermal growth factor receptor mutations in non-small cell lung cancer. Front Oncol. 7:1132017. View Article : Google Scholar : PubMed/NCBI
7	Nosaki K, Satouchi M, Kurata T, Yoshida T, Okamoto I, Katakami N, Imamura F, Tanaka K, Yamane Y, Yamamoto N, et al: Re-biopsy status among non-small cell lung cancer patients in Japan: A retrospective study. Lung Cancer. 101:1–8. 2016. View Article : Google Scholar : PubMed/NCBI
8	Arcila ME, Oxnard GR, Nafa K, Riely GJ, Solomon SB, Zakowski MF, Kris MG, Pao W, Miller VA and Ladanyi M: Rebiopsy of lung cancer patients with acquired resistance to EGFR inhibitors and enhanced detection of the T790M mutation using a locked nucleic acid-based assay. Clin Cancer Res. 17:1169–1180. 2011. View Article : Google Scholar : PubMed/NCBI
9	Takezawa K, Pirazzoli V, Arcila ME, Nebhan CA, Song X, de Stanchina E, Ohashi K, Janjigian YY, Spitzler PJ, Melnick MA, et al: HER2 amplification: A potential mechanism of acquired resistance to EGFR inhibition in EGFR-mutant lung cancers that lack the second-site EGFRT790M mutation. Cancer Discov. 2:922–933. 2012. View Article : Google Scholar : PubMed/NCBI
10	Scott LJ: Osimertinib as first-line therapy in advanced NSCLC: A profile of its use. Drugs Ther Perspect. 34:351–357. 2018. View Article : Google Scholar
11	Kujtan L and Subramanian J: Epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of non-small cell lung cancer. Expert Rev Anticancer Ther. 19:547–559. 2019. View Article : Google Scholar : PubMed/NCBI
12	Imai H, Kaira K and Minato K: Clinical significance of post-progression survival in lung cancer. Thorac Cancer. 8:379–386. 2017. View Article : Google Scholar : PubMed/NCBI
13	Planchard D, Popat S, Kerr K, Novello S, Smit EF, Faivre-Finn C, Mok TS, Reck M, Van Schil PE, Hellmann MD, et al: Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 29(Suppl 4): iv192–iv237. 2018. View Article : Google Scholar : PubMed/NCBI
14	Ettinger DS, Wood DE, Aggarwal C, Aisner DL, Akerley W, Bauman JR, Bharat A, Bruno DS, Chang JY, Chirieac LR, et al: NCCN Guidelines Insights: Non-small cell lung cancer, version 1.2020. J Natl Compr Canc Netw. 17:1464–1472. 2019. View Article : Google Scholar : PubMed/NCBI
15	Rajappa S, Krishna MV and Narayanan P: Integrating osimertinib in clinical practice for non-small cell lung cancer treatment. Adv Ther. 36:1279–1290. 2019. View Article : Google Scholar : PubMed/NCBI
16	Hsu WH, Yang JC, Mok TS and Loong HH: Overview of current systemic management of EGFR-mutant NSCLC. Ann Oncol. 29(Suppl 1): i3–i9. 2018. View Article : Google Scholar : PubMed/NCBI
17	U.S. Food and drug administration: Center for Drug Evaluation and Research: Approval letter IRESSA, NDA21-399. 2003, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/21-399_IRESSA_Approv.pdf.
18	Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y, et al: Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 361:947–957. 2009. View Article : Google Scholar : PubMed/NCBI
19	Fukuoka M, Wu YL, Thongprasert S, Sunpaweravong P, Leong SS, Sriuranpong V, Chao TY, Nakagawa K, Chu DT, Saijo N, 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. 29:2866–2874. 2011. View Article : Google Scholar : PubMed/NCBI
20	Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, Seto T, Satouchi M, Tada H and Hirashima T: Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): An open label, randomised phase 3 trial. Lancet Oncol. 11:121–128. 2010. View Article : Google Scholar
21	Yoshioka H, Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Seto T, Satouchi M, Tada H, Hirashima T, et al: Final overall survival results of WJTOG 3405, a randomized phase 3 trial comparing gefitinib (G) with cisplatin plus docetaxel (CD) as the first-line treatment for patients with non-small cell lung cancer (NSCLC) harboring mutations of the epidermal growth factor receptor (EGFR). J Clin Oncol. 32(Suppl 15): S81172014. View Article : Google Scholar
22	Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, Gemma A, Harada M, Yoshizawa H, Kinoshita I, et al: Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 362:2380–2388. 2010. View Article : Google Scholar : PubMed/NCBI
23	Inoue A, Kobayashi K, Maemondo M, Sugawara S, Oizumi S, Isobe H, Gemma A, Harada M, Yoshizawa H, Kinoshita I, et al: Updated overall survival results from a randomized phase III trial comparing gefitinib with carboplatin-paclitaxel for chemo-naïve non-small cell lung cancer with sensitive EGFR gene mutations (NEJ002). Ann Oncol. 24:54–59. 2013. View Article : Google Scholar
24	Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, Zhang S, Wang J, Zhou S, Ren S, et al: Erlotinib versus chemotherapy as first-line treatment forpatients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): A multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 12:735–742. 2011. View Article : Google Scholar : PubMed/NCBI
25	Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, Zhang S, Wang J, Zhou S, Ren S, et al: Final overall survival results from a randomised, phase III study of erlotinib versus chemotherapy as first-line treatment of EGFR mutation-positive advanced non-small-cell lung cancer (OPTIMAL, CTONG-0802). Ann Oncol. 26:1877–1883. 2015. View Article : Google Scholar : PubMed/NCBI
26	Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, Palmero R, Garcia Gomez R, Pallares C, Sanchez JM, 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. 13:239–246. 2012. View Article : Google Scholar : PubMed/NCBI
27	Leon LF, Golsorkhi A, Liu S, Drozdowskyj A and Rosell R: Overall survival analyses of first-line erlotinib versus chemotherapy in the EURTAC study population controlling for the use of post-study therapy. Ann Oncol. 25(Suppl 4): iv426–iv470. 2014. View Article : Google Scholar
28	Wu YL, Zhou C, Liam CK, Wu G, Liu X, Zhong Z, Lu S, Cheng Y, Han B, Chen L, et al: First-line erlotinib versus gemcitabine/cisplatin in patients with advanced EGFR mutation-positive non-small-cell lung cancer: Analyses from the phase III, randomized, open-label, ENSURE study. Ann Oncol. 26:1883–1889. 2015. View Article : Google Scholar : PubMed/NCBI
29	Sequist LV, Yang JC, Yamamoto N, O'Byrne K, Hirsh V, Mok T, Geater SL, Orlov S, Tsai CM, Boyer M, et al: Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 31:3327–3334. 2013. View Article : Google Scholar : PubMed/NCBI
30	Yang JC, Wu YL, Schuler M, Sebastian M, Popat S, Yamamoto N, Zhou C, Hu CP, O'Byrne K, Feng J, et al: Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): Analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol. 16:141–151. 2015. View Article : Google Scholar : PubMed/NCBI
31	Wu YL, Zhou C, Hu CP, Feng J, Lu S, Huang Y, Li W, Hou M, Shi JH, Lee KY, et al: Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): An open-label, randomised phase 3 trial. Lancet Oncol. 15:213–222. 2014. View Article : Google Scholar : PubMed/NCBI
32	Mok TS, Wu YL, Ahn MJ, Garassino MC, Kim HR, Ramalingam SS, Shepherd FA, He Y, Akamatsu H, Theelen WS, et al: Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med. 376:629–640. 2017. View Article : Google Scholar
33	Papadimitrakopoulou VA, Mok TS, Han JY, Ahn MJ, Delmonte A, Ramalingam SS, Kim SW, Shepherd FA, Laskin J, He Y, et al: Osimertinib versus platinum-pemetrexed for patients with EGFR T790M advanced NSCLC and progression on a prior EGFR-tyrosine kinase inhibitor: AURA3 overall survival analysis. Ann Oncol. S0923-7534:42155–42156. 2020.
34	Park K, Tan EH, O'Byrne K, Zhang L, Boyer M, Mok T, Hirsh V, Yang JC, Lee KH, Lu S, 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. 17:577–589. 2016. View Article : Google Scholar : PubMed/NCBI
35	Paz-Ares L, Tan EH, O'byrne K, Zhang L, Hirsh V, Boyer M, Yang JH, Mok T, Lee KH, Lu S, 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. 28:270–277. 2017. View Article : Google Scholar : PubMed/NCBI
36	Wu YL, Cheng Y, Zhou X, Lee KH, Nakagawa K, Niho S, Tsuji F, Linke R, Rosell R, Corral J, 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. 18:1454–1466. 2017. View Article : Google Scholar : PubMed/NCBI
37	Mok TS, Cheng Y, Zhou X, Lee KH, Nakagawa K, Niho S, Lee M, Linke R, Rosell R, Corral J, 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. 36:2244–2250. 2018. View Article : Google Scholar : PubMed/NCBI
38	U.S. Food and Drug Administration, Center for Drug Evaluation and Research: NDA multi-disciplinary review and evaluation, 211288Orig1s000, VIZIMPRO/dacomitinib. 2018, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/211288Orig1s000MultidisciplineR.pdf.
39	Sequist LV, Waltman BA, Dias-Santagata D, Digumarthy S, Turke AB, Fidias P, Bergethon K, Shaw AT, Gettinger S, Cosper AK, et al: Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 3:75ra262011. View Article : Google Scholar : PubMed/NCBI
40	Yu HA, Arcila ME, Rekhtman N, Sima CS, Zakowski MF, Pao W, Kris MG, Miller VA, Ladanyi M and Riely GJ: 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. 19:2240–2247. 2013. View Article : Google Scholar : PubMed/NCBI
41	Koyyala VP, Batra U, Jain P, Sharma M, Goyal P, Medisetty P, Jajodia A and Maheshwari UD: Frequency of T790M mutations after progression on epidermal growth factor receptor tyrosine kinase inhibitor in metastatic non-small cell lung cancer in Indian patients: Real-time data from tertiary cancer hospital. Lung India. 35:390–394. 2018. View Article : Google Scholar
42	Oxnard GR, Arcila ME, Sima CS, Riely GJ, Chmielecki J, Kris MG, Pao W, Ladanyi M and Miller VA: Acquired resis-tance to EGFR tyrosine kinase inhibitors in EGFR-mutant lung cancer: Distinct natural history of patients with tumors harboring the T790M mutation. Clin Cancer Res. 17:1616–1622. 2011. View Article : Google Scholar
43	Jaiswal R, Pinninti R, Krishna Mohan MV, Santa A, Boyella PK, Nambaru L, Murthy SS, Chowdary KV and Rajappa S: T790M mutation and clinical outcomes with osimertinib in patients with epidermal growth factor receptor-mutant non-small cell lung cancer. Indian J Med Paediatr Oncol. 40:73–78. 2019. View Article : Google Scholar
44	Westover D, Zugazagoitia J, Cho BC, Lovly CM and Paz-Ares L: Mechanisms of acquired resistance to first- and second-generation EGFR tyrosine kinase inhibitors. Ann Oncol. 29(Suppl 1): i10–i19. 2018. View Article : Google Scholar : PubMed/NCBI
45	Rangachari D, Yamaguchi N, VanderLaan PA, Folch E, Mahadevan A, Floyd SR, Uhlmann EJ, Wong ET, Dahlberg SE, Huberman MS and Costa DB: Brain metastases in patients with EGFR-mutated or ALK-rearranged non-small-cell lung cancers. Lung Cancer. 88:108–111. 2015. View Article : Google Scholar : PubMed/NCBI
46	Ali A, Goffin JR, Arnold A and Ellis PM: Survival of patients with non-small-cell lung cancer after a diagnosis of brain metastases. Curr Oncol. 20:e300–e306. 2013. View Article : Google Scholar : PubMed/NCBI
47	Peters S, Bexelius C, Munk V and Leighl N: The impact of brain metastasis on quality of life, resource utilization and survival in patients with non-small-cell lung cancer. Cancer Treat Rev. 45:139–162. 2016. View Article : Google Scholar : PubMed/NCBI
48	Heon S, Yeap BY, Lindeman NI, Joshi VA, Butaney M, Britt GJ, Costa DB, Rabin MS, Jackman DM and Johnson BE: The impact of initial gefitinib or erlotinib versus chemotherapy on central nervous system progression in advanced non-small cell lung cancer with EGFR mutations. Clin Cancer Res. 18:4406–4414. 2012. View Article : Google Scholar : PubMed/NCBI
49	Omuro AM, Kris MG, Miller VA, Franceschi E, Shah N, Milton DT and Abrey LE: High incidence of disease recurrence in the brain and leptomeninges in patients with nonsmall cell lung carcinoma after response to gefitinib. Cancer. 103:2344–2348. 2005. View Article : Google Scholar : PubMed/NCBI
50	Chen YH, Chen YF, Chen CY, Shih JY and Yu CJ: Clinical factors associated with treatment outcomes in EGFR mutant non-small cell lung cancer patients with brain metastases: A case-control observational study. BMC Cancer. 19:10062019. View Article : Google Scholar : PubMed/NCBI
51	Hoffknecht P, Tufman A, Wehler T, Pelzer T, Wiewrodt R, Schütz M, Serke M, Stöhlmacher-Williams J, Märten A, Maria Huber R, et al: Efficacy of the irreversible ErbB family blocker afatinib in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-pretreated non-small-cell lung cancer patients with brain metastases or leptomeningeal disease. J Thorac Oncol. 10:156–163. 2015. View Article : Google Scholar
52	Doval DC, Desai CJ and Sahoo TP: Molecularly targeted therapies in non-small cell lung cancer: The evolving role of tyrosine kinase inhibitors. Indian J Cancer. 56(Suppl): S23–S30. 2019. View Article : Google Scholar : PubMed/NCBI
53	Shah RR and Shah DR: Safety and tolerability of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in oncology. Drug Saf. 42:181–198. 2019. View Article : Google Scholar : PubMed/NCBI
54	Tan CS, Kumarakulasinghe NB, Huang YQ, Ang YLE, Choo JR, Goh BC and Soo RA: Third generation EGFR TKIs: Current data and future directions. Mol Cancer. 17:292018. View Article : Google Scholar : PubMed/NCBI
55	Finlay MR, Anderton M, Ashton S, Ballard P, Bethel PA, Box MR, Bradbury RH, Brown SJ, Butterworth S, Campbell A, 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. 57:8249–8267. 2014. View Article : Google Scholar : PubMed/NCBI
56	Murtuza A, Bulbul A, Shen JP, Keshavarzian P, Woodward BD, Lopez-Diaz FJ, Lippman SM and Husain H: Novel third-generation EGFR tyrosine kinase inhibitors and strategies to overcome therapeutic resistance in lung cancer. Cancer Res. 79:689–698. 2019. View Article : Google Scholar : PubMed/NCBI
57	Liu S, Li S, Hai J, Wang X, Chen T, Quinn MM, Gao P, Zhang Y, Ji H, Cross DAE and Wong KK: Targeting HER2 aberrations in non-small cell lung cancer with osimertinib. Clin Cancer Res. 24:2594–2604. 2018. View Article : Google Scholar : PubMed/NCBI
58	U.S. Food and Drug Administration, Center for Drug Evaluation and Research: Application number: 208065Orig1s000, Tagrisso/osimertinib. https://www.accessdata.fda.gov/drug-satfda_docs/nda/2015/208065Orig1s000SumR.pdf. Accessed September 4, 2019.
59	Jänne PA, Yang JC, Kim DW, Planchard D, Ohe Y, Ramalingam SS, Ahn MJ, Kim SW, Su WC, Horn L, et al: AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med. 372:1689–1699. 2015. View Article : Google Scholar : PubMed/NCBI
60	Goss G, Tsai CM, Shepherd FA, Bazhenova L, Lee JS, Chang GC, Crino L, Satouchi M, Chu Q, Hida T, et al: Osimertinib for pretreated EGFR Thr790Met-positive advanced non-small-cell lung cancer (AURA2): A multicentre, open-label, single-arm, phase 2 study. Lancet Oncol. 17:1643–1652. 2016. View Article : Google Scholar : PubMed/NCBI
61	Yang JC, Ahn MJ, Kim DW, Ramalingam SS, Sequist LV, Su WC, Kim SW, Kim JH, Planchard D, Felip E, et al: Osimertinib in pretreated T790M-positive advanced non-small-cell lung cancer: AURA study phase II extension component. J Clin Oncol. 35:1288–1296. 2017. View Article : Google Scholar : PubMed/NCBI
62	U.S. Food and Drug Administration: Osimertinib (TAGRISSO): https://www.fda.gov/drugs/resources-information-approved-drugs/osimertinib-tagrisso.
63	Lee CK, Novello S, Rydén A, Mann H and Mok T: Patient-reported symptoms and impact of treatment with osimertinib versus chemotherapy in advanced non-small-cell lung cancer: The AURA3 trial. J Clin Oncol. 36:1853–1860. 2018. View Article : Google Scholar : PubMed/NCBI
64	Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, Dechaphunkul A, Imamura F, Nogami N, Kurata T, et al: Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 378:113–125. 2018. View Article : Google Scholar
65	U.S. Food and Drug Administration: FDA approves osimer-tinib for first-line treatment of metastatic NSCLC with most common EGFR mutations. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-osimertinib-first-line-treatment-metastatic-nsclc-most-common-egfr-mutations. Accessed September 5, 2019.
66	Cho BC, Chewaskulyong B, Lee KH, Dechaphunkul A, Sriuranpong V, Imamura F, Nogami N, Kurata T, Okamoto I, Zhou C, et al: Osimertinib versus standard of care EGFR TKI as first-line treatment in patients with EGFRm advanced NSCLC: FLAURA Asian subset. J Thorac Oncol. 14:99–106. 2019. View Article : Google Scholar
67	Soria JC, Massard C and Le Chevalier T: Should progression-free survival be the primary measure of efficacy for advanced NSCLC therapy? Ann Oncol. 21:2324–2332. 2010. View Article : Google Scholar : PubMed/NCBI
68	Pasalic D, McGinnis GJ, Fuller CD, Grossberg AJ, Verma V, Mainwaring W, Miller AB, Lin TA, Jethanandani A, Espinoza AF, et al: Progression-free survival is a suboptimal predictor for overall survival among metastatic solid tumour clinical trials. Eur J Cancer. 136:176–185. 2020. View Article : Google Scholar : PubMed/NCBI
69	U.S. Food and Drug Administration: Clinical trial endpoints for the approval of cancer drugs and biologics. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/clinical-trial-endpoints-approval-cancer-drugs-and-biologics. Accessed September 5, 2019.
70	Ellis LM, Bernstein DS, Voest EE, Berlin JD, Sargent D, Cortazar P, Garrett-Mayer E, Herbst RS, Lilenbaum RC, Sima C, et al: American society of clinical oncology perspec-tive: Raising the bar for clinical trials by defining clinically meaningful outcomes. J Clin Oncol. 32:1277–1280. 2014. View Article : Google Scholar : PubMed/NCBI
71	Ramalingam SS, Vansteenkiste J, Planchard D, Cho BC, Gray JE, Ohe Y, Zhou C, Reungwetwattana T, Cheng Y, Chewaskulyong B, et al: Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med. 382:41–50. 2020. View Article : Google Scholar
72	Mok T, Ahn MJ, Han JY, Kang JH, Katakami N, Kim H, Hodge R, Ghiorghiu DC, Cantarini M, Wu YL, et al: CNS response to osimertinib in patients (pts) with T790M-positive advanced NSCLC: Data from a randomized phase III trial (AURA3). J Clin Oncol. 35(15_Suppl): S90052017. View Article : Google Scholar
73	Reungwetwattana T, Nakagawa K, Cho BC, Cobo M, Cho EK, Bertolini A, Bohnet S, Zhou C, Lee KH, Nogami N, et al: CNS response to osimertinib versus standard epidermal growth factor receptor tyrosine kinase inhibitors in patients with untreated EGFR-mutated advanced non-small-cell lung cancer. J Clin Oncol. JCO20187831182018. View Article : Google Scholar : Epub ahead of print. PubMed/NCBI
74	Monaco EA III, Faraji AH, Berkowitz O, Parry PV, Hadelsberg U, Kano H, Niranjan A, Kondziolka D and Lunsford LD: Leukoencephalopathy after whole-brain radiation therapy plus radiosurgery versus radiosurgery alone for metastatic lung cancer. Cancer. 119:226–232. 2013. View Article : Google Scholar
75	Mulvenna P, Nankivell M, Barton R, Faivre-Finn C, Wilson P, McColl E, Moore B, Brisbane I, Ardron D, Holt T, et al: Dexamethasone and supportive care with or without whole brain radiotherapy in treating patients with non-small cell lung cancer with brain metastases unsuitable for resection or stereotactic radiotherapy (QUARTZ): Results from a phase 3, non-inferiority, randomised trial. Lancet. 388:2004–2014. 2016. View Article : Google Scholar : PubMed/NCBI
76	Metro G, Provencio M, Kim DW, Cho BC, Park K, Pan Y, Shi Y, Migliorino R, Tiseo M, Yu J, et al: Osimertinib in epidermal growth factor receptor (EGFR) T790M advanced non-small cell lung cancer (NSCLC): Analysis of patients with central nervous system (CNS) metastases in a real-world study (ASTRIS). Ann Oncol. 30(Suppl 5): v6242019. View Article : Google Scholar
77	Erickson AW, Brastianos PK and Das S: Assessment of effectiveness and safety of osimertinib for patients with intracranial metastatic disease: A systematic review and meta-analysis. JAMA Netw Open. 3:e2016172020. View Article : Google Scholar : PubMed/NCBI
78	Yang JCH, Kim SW, Kim DW, Lee JS, Cho BC, Ahn JS, Lee DH, Kim TM, Goldman JW, Natale RB, et al: Osimertinib in patients with epidermal growth factor receptor mutation-positive non-small-cell lung cancer and leptomeningeal metastases: The BLOOM study. J Clin Oncol. 38:538–547. 2020. View Article : Google Scholar
79	Ahn MJ, Chiu CH, Cheng Y, Han JY, Goldberg SB, Greystoke A, Crawford J, Zhao Y, Huang X, Johnson M, et al: Osimertinib for patients with leptomeningeal metastases associated with EGFR T790M-positive advanced NSCLC: The AURA leptomeningeal metastases analysis. J Thorac Oncol. 15:637–648. 2020. View Article : Google Scholar
80	Park S, Lee MH, Seong M, Kim ST, Kang JH, Cho BC, Lee KH, Cho EK, Sun JM, Lee SH, et al: A Phase II, multicenter, two cohort study of 160 mg osimertinib in EGFR T790M-positive non-small cell lung cancer patients with brain metastases or leptomeningeal disease who progressed on prior EGFR TKI therapy. Ann Oncol. 31:1397–1404. 2020. View Article : Google Scholar : PubMed/NCBI
81	Lee J, Choi Y, Han J, Park S, Jung HA, Su JM, Lee SH, Ahn JS, Park K and Ahn MJ: Osimertinib improves overall survival in patients with EGFR-Mutated NSCLC with leptomeningeal metastases regardless of T790M mutational status. J Thorac Oncol. 15:1758–1766. 2020. View Article : Google Scholar : PubMed/NCBI
82	Girard N: Optimizing outcomes in EGFR mutation-positive NSCLC: Which tyrosine kinase inhibitor and when? Future Oncol. 14:1117–1132. 2018. View Article : Google Scholar : PubMed/NCBI
83	Gelatti ACZ, Drilon A and Santini FC: Optimizing the sequencing of tyrosine kinase inhibitors (TKIs) in epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC). Lung Cancer. 137:113–122. 2019. View Article : Google Scholar : PubMed/NCBI
84	Kawamura T, Kenmotsu H, Taira T, Omori S, Nakashima K, Wakuda K, Ono A, Naito T, Murakami H, Mori K, et al: Rebiopsy for patients with non-small-cell lung cancer after epidermal growth factor receptor-tyrosine kinase inhibitor failure. Cancer Sci. 107:1001–1005. 2016. View Article : Google Scholar : PubMed/NCBI
85	Shah R and Lester JF: Tyrosine kinase inhibitors for the treatment of EGFR mutation-positive non-small-cell lung cancer: A clash of the generations. Clin Lung Cancer. 21:e216–e228. 2020. View Article : Google Scholar : PubMed/NCBI
86	Zhang H, Chen J, Liu T, Dang J and Li G: First-line treatments in EGFR-mutated advanced non-small cell lung cancer: A network meta-analysis. PLoS One. 14:e02235302019. View Article : Google Scholar : PubMed/NCBI
87	Aguilar-Serra J, Gimeno-Ballester V, Pastor-Clerigues A, Milara J, Marti-Bonmati E, Trigo-Vicente C, Alós-Almiñana M and Cortijo J: Osimertinib in first-line treatment of advanced EGFR-mutated non-small-cell lung cancer: A cost-effectiveness analysis. J Comp Eff Res. 8:853–863. 2019. View Article : Google Scholar : PubMed/NCBI
88	Jiang SX, Walton RN, Hueniken K, Baek J, McCartney A, Labbé C, Smith E, Chan SW, Chen R, Brown C, et al: Real-world health utility scores and toxicities to tyrosine kinase inhibitors in epidermal growth factor receptor mutated advanced non-small cell lung cancer. Cancer Med. 8:7542–7555. 2019. View Article : Google Scholar : PubMed/NCBI
89	Schuler M: Liquid biopsies for dynamic monitoring of EGFR mutations in lung cancer. J Thorac Oncol. 12(Suppl): S852017. View Article : Google Scholar
90	Leonetti A, Sharma S, Minari R, Perego P, Giovannetti E and Tiseo M: Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer. Br J Cancer. 121:725–737. 2019. View Article : Google Scholar : PubMed/NCBI
91	Nakamura A, Inoue A, Morita S, Hosomi Y, Kato T, Fukuhara T, Gemma A, Takahashi K, Fujita Y, Harada T, et al: Phase III study comparing gefitinib monotherapy (G) to combination therapy with gefitinib, carboplatin, and pemetrexed (GCP) for untreated patients (pts) with advanced non-small cell lung cancer (NSCLC) with EGFR mutations (NEJ009). J Clin Oncol. 36(15_suppl): S90052018. View Article : Google Scholar
92	Nakagawa K, Garon EB, Seto T, Nishio M, Santiago PA, Chiu CH, Park K, Novello S, Nadal E, Imamura F, et al: RELAY: A multi-national, double-blind, randomized Phase 3 study of erlotinib (ERL) in combination with ramucirumab (RAM) or placebo (PL) in previously untreated patients with epidermal growth factor receptor mutation-positive (EGFRm) metastatic non-small cell lung cancer (NSCLC). J Clin Oncol. 37(15_Suppl): 90002019. View Article : Google Scholar
93	Noronha V, Joshi A, Patil VM, Chougule A, Mahajan A, Janu A, Purandare N, Kumar R, More S, Goud S, et al: Phase III randomized trial comparing gefitinib to gefitinib with pemetrexed-carboplatin chemotherapy in patients with advanced untreated EGFR mutant non-small cell lung cancer (gef vs gef+ C). J Clin Oncol. 37(15_Suppl): S90012019. View Article : Google Scholar
94	Saito H, Fukuhara T, Furuya N, Watanabe K, Sugawara S, Iwasawa S, Tsunezuka Y, Yamaguchi O, Okada M, Yoshimori K, 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. 20:625–635. 2019. View Article : Google Scholar : PubMed/NCBI
95	ClinicalTrials.gov: Assessing an oral janus kinase inhibitor, AZD4205, in combination with osimertinib in patients who have advanced non-small cell lung cancer (JACKPOT1). ClinicalTrials.gov Identifier: NCT03450330. https://clinical-trials.gov/ct2/show/NCT03450330. Accessed March 1, 2018.
96	ClinicalTrials.gov: Dasatinib and osimertinib (AZD9291) in advanced non-small cell lung cancer with EGFR mutations. ClinicalTrials.gov Identifier: NCT02954523. https://clinical-trials.gov/ct2/show/NCT02954523. Accessed November 3, 2016.
97	ClinicalTrials.gov: Testing the Combination of MLN0128 (TAK-228) and AZD9291 in Advanced EGFR (Epidermal Growth Factor Receptor) Mutation Positive Non-small Cell Lung Cancer. ClinicalTrials.gov Identifier: NCT02503722. https://clinicaltrials.gov/ct2/show/NCT02503722?term=osimertinib&cond=NSCLC+Stage+IV&rank=3. Accessed July 21, 2015.
98	ClinicalTrials.gov: Telaglenastat Hydrochloride and Osimertinib in Treating Patients With EGFR-Mutated Stage IV Non-small Cell Lung Cancer. ClinicalTrials.gov Identifier: NCT03831932 https://clinicaltrials.gov/ct2/show/NCT03831932?term=osimertinib&cond=NSCLC+Stage+IV&rank=6. Accessed February 6, 2019.
99	ClinicalTrials.gov: Osimertinib and Necitumumab in Treating Patients With EGFR-Mutant Stage IV or Recurrent Non-small Cell Lung Cancer Who Have Progressed on a Previous EGFR Tyrosine Kinase Inhibitor. ClinicalTrials.gov Identifier: NCT02496663. https://clinicaltrials.gov/ct2/show/NCT02496663?term=osimertinib&cond=NSCLC+Stage+IV&rank=7. Accessed July 14, 2015.
100	ClinicalTrials.gov: Study of anlotinib combined with osimer-tinib as second-line treatment in stage IIIb-IV NSCLC with confirmed EGFRm and T790M (ALTN-03). ClinicalTrials.gov Identifier: NCT04029350. https://clinicaltrials.gov/ct2/show/NCT04029350?term=osimertinib&cond=NSCLC+Stage+IV&rank=12 Accessed July 23, 2019.
101	ClinicalTrials.gov: Osimertinib and Navitoclax in treating patients with EGFR-positive previously treated advanced or metastatic non-small cell lung cancer. ClinicalTrials.Gov Identifier: NCT02520778. https://clinicaltrials.gov/ct2/show/NCT02520778 Accessed August 13, 2015.
102	ClinicalTrials.gov: Phase 2 Platform Study in patients with advanced non-small lung cancer who progressed on first-line osimertinib therapy (ORCHARD) (ORCHARD). ClinicalTrials.gov Identifier: NCT03944772. https://www.clinicaltrials.gov/ct2/show/NCT03944772. Accessed May 10, 2019.
103	Uchibori K, Inase N, Araki M, Kamada M, Sato S, Okuno Y, Fujita N and Katayama R: Brigatinib combined with anti-EGFR antibody overcomes osimertinib resistance in EGFR-mutated non-small-cell lung cancer. Nat Commun. 8:147682017. View Article : Google Scholar : PubMed/NCBI
104	ClinicalTrials.gov: A Study of Osimertinib With or Without Chemotherapy as 1st Line Treatment in Patients With Mutated Epidermal Growth Factor Receptor Non-Small Cell Lung Cancer (FLAURA2) (FLAURA2). ClinicalTrials.gov Identifier: NCT04035486. https://clinicaltrials.gov/ct2/show/NCT04035486?term=flaura+2&draw=2&rank=1 Accessed July 29, 2019.
105	Clinical trial.gov: Osimertinib Plus Savolitinib in EGFRm+/MET+ NSCLC Following Prior Osimertinib (SAVANNAH). ClinicalTrials.gov Identifier: NCT03778229. https://clinical-trials.gov/ct2/show/NCT03778229?term=SAVANNAH&draw=2&rank=1 Accessed December 19, 2018.