The Time to Progression in Lung Adenocarcinoma Patients Receiving First- and Second-Generation EGFR-TKI in Indonesia
Downloads
Introduction: Targeted therapy, particularly epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), is the first-line treatment for non-small cell lung cancer (NSCLC). However, drug resistance has grown in the last few decades. This study compared the progression time of lung cancer patients treated with first- and second-generation EGFR-TKI.
Methods: Based on cytology and histological results, this cross-sectional study included 1,008 participants diagnosed with lung adenocarcinoma (LUAD) from 11 Indonesian Respiratory Centers. Every three months, the response to treatment was assessed using the Response Evaluation Criteria in Solid Tumours (RECIST) criteria in 1.1. Significant differences in the clinical features of the three TKI treatment groups were identified using logistic regression analysis, the median time to disease progression was estimated using the Kaplan-Meier technique, and independent prognostic factors related to the time to progression (TTP) were assessed using Cox proportional hazards regression.
Results: This study examined 505 patients, the majority of whom were females (50.9%), never smoked (59.8%), diagnosed at an advanced stage (99.2%), and had an Eastern Cooperative Oncology Group (ECOG) scale of 0-1 (83.2%). Approximately 98.1% of patients were treated with afatinib (14.8%), erlotinib (18.6%), and gefitinib (66.1%) due to common mutations. The groups did not differ significantly (p>0.05). The median overall survival (OS) rate was 9 months. The time to LUAD progression in lung cancer was significantly impacted by poor performance (p=0.001).
Conclusion: Epidermal growth factor receptor-tyrosine kinase inhibitor treatment can only prolong the TTP of LUAD by up to 9 months, and the performance scale when receiving the EGFR-TKI significantly affects the prognosis.
Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021; 71: 209–249. [PubMed]
Asmara OD, Tenda ED, Singh G, et al. Lung Cancer in Indonesia. Journal of Thoracic Oncology : Official Publication of the International Association for the Study of Lung Cancer 2023; 18: 1134–1145. [PubMed]
Liu T, Wang J, Li T, et al. Predicting Disease Progression in Advanced Non-Small Cell Lung Cancer with Circulating Neutrophil-Derived and Platelet-Derived Microparticles. BMC Cancer 2021; 21: 939. [Journal]
Schwartz LH, Litière S, de Vries E, et al. RECIST 1.1-Update and Clarification: From the RECIST Committee. Eur J Cancer 2016; 62: 132–137. [PubMed]
Araghi M, Mannani R, Maleki AH, et al. Recent Advances in Non-Small Cell Lung Cancer Targeted Therapy; An Update Review. Cancer Cell Int 2023; 23: 162. [PubMed]
Wang F, Wang LD, Li B, et al. Gefitinib Compared with Systemic Chemotherapy as First-Line Treatment for Chemotherapy-Naive Patients with Advanced Non-Small Cell Lung Cancer: A Meta-Analysis of Randomised Controlled Trials. Clin Oncol (R Coll Radiol) 2012; 24: 396–401. [PubMed]
Guardiola S, Varese M, Sánchez-Navarro M, et al. A Third Shot at EGFR: New Opportunities in Cancer Therapy. Trends Pharmacol Sci 2019; 40: 941–955. [PubMed]
Du X, Yang B, An Q, et al. Acquired Resistance to Third-Generation EGFR-TKIs and Emerging Next-Generation EGFR Inhibitors. Innov (Cambridge 2021; 2: 100103. [PubMed]
Doroshow DB, Herbst RS. Treatment of Advanced Non-Small Cell Lung Cancer in 2018. JAMA Oncol 2018; 4: 569–570. [PubMed]
Wu TH, Hsiue EHC, Lee JH, et al. Best Response according to RECIST during First-Line EGFR-TKI Treatment Predicts Survival in EGFR Mutation-Positive Non-Small-Cell Lung Cancer Patients. Clin Lung Cancer 2018; 19: e361–e372. [PubMed]
Park K, Lim DWT, Okamoto I, et al. First-Line Afatinib for the Treatment of EGFR Mutation-Positive Non-Small-Cell Lung Cancer in the ‘Real-World’ Clinical Setting. Ther Adv Med Oncol 2019; 11: 1758835919836374. [PubMed]
Syahruddin E, Wulandari L, Sri Muktiati N, et al. Uncommon EGFR Mutations in Cytological Specimens of 1,874 Newly Diagnosed Indonesian Lung Cancer Patients. Lung Cancer (Auckland, NZ) 2018; 9: 25–34. [PubMed]
Ettinger DS, Wood DE, Aisner DL, et al. Non-Small Cell Lung Cancer, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2022; 20: 497–530. [PubMed]
Yoon HY, Ryu JS, Sim YS, et al. Clinical Significance of EGFR Mutation Types in Lung Adenocarcinoma: A Multi-Centre Korean Study. PLoS One 2020; 15: e0228925. [PubMed]
Hsu WH, Yang JCH, Mok TS, et al. Overview of Current Systemic Management of EGFR-Mutant NSCLC. Ann Oncol Off J Eur Soc Med Oncol 2018; 29: i3–i9. [PubMed]
Ren JH, He WS, Yan GL, et al. EGFR Mutations in Non-Small-Cell Lung Cancer among Smokers and Non-Smokers: A Meta-Analysis. Environ Mol Mutagen 2012; 53: 78–82. [PubMed]
Chapman AM, Sun KY, Ruestow P, et al. Lung Cancer Mutation Profile of EGFR, ALK, and KRAS: Meta-Analysis and Comparison of Never and Ever Smokers. Lung Cancer 2016; 102: 122–134. [PubMed]
Lin L, Zhao J, Hu J, et al. Current Smoking has a Detrimental Effect on Survival for Epidermal Growth Factor Receptor (EGFR) and Anaplastic Lymphoma Kinase (ALK) Negative Advanced Non-Squamous Non-Small Cell Lung Cancer (NSCLC) Patients Treated with Pemetrexed Continuation Maintenance. J Cancer 2018; 9: 2140–2146. [PubMed]
Löfling L, Karimi A, Sandin F, et al. Clinical Characteristics and Survival in Non-Small Cell Lung Cancer Patients by Smoking History: A Population-Based Cohort Study. Acta Oncol 2019; 58: 1618–1627. [PubMed]
Hasegawa Y, Ando M, Maemondo M, et al. The Role of Smoking Status on the Progression-Free Survival of Non-Small Cell Lung Cancer Patients Harboring Activating Epidermal Growth Factor Receptor (EGFR) Mutations Receiving First-Line EGFR Tyrosine Kinase Inhibitor versus Platinum Doublet Chemother. Oncologist 2015; 20: 307–315. [PubMed]
Zhang Y, Kang S, Fang W, et al. Impact of Smoking Status on EGFR-TKI Efficacy for Advanced Non-Small-Cell Lung Cancer in EGFR Mutants: A Meta-Analysis. Clin Lung Cancer 2015; 16: 144-151.e1. [PubMed]
Sohn HS, Kwon JW, Shin S, et al. Effect of Smoking Status on Progression-Free and Overall Survival in Non-Small Cell Lung Cancer Patients Receiving Erlotinib or Gefitinib: A Meta-Analysis. J Clin Pharm Ther 2015; 40: 661–671. [PubMed]
Lee CK, Davies L, Wu YL, et al. Gefitinib or Erlotinib vs Chemotherapy for EGFR Mutation-Positive Lung Cancer: Individual Patient Data Meta-Analysis of Overall Survival. J Natl Cancer Inst; 109. Epub ahead of print June 2017. [PubMed]
Masykura N, Zaini J, Syahruddin E, et al. Impact of Smoking on Frequency and Spectrum of K-RAS and EGFR Mutations in Treatment Naive Indonesian Lung Cancer Patients. Lung Cancer (Auckland, NZ) 2019; 10: 57–66. [PubMed]
Siegel RL, Miller KD, Fuchs HE, et al. Cancer Statistics, 2022. CA Cancer J Clin 2022; 72: 7–33. [PubMed]
Wang Y, Yu W, Shi J, et al. Evaluating the Efficacy of EGFR-TKIs Combined with Radiotherapy in Advanced Lung Adenocarcinoma Patients with EGFR Mutation: A Retrospective Study. Technol Cancer Res Treat 2022; 21: 15330338221100358. [PubMed]
Zhang T, Wan B, Zhao Y, et al. Treatment of Uncommon EGFR Mutations in Non-Small Cell Lung Cancer: New Evidence and Treatment. Transl Lung Cancer Res 2019; 8: 302–316. [PubMed]
Brindel A, Althakfi W, Barritault M, et al. Uncommon EGFR Mutations in Lung Adenocarcinoma: Features and Response to Tyrosine Kinase Inhibitors. J Thorac Dis 2020; 12: 4643–4650. [PubMed]
John T, Taylor A, Wang H, et al. Uncommon EGFR Mutations in Non-Small-Cell Lung Cancer: A Systematic Literature Review of Prevalence and Clinical Outcomes. Cancer Epidemiol 2022; 76: 102080. [PubMed]
Girard N. Optimizing Outcomes in EGFR Mutation-Positive NSCLC: Which Tyrosine Kinase Inhibitor and When? Future Oncol 2018; 14: 1117–1132. [PubMed]
Solca F, Dahl G, Zoephel A, et al. Target Binding Properties and Cellular Activity of Afatinib (BIBW 2992), an Irreversible ErbB Family Blocker. J Pharmacol Exp Ther 2012; 343: 342–350. [PubMed]
Park S, Lee SY, Kim D, et al. Comparison of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors for Patients with Lung Adenocarcinoma Harboring Different Epidermal Growth Factor Receptor Mutation Types. BMC Cancer 2021; 21: 52. [PubMed]
Sutandyo N, Hanafi A, Jayusman M. Comparison of Effectiveness of Gefitinib, Erlotinib, and Afatinib in Advanced Non-small Cell Lung Cancer Patients with EGFR Mutation Positive in Indonesian Population. Zhongguo Fei Ai Za Zhi 2019; 22: 562–567. [PubMed]
Krawczyk P, Kowalski DM, Ramlau R, et al. Comparison of the Effectiveness of Erlotinib, Gefitinib, and Afatinib for Treatment of Non-Small Cell Lung Cancer in Patients with Common and Rare EGFR Gene Mutations. Oncol Lett 2017; 13: 4433–4444. [PubMed]
Nurhayati F, Yusi A, Syahruddin E, et al. Cost-Effectiveness Analysis of Tyrosine Kinase Inhibitors (Erlotinib vs. Gefitinib vs. Afatinib) in Non-Small-Cell Lung Cancer. J Appl Pharm Sci 2021; 11: 88–95. [Journal]
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: 400–410. [PubMed]
Yu HA, Riely GJ. Second-Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Lung Cancers. J Natl Compr Canc Netw 2013; 11: 161–169. [PubMed]
Wu SG, Shih JY. Management of Acquired Resistance to EGFR TKI-Targeted Therapy in Advanced Non-Small Cell Lung Cancer. Mol Cancer 2018; 17: 38. [PubMed]
Karachaliou N, Fernandez-Bruno M, Bracht JWP, et al. EGFR First- and Second-Generation TKIs-There is Still Place for Them in EGFR-Mutant NSCLC Patients. Transl Cancer Res 2019; 8: S23–S47. [PubMed]
Inomata M, Minatoyama S, Takata N, et al. Comparison of the Efficacy of First‑/Second‑Generation EGFR‑Tyrosine Kinase Inhibitors and Osimertinib for EGFR‑Mutant Lung Cancer with Negative or Low PD‑L1 Expression. Mol Clin Oncol 2024; 20: 43. [Journal]
Donowati M, Kristin E, Hutajulu S, et al. The Comparative Effectiveness of First-Line Treatment EGFR TKIs in Asian Lung Cancer Population: A Systematic Review and Meta-Analysis. J Appl Pharm Sci. Epub ahead of print 1 January 2024. [Journal]
Wright NMA, Goss GD. Third-Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors for the Treatment of Non-Small Cell Lung Cancer. Transl Lung Cancer Res 2019; 8: S247–S264. [PubMed]
Cheng Z, Cui H, Wang Y, et al. The Advance of the Third‑Generation EGFR‑TKI in the Treatment of Non‑Small Cell Lung Cancer (Review). Oncol Rep; 51. Epub ahead of print January 2024. [PubMed]
He J, Huang Z, Han L, et al. Mechanisms and Management of 3rd‑Generation EGFR‑TKI Resistance in Advanced Non‑Small Cell Lung Cancer (Review). Int J Oncol; 59. Epub ahead of print November 2021. [PubMed]
Li Z, Lu S. Third-Generation EGFR Tyrosine Kinase Inhibitor for Central Nervous System Metastases EGFR-Mutant NSCLC: Current Evidence and Future Perspectives. Journal of Thoracic Oncology : Official Publication of the International Association for the Study of Lung Cancer 2023; 18: 1625–1628. [PubMed]
Wu H, Zhang Q, Zhai W, et al. Effectiveness of High-Dose Third-Generation EGFR-Tyrosine Kinase Inhibitors in Treating EGFR-Mutated Non-Small Cell Lung Cancer Patients with Leptomeningeal Metastasis. Lung Cancer 2024; 188: 107475. [PubMed]
Buttitta F, Felicioni L, Lorito A Di, et al. Early Prediction of Resistance to Tyrosine Kinase Inhibitors by Plasma Monitoring of EGFR Mutations in NSCLC: A New Algorithm for Patient Selection and Personalized Treatment. Oncotarget 2020; 11: 982–991. [PubMed]
Setyawan UA, Tantular R, Bahar C. Survival Rate of Lung Adenocarcinoma Patients Receiving EGFR - Tyrosine Kinase Inhibitor Targeted Therapy. J Kedokt Brawijaya 2023; 32: 165–170. [Journal]
Haryati H, Arganita FR, Oktaviyanti IK. Survival of Lung Adenocarcinoma Patients with Tyrosine Kinase Inhibitor Therapy Based on EGFR Mutation Status in Tumor and Plasma Samples. Indones J Cancer 2023; 17: 280–286. [Journal]
Prasetyo SJ, Soeroso NN, Tarigan SP, et al. Survival Analysis of Lung Adenocarcinoma Patients with Exon 19 Del and 21 L858R Mutations Receiving EGFR-TKI Treatment. J Respirasi 2023; 9: 101–107. [Journal]
Copyright (c) 2025 Elisna Syahruddin, Noni Novisari Soeroso, Fannie Rizki Ananda, Laksmi Wulandari, Ana Rima Setijadi, Sabrina Ermayanti, Suryanti Dwi Pratiwi, Andreas Infianto, Novita Andayani, Sri Melati Munir, Avissena Dutha Pratama, Ida Ayu Jasminarti Dwi Kusumawardani, Haryati Haryati, Natalie Duyen, Muhammad Alfin Hanif, Darren Wan-Teck Lim

This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.
1. The journal allows the author to hold the copyright of the article without restrictions.
2. The journal allows the author(s) to retain publishing rights without restrictions.
3. The legal formal aspect of journal publication accessibility refers to Creative Commons Attribution Share-Alike (CC BY-SA).
4. The Creative Commons Attribution Share-Alike (CC BY-SA) license allows re-distribution and re-use of a licensed work on the conditions that the creator is appropriately credited and that any derivative work is made available under "the same, similar or a compatible license”. Other than the conditions mentioned above, the editorial board is not responsible for copyright violation.