Cancer Research and Treatment

Original Articles

Lung and Thoracic cancer

Final Report on Real-World Effectiveness of Sequential Afatinib and Osimertinib in EGFR-Positive Advanced Non–Small Cell Lung Cancer: Updated Analysis of the RESET Study: Taeyun Kim, Tae Won Jang, Chang Min Choi, Mi-Hyun Kim, Sung Yong Lee, Yoon Soo Chang, Kye Young Lee, Seung Joon Kim, Sei Hoon Yang, Jeong Seon Ryu, Jeong Eun Lee, Shin Yup Lee, Chan Kwon Park, Sang Hoon Lee, Seung Hun Jang, Seong Hoon Yoon, Hyung-Joo Oh; Cancer Res Treat. 2023;55(4):1152-1170. Published online May 19, 2023; DOI: https://doi.org/10.4143/crt.2023.493

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Purpose
This study aimed to report the final analysis of time-on-treatment (TOT) and overall survival (OS) in patients with advanced-stage epidermal growth factor receptor (EGFR)+ non–small cell lung cancer (NSCLC) who received sequential afatinib and osimertinib and to compare the outcomes with other second-line regimens (comparator group).
Materials and Methods
In this updated report, the existing medical records were reviewed and rechecked. TOT and OS were updated and analyzed according to clinical features using the Kaplan-Meier method and log-rank test. TOT and OS were compared with those of the comparator group, in which most patients received pemetrexed-based treatments. A multivariable Cox proportional hazard model was used to evaluate features that could affect survival outcomes.
Results
The median observation time was 31.0 months. The follow-up period was extended to 20 months. A total of 401 patients who received first-line afatinib were analyzed (166 with T790M+ and second-line osimertinib, and 235 with unproven T790M and other second-line agents). Median TOTs on afatinib and osimertinib were 15.0 months (95% confidence interval [CI], 14.0 to 16.1) and 11.9 months (95% CI, 8.9 to 14.6), respectively. The median OS in the osimertinib group was 54.3 months (95% CI, 46.7 to 61.9), much longer than that in the comparator group. In patients who received osimertinib, the OS was longest with Del19+ (median, 59.1; 95% CI, 48.7 to 69.5).
Conclusion
This is one of the largest real-world studies reporting the encouraging activity of sequential afatinib and osimertinib in Asian patients with EGFR+ NSCLC who acquired the T790M mutation, particularly Del19+.

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Real-World Outcomes of Sequential Afatinib and Osimertinib Versus Afatinib and Chemotherapy in EGFR-Mutant NSCLC: Taiwan Multicenter GIANT Study
How-Wen Ko, Ying-Ting Liao, Sheng-Kai Liang, Yen-Hsiang Huang, Yu-Ching Lin, Ping-Chi Liu, Chin-Chou Wang, Jeng-Shiuan Tsai, Yuh-Min Chen, Jin-Yuan Shih, Tsung-Ying Yang, Cheng-Ta Yang
Targeted Oncology.2026; 21(2): 213. CrossRef
Clinical impact of local consolidative therapy in EGFR-mutant metastatic NSCLC: A propensity-matched multicenter analysis
Eun Hye Lee, Mi-Hyun Kim, Da Hyun Kang, Jisu Moon, Se Hyun Kwak, Jung Seop Eom, Jeong Eun Lee, Chi Young Kim, Yoon Soo Chang, Sang Hoon Lee, Eun Young Kim, Chang Young Lee, Jaeho Cho
Lung Cancer.2026; 217: 109423. CrossRef
KEAP1-NRF2 Pathway as a Novel Therapeutic Target for EGFR-Mutant Non-small Cell Lung Cancer
Jae-Sun Choi, Hye-Min Kang, Kiyong Na, Jiwon Kim, Tae-Woo Kim, Junyang Jung, Heejin Lim, Hyewon Seo, Seung Hyeun Lee
Tuberculosis and Respiratory Diseases.2025; 88(1): 138. CrossRef
J-REGISTER: real-world study of Japanese patients with EGFR mutation-positive NSCLC treated with first-line afatinib
Teppei Yamaguchi, Haruko Daga, Hisashi Tanaka, Takashi Kijima, Masaya Mizushima
Future Oncology.2025; 21(16): 2039. CrossRef
A real-world cohort study of first-line afatinib in patients with EGFR-mutant advanced non-small cell lung cancer in Vietnam
Cam Phuong Pham, Thi Thai Hoa Nguyen, Anh Tu Do, Tuan Khoi Nguyen, Thi Anh Thu Hoang, Tuan Anh Le, Dinh Thy Hao Vuong, Dac Nhan Tam Nguyen, Van Khiem Dang, Thi Oanh Nguyen, Van Luan Pham, Minh Hai Nguyen, Thi Huyen Trang Vo, Hung Kien Do, Ha Thanh Vu, Thi
BMC Cancer.2024;[Epub] CrossRef
Real‐world evidence of brigatinib as second‐line treatment after crizotinib for ALK+ non‐small cell lung cancer using South Korean claims data (K‐AREAL)
Jeong Eun Lee, Jin Hyun Nam, Sun Hong Kwon, Bo Kyung Kim, Seung Min Ha
Cancer Medicine.2024;[Epub] CrossRef
Serum Concentrations of IGF-1R, ERK2, and EGFR and Their Clinical Significance in Patients with Neuroendocrine Tumors
Roksana Duszkiewicz, Janusz Strzelczyk, Elżbieta Chełmecka, Joanna Katarzyna Strzelczyk
Applied Sciences.2024; 14(16): 6998. CrossRef
Optimal first-line treatment for EGFR-mutated NSCLC: a comparative analysis of osimertinib and second-generation EGFR-TKIs
Hsu-Yuan Chen, Chia-Hung Chen, Wei-Chih Liao, Yu-Chao Lin, Hung-Jen Chen, Te-Chun Hsia, Wen-Chien Cheng, Chih-Yen Tu
BMC Pulmonary Medicine.2024;[Epub] CrossRef
Osimertinib as Second- and ≥Third-Line Treatment in Advanced and Recurrence EGFR-Mutant NSCLC Patients Harboring Acquired T790M Mutation
Mu-Han Peng, Yen-Hsiang Huang, Kuo-Hsuan Hsu, Jeng-Sen Tseng, Po-Hsin Lee, Kun-Chieh Chen, Gee-Chen Chang, Tsung-Ying Yang
Cancers.2024; 16(24): 4174. CrossRef
Effectiveness of first-line anticancer treatment may predict treatment response in further lines in stage III/IV patients with non-small cell lung cancer
Monika Bratova, Jana Skrickova, Magda Matusikova, Karolina Hrabcova, Libor Havel, Leona Koubkova, Michal Hrnciarik, Jana Krejci, Ondrej Fischer, Martin Svaton, Kristian Brat
Journal of Cancer Research and Clinical Oncology.2023; 149(19): 17123. CrossRef

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Real-World Study of Osimertinib in Korean Patients with Epidermal Growth Factor Receptor T790M Mutation–Positive Non–Small Cell Lung Cancer: Jang Ho Lee, Eun Young Kim, Cheol-Kyu Park, Shin Yup Lee, Min ki Lee, Seong-Hoon Yoon, Jeong Eun Lee, Sang Hoon Lee, Seung Joon Kim, Sung Yong Lee, Jun Hyeok Lim, Tae-Won Jang, Seung Hun Jang, Kye Young Lee, Seung Hyeun Lee, Sei Hoon Yang, Dong Won Park, Chan Kwon Park, Hye Seon Kang, Chang Dong Yeo, Chang-Min Choi, Jae Cheol Lee; Cancer Res Treat. 2023;55(1):112-122. Published online July 19, 2022; DOI: https://doi.org/10.4143/crt.2022.381

Abstract PDF Supplementary Material PubReader ePub

Purpose
Although osimertinib is the standard-of-care treatment of epidermal growth factor receptor (EGFR) T790M mutation–positive non–small cell lung cancer, real-world evidence on the efficacy of osimertinib is not enough to reflect the complexity of the entire course of treatment. Herein, we report on the use of osimertinib in patients with EGFR T790M mutation–positive non–small cell lung cancer who had previously received EGFR tyrosine kinase inhibitor (TKI) treatment in Korea.
Materials and Methods
Patients with confirmed EGFR T790M after disease progression of prior EGFR-TKI were enrolled and administered osimertinib 80 mg daily. The primary effectiveness outcome was progression-free survival, with time-to-treatment discontinuation, treatment and adverse effects leading to treatment discontinuation, and overall survival being the secondary endpoints.
Results
A total of 558 individuals were enrolled, and 55.2% had investigator-assessed responses. The median progression-free survival was 14.2 months (95% confidence interval [CI], 13.0 to 16.4), and the median time-to-treatment discontinuation was 15.0 months (95% CI, 14.1 to 15.9). The median overall survival was 36.7 months (95% CI, 30.9 to not reached). The benefit with osimertinib was consistent regardless of the age, sex, smoking history, and primary EGFR mutation subtype. However, hepatic metastases at the time of diagnosis, the presence of plasma EGFR T790M, and the shorter duration of prior EGFR-TKI treatment were poor predictors of osimertinib treatment. Ten patients (1.8%), including three with pneumonitis, had to discontinue osimertinib due to severe adverse effects.
Conclusion
Osimertinib demonstrated its clinical effectiveness and survival benefit for EGFR T790M mutation–positive in Korean patients with no new safety signals.

Citations

Citations to this article as recorded by

Germ-line exon 21 EGFR V831H mutation in advanced NSCLC resistance to almonertinib: a case report
Daxia Cai, Jian Lou, Yanyan Zhu, Yonghui Wang
Frontiers in Oncology.2026;[Epub] CrossRef
Clinical impact of local consolidative therapy in EGFR-mutant metastatic NSCLC: A propensity-matched multicenter analysis
Eun Hye Lee, Mi-Hyun Kim, Da Hyun Kang, Jisu Moon, Se Hyun Kwak, Jung Seop Eom, Jeong Eun Lee, Chi Young Kim, Yoon Soo Chang, Sang Hoon Lee, Eun Young Kim, Chang Young Lee, Jaeho Cho
Lung Cancer.2026; 217: 109423. CrossRef
Impact of chronic obstructive pulmonary disease on clinical outcomes of EGFR-mutated non–small cell lung cancer patients receiving osimertinib
Chiyo Ishikawa, Yuki Ikematsu, Hiroaki Ogata, Toshifumi Ninomiya, Takahiro Utsumi, Norio Yamamoto, Daisuke Shibahara, Kohei Otsubo, Yoshimasa Shiraishi, Eiji Iwama, Isamu Okamoto
International Journal of Lung Cancer.2026; 1(2): 100032. CrossRef
Osimertinib in EGFR-mutated non-small cell lung cancer: a comprehensive narrative review of clinical evidence
Xiumei Tang, Yuan Zhu, Jiayi Yan, Haoying Wu, Yanmei Chen, Yuan Liu, Huairong Tang, Wenzhao Wang, Zhoufeng Wang
Journal of Translational Genetics and Genomics.2026; 10(2): 228. CrossRef
Molecular testing, treatment patterns, and outcomes in EGFR-mutated non-small cell lung cancer: the PISCES study
Panwen Tian, Lin Wu, Chengzhi Zhou, Jie Tan, Ke Wang, Feng Luo, Yongmei Liu, Yubiao Guo, Yinyin Li, Zhe Liu, Youling Gong, Yongsheng Wang, Jinghong Xian, Weimin Li
Future Oncology.2025; 21(19): 2537. CrossRef
Safety of osimertinib in Chinese patients with non-small cell lung cancer: a multi-center, prospective, observational study
Hua Zhong, Shunjun Jiang, Wenxiu Yao, Xia Song, Dongqing Lv, Dan Zhu, Yubiao Guo, Cuimin Ding, Yingjie Xue, Xiuli Bai, Liguo Xiao, Peifeng Chen, Yan Wang, Panwen Tian, Gen Lin, Wen Li, Jun Chen, Yanping Hu, Bing Xia, Ziping Wang, Hao Long, Weirong Yao, Ha
Future Oncology.2025; 21(28): 3639. CrossRef
Real-world treatment outcomes in South Korean patients with epidermal growth factor receptor-mutant non-small cell lung cancer
Young Saing Kim, Eun Young Lee, Hyun Woo Lee, Jin-Hyuk Choi, Tae-Hwan Kim, Yong Won Choi, Mi Sun Ahn
The Korean Journal of Internal Medicine.2025; 40(6): 1029. CrossRef
The importance of re-biopsy in the era of molecular therapy for lung cancer
Nensi Lalic, Daliborka Bursac, Marko Bojovic, Marko Nemet, Ivan Ergelasev
Srpski arhiv za celokupno lekarstvo.2024; 152(3-4): 209. CrossRef
Detection of EGFR exon 20 insertion mutations in non-small cell lung cancer: implications for consistent nomenclature in precision medicine
Jieun Park, Boram Lee, Ji-Young Song, Minjung Sung, Mi Jeong Kwon, Chae Rin Kim, Sangjin Lee, Young Kee Shin, Yoon-La Choi
Pathology.2024; 56(5): 653. CrossRef
Real‐world study of lazertinib as second‐line or greater treatment in advanced non‐small cell lung cancer
Jeong Uk Lim, Kyuhwan Kim, Kyu Yean Kim, Hye Seon Kang, Ah. Young Shin, Chang Dong Yeo, Sung Kyoung Kim, Chan Kwon Park, Sang Haak Lee, Seung Joon Kim
Thoracic Cancer.2024; 15(19): 1513. CrossRef
Comparative effectiveness of lazertinib in patients with EGFR T790M-positive non-small-cell lung cancer using a real-world external control
Ha-Lim Jeon, Meesong Kwak, Sohee Kim, Hye-Yeon Yu, Ju-Young Shin, Hyun Ae Jung
Scientific Reports.2024;[Epub] CrossRef
A Randomized, Multi-Center, Open Label Study to Compare the Safety and Efficacy between Afatinib Monotherapy and Combination Therapy with HAD-B1 for the Locally Advanced or Metastatic NSCLC Patients with EGFR Mutations
Eunbin Kwag, Soo-Dam Kim, Seong-Hoon Shin, Chulho Oak, So-Jung Park, Jun-Yong Choi, Seong Hoon Yoon, In-Cheol Kang, Mi-Kyung Jeong, Hyun Woo Lee, Sun-Hwi Bang, Ji Woong Son, Sanghun Lee, Seung Joon Kim, Hwa-Seung Yoo
Integrative Cancer Therapies.2024;[Epub] CrossRef
Clinical utility of repeated rebiopsy for EGFR T790M mutation detection in non-small cell lung cancer
Eun Hye Lee, Se Hyun Kwak, Kyeong Yeon Kim, Chi Young Kim, Sang Hoon Lee, Seok-Jae Heo, Yoon Soo Chang, Eun Young Kim
Frontiers in Oncology.2024;[Epub] CrossRef
Real-world evidence of osimertinib in Chinese patients with EGFR T790M-positive non-small cell lung cancer: a subgroup analysis from ASTRIS study
Qing Zhou, He-Long Zhang, Li-Yan Jiang, Yuan-Kai Shi, Yuan Chen, Jin-Ming Yu, Cai-Cun Zhou, Yong He, Yan-Ping Hu, Zong-An Liang, Yue-Yin Pan, Wen-Lei Zhuo, Yong Song, Gang Wu, Gong-Yan Chen, You Lu, Cui-Ying Zhang, Yi-Ping Zhang, Ying Cheng, Shun Lu, Chan
Journal of Cancer Research and Clinical Oncology.2023; 149(12): 10771. CrossRef

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miR-4487 Enhances Gefitinib-Mediated Ubiquitination and Autophagic Degradation of EGFR in Non-Small Cell Lung Cancer Cells by Targeting USP37: Mi Seong Kim, So Hui Kim, Sei Hoon Yang, Min Seuk Kim; Cancer Res Treat. 2022;54(2):445-457. Published online August 3, 2021; DOI: https://doi.org/10.4143/crt.2021.622

Abstract PDF PubReader ePub

Purpose
With the identification of epidermal growth factor receptor (EGFR) mutations in non–small cell lung cancer (NSCLC) cells, EGFR–tyrosine kinase inhibitors (TKIs) are being used widely as the first-line of treatment in NSCLC. These inhibitors block auto-phosphorylation of activated EGFR by competing with ATP binding and mediate EGFR degradation independent of exogenous epidermal growth factor, which is associated with the mutation variants of EGFR. However, the precise mechanisms underlying the TKI-mediated EGFR degradation are still unclear.
Materials and Methods
To examine the physiological roles of miR-4487 and ubiquitin-specific peptidase 37 (USP37) in gefitinib-mediated EGFR degradation in NSCLC cells, multiple NSCLC cell lines were applied. The level of EGFR expression, apoptosis marker and autophagic flux were determined by western blot. Expression level of miR-4487 and cell cycle arrest was analyzed by TaqMan assay and flow cytometry respectively.
Results
We found that gefitinib mediates EGFR degradation under normal culture conditions, and is dependent on autophagic flux and the mutation variants of EGFR. Gefitinib reduced expression levels of USP37, which mediated EGFR degradation similar to gefitinib. Our results also showed a gefitinib-mediated increase in endogenous miR-4487 level and presented evidence for the direct targeting of USP37 by miR-4487, resulting in the sequential enhancement of ubiquitination, autophagy, and EGFR degradation. Thus, the depletion of USP37 and overexpression of miR-4487 led to an increase in gefitinib-mediated apoptotic cell death.
Conclusion
These data suggest that miR-4487 is a potential target for treating NSCLC, and miR-4487/USP37-regulated EGFR degradation is a determinant for developing gefitinib resistance.

Citations

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Oncogene.2026; 45(4): 521. CrossRef
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L Xu, L Wang, R Yang, T Li, X Zhu
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