Efficacy and safety of limertinib versus gefitinib as first-line treatment for locally advanced or metastatic non-small-cell lung cancer with EGFR-sensitising mutation: a randomised, double-blind, double-dummy, phase 3 trial
Open accessAbstract
Background Limertinib is a new third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. This study aimed to prospectively assess the efficacy and safety of limertinib versus gefitinib as a first-line treatment for locally advanced or metastatic non-small-cell lung cancer (NSCLC) with EGFR-sensitising mutation.Methods This multicentre, randomised, double-blind, double-dummy, phase 3 trial was done at 56 hospitals in China. Eligible patients were aged ≥18 years with locally advanced or metastatic NSCLC with EGFR-sensitising mutation (exon 19 deletion or exon 21 L858R mutation) detected in tumour tissue samples using the Cobas EGFR Mutation Test at a central laboratory. Patients were randomly assigned (1:1) to receive oral limertinib 80 mg twice a day and gefitinib-matching placebo 250 mg once a day or oral gefitinib 250 mg once a day plus limertinib-matching placebo 80 mg twice a day in 21-day cycles, until disease progression or other discontinuation criteria was met. Random assignment was stratified according to EGFR mutation type (exon 19 deletion or exon 21 L858R mutation) and CNS metastasis (yes or no) using permuted blocks (block size four) through an interactive web-based response system. The primary endpoint was independent central review (ICR)-assessed progression-free survival. All enrolled patients who received at least one dose of study treatment were included in the full analysis set for efficacy analysis. All enrolled patients who received at least one dose of study treatment and one safety assessment were included in the safety set. This study is registered with ClinicalTrials.gov, NCT04143607, and follow-up is ongoing.Findings Between June 30, 2021, and Sept 22, 2022, 337 patients were enrolled and 168 were randomly assigned to the limertinib group and 169 to the gefitinib group. Patients' median age was 63 years (34-82). 214 (64%) of 337 patients were female and 123 (36%) were male. The median masked ICR-assessed progression-free survival was 20·7 months (95% CI 15·2-22·1) in the limertinib group and 9·7 months (95% CI 8·3-11·1) in the gefitinib group (hazard ratio [HR] 0·44 [95% CI 0·34-0·58]; p<0·0001). Treatment-related adverse events of grade 3 or worse occurred in 42 (25%) of 168 patients in the limertinib group and 42 (25%) of 169 patients in the gefitinib group. Treatment-related serious adverse events occurred in nine (5%) patients and 17 (10%) patients in each group, respectively. Six (4%) patients in the limertinib group died due to adverse events, all of which were considered possibly unrelated to the study drug by investigators. In the gefitinib group, seven (4%) patients died due to adverse events, with three (2%) of those deaths judged as possibly related to the study drug by investigators. Three treatment-related deaths in the gefitinib group were recorded (one case related to pneumonia and two with cause of death unknown).Interpretation Limertinib showed superior efficacy compared with gefitinib and a manageable safety profile for locally advanced or metastatic NSCLC patients with EGFR-sensitising mutation and should be considered as another first-line treatment option for this patient population.Funding Jiangsu Aosaikang Pharmaceutical.Translation For the Chinese translation of the abstract see Supplementary Materials section.
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Cites
Bray, F., Laversanne, M., Sung, H., Ferlay, J., Siegel, R. L., Soerjomataram, I., & Jemal, A. (2024) · CA: a cancer journal for clinicians · doi:10.3322/caac.21834 · Cited by 27,064 · see citing works
Gefitinib or Carboplatin–Paclitaxel in Pulmonary Adenocarcinoma
Mok, T. S., Wu, Y.-L., Thongprasert, S., Yang, C.-H., Chu, D.-T., Saijo, N., Sunpaweravong, P., Han, B., Margono, B., Ichinose, Y., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0810699 · Cited by 8,261 · see citing works
Osimertinib in Untreated <i>EGFR</i> -Mutated Advanced Non–Small-Cell Lung Cancer
Soria, J.-C., Ohe, Y., Vansteenkiste, J., Reungwetwattana, T., Chewaskulyong, B., Lee, K. H., Dechaphunkul, A., Imamura, F., Nogami, N., Kurata, T., et al. (2018) · New England Journal of Medicine · doi:10.1056/nejmoa1713137 · Cited by 5,508 · see citing works
Zhou, C., Wu, Y.-L., Chen, G., Feng, J., Liu, X.-Q., Wang, C., Zhang, S., Wang, J., Zhou, S., Ren, S., et al. (2011) · The Lancet Oncology · doi:10.1016/s1470-2045(11)70184-x · Cited by 4,081 · see citing works
Self-citationSequist, L. V., Yang, J. C.-H., Yamamoto, N., O'Byrne, K., Hirsh, V., Mok, T., Geater, S. L., Orlov, S., Tsai, C.-M., Boyer, M., et al. (2013) · Journal of Clinical Oncology · doi:10.1200/jco.2012.44.2806 · Cited by 3,228 · see citing works
Thai, A. A., Solomon, B., Sequist, L. V. D., Gainor, J. F., & Heist, R. S. (2021) · The Lancet · doi:10.1016/s0140-6736(21)00312-3 · Cited by 2,629 · see citing works
AZD9291 in EGFR Inhibitor–Resistant Non–Small-Cell Lung Cancer
Jänne, P. A., Yang, J. C.-H., Kim, D.-W., Planchard, D., Ohe, Y., Ramalingam, S. S., Ahn, M.-J., Kim, S.-W., Su, W.-C., Horn, L., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1411817 · Cited by 2,116 · see citing works
Wu, Y.-L., Cheng, Y., Zhou, X., Lee, K. H., Nakagawa, K., Niho, S., Tsuji, F., Linke, R., Rosell, R., Corral, J., et al. (2017) · The Lancet Oncology · doi:10.1016/s1470-2045(17)30608-3 · Cited by 1,216 · see citing works
Shi, Y., Wang, L., Han, B., Li, W., Yu, P., Liu, Y. P., Ding, C. M., Song, X., Ma, Z. Y., Ren, X. L., et al. (2017) · Annals of Oncology · doi:10.1093/annonc/mdx359 · Cited by 334 · see citing works
Self-citationLü, S., Dong, X., Jian, H., Chen, J., Chen, G., Sun, Y., Ji, Y., Wang, Z., Shi, J., Lu, J., et al. (2022) · Journal of Clinical Oncology · doi:10.1200/jco.21.02641 · Cited by 311 · see citing works
Self-citationMolecular Pathways: Resistance to Kinase Inhibitors and Implications for Therapeutic Strategies
Lovly, C. M., & Shaw, A. T. (2014) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-13-1610 · Cited by 276 · see citing works
Clinical Implications of Genomic Discoveries in Lung Cancer
Swanton, C., & Govindan, R. (2016) · New England Journal of Medicine · doi:10.1056/nejmra1504688 · Cited by 271 · see citing works
Shi, Y., Chen, G., Wang, X., Liu, Y., Wu, L., Hao, Y., Liu, C., Zhu, S., Zhang, X., Li, Y., et al. (2022) · The Lancet Respiratory Medicine · doi:10.1016/s2213-2600(22)00168-0 · Cited by 236 · see citing works
Self-citationEpidermal Growth Factor and Intestinal Barrier Function
Tang, X., Liu, H., Yang, S., Li, Z., Zhong, J., & Fang, R. (2016) · Mediators of Inflammation · doi:10.1155/2016/1927348 · Cited by 171 · see citing works
Self-citationCho, B. C., Ahn, M., Kang, J. H., Soo, R. A., Reungwetwattana, T., Yang, J. C., Çiçin, İ., Kim, D., Wu, Y.-L. L. C., Lü, S., et al. (2023) · Journal of Clinical Oncology · doi:10.1200/jco.23.00515 · Cited by 155 · see citing works
Lü, S., Wang, Q., Zhang, G., Dong, X., Yang, C., Song, Y., Chang, G., Lü, Y., Pan, H., Chiu, C., et al. (2021) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2021.10.024 · Cited by 149 · see citing works
Self-citationZhang, T., Qu, R., Chan, S., Lai, M., Tong, L., Fěng, F., Chen, H., Song, T., Song, P., Bai, G., et al. (2020) · Molecular Cancer · doi:10.1186/s12943-020-01202-9 · Cited by 147 · see citing works
Self-citationShi, Y., Hu, X., Zhang, S., Lv, D., Wu, L., Yu, Q., Zhang, Y., Liu, L., Wang, X., Cheng, Y., et al. (2021) · The Lancet Respiratory Medicine · doi:10.1016/s2213-2600(20)30455-0 · Cited by 119 · see citing works
Self-citationShi, Y., Zhang, S., Hu, X., Feng, J., Ma, Z., Zhou, J., Yang, N., Wu, L., Liao, W., Zhong, D., et al. (2020) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2020.01.010 · Cited by 111 · see citing works
Self-citationLü, S., Zhou, J., Jian, H., Wu, L., Cheng, Y., Fan, Y., Fang, J., Chen, G., Zhang, Z., Lv, D., et al. (2023) · The Lancet Respiratory Medicine · doi:10.1016/s2213-2600(23)00183-2 · Cited by 77 · see citing works
Self-citationShi, Y., Li, B., Wu, L., Pan, Y., Pan, Z., Liu, Y., Fan, Y., Ji, Y., Fang, J., Shi, Q., et al. (2022) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2022.05.011 · Cited by 34 · see citing works
Self-citationShi, Y., Wu, S., Wang, K., Cang, S., Yao, W., Fan, Y., Wu, L., Huang, M., Li, X., Pan, Y., et al. (2022) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2022.08.015 · Cited by 33 · see citing works
Self-citationShi, Y., Zhao, Y., Yang, S., Zhou, J., Zhang, L., Chen, G., Fang, J., Zhu, B., Li, X., Shu, Y., et al. (2022) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2022.01.015 · Cited by 27 · see citing works
Self-citationLü, S., Zhang, Y., Zhang, G., Zhou, J., Cang, S., Cheng, Y., Wu, G., Cao, P., Lv, D., Jian, H., et al. (2022) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2022.06.002 · Cited by 27 · see citing works
Self-citationShi, Y., Guo, Y., Li, X., Wu, L., Chen, Z., Yang, S., Bi, M., Zhao, Y., Yao, W., Yu, H., et al. (2025) · The Lancet Respiratory Medicine · doi:10.1016/s2213-2600(24)00417-x · Cited by 21 · see citing works
Self-citationXiong, A., Ren, S., Liu, H., Miao, L., Wang, L., Chen, J., Li, W., Li, R., Wang, X., Lu, Z., et al. (2022) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2022.06.013 · Cited by 20 · see citing works
Self-citationShi, Y., Zhou, J., Zhao, Y., Zhu, B., Zhang, L., Li, X., Fang, J., Shi, J., Zhuang, Z., Yang, S., et al. (2023) · BMC Medicine · doi:10.1186/s12916-022-02692-8 · Cited by 13 · see citing works
Self-citationZhou, C., & Xiong, A. (2024) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2024.09.027 · Cited by 9 · see citing works
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Research works printed but not linked: 1
- Thai AA, Solomon BJ, Sequist LV, Gainor JF, Heist RS. Lung cancer. Lancet 2021; 398: 535-54.
- Authors
- Shi, Y., Wu, L., Ji, Y., Chen, G., Li, B., Bi, M., Yang, R., Miao, L., Zhang, G., Gao, H., Sun, L., Zhang, M., Cang, S., Sun, M., Yao, W., Pan, Z., Cui, J., Xiao, Y., Wang, Q., Song, Y., Shi, M., Wang, D., Li, Z., Liu, H., Dong, X., Wang, X., Fang, J., Xie, Y., Zang, A., Chen, M., Song, X., Wang, K., Chen, B., Chen, Q., Wang, H., Sun, P., Li, W., Zhang, Y., Zhong, D., Hao, X., Zhou, T., Bai, Y., Shi, J., Zhang, Y., Li, J., Li, Y., Xiao, J., Pan, H., Zhao, Y., Lu, H., Yin, M., Chen, H., Song, T., & Wei, X.
- Affiliations
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Central South University (CN)
- First Affiliated Hospital of Xinxiang Medical University (CN)
- Harbin Medical University (CN)
- Capital Medical University (CN)
- First Affiliated Hospital of Bengbu Medical College (CN)
- Nanjing Drum Tower Hospital (CN)
- Chinese PLA General Hospital (CN)
- First Affiliated Hospital of Nanchang University (CN)
- Second Affiliated Hospital of Anhui Medical University (CN)
- Henan Provincial People's Hospital (CN)
- Jinan Central Hospital (CN)
- University of Electronic Science and Technology of China (CN)
- First Affiliated Hospital Zhejiang University (CN)
- First Hospital of Jilin University (CN)
- Yan'an Hospital Affiliated To Kunming Medical University (CN)
- Zhengzhou University (CN)
- Corresponding author
- Shi, Yuankai
- ORCID
- Venue
- The Lancet Respiratory Medicine
- Publisher
- Elsevier BV
- Published
- 2025-08
- Volume
- 13
- Issue
- 8
- Pages
- 677-686
- ISSN
- 2213-2600 (ISSN-L)
- OpenAlex
- W4411477030
- Cited by
- 16
- References
- 28
- Citations by year
- 2026: 11 · 2025: 5
- FWCI
- 10.44
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The Lancet Respiratory Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Transformation Program of Scientific and Technological Achievements of Jiangsu Province (BA2021011)
- National Science and Technology Major Project (2017ZX09304015)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Diagnosis and Treatment
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Keywords
- gefitinib, non-small cell lung cancer, EGFR mutation, EGFR tyrosine kinase inhibitors, first-line therapy, exon 19 deletion, L858R mutation, progression-free survival, central nervous system metastasis, drug safety, third-generation EGFR tyrosine kinase inhibitors
- MeSH terms
- Gefitinib, Adult, Aged, Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, China, Double-Blind Method, Female, Humans, Lung Neoplasms, Male, Middle Aged, Mutation, Protein Kinase Inhibitors, ErbB Receptors
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