Treatment for EGFR-Sensitive Mutation NSCLC
Numerous EGFR-TKIs are approved for EGFR-sensitive mutation NSCLC, including gefitinib, erlotinib, icotinib, osimertinib, and 11 others. First-line monotherapy yields a median PFS of 9.6–22.1 months and OS of 16.6–38.6 months. The FLAURA2 study confirmed osimertinib + chemotherapy significantly prolonged PFS (29.4 vs. 19.9 months; HR 0.62, p<0.001), approved by FDA (Feb 2024) and NMPA (Jun 2024). The MARIPOSA study showed lazertinib + amivantamab improved PFS (23.7 vs. 16.6 months; HR 0.70, p<0.001), FDA-approved in Aug 2024. Combinations with anti-angiogenic agents, immunotherapy, or radiotherapy are under investigation.
Treatment for Uncommon EGFR Mutation NSCLC
Uncommon mutations include exon 20 insertions, G719X, L861Q, and S768I. The WU-KONG6 study reported sunvozertinib’s ORR of 61% (post-line) and 73.1% (first-line) for exon 20 insertions, NMPA-approved in Aug 2023. The PAPILLON study showed amivantamab + chemotherapy prolonged PFS (11.4 vs. 6.7 months; HR 0.40, p<0.001), FDA-approved in Mar 2024. Phase 3 trials for exon 20 insertions include sunvozertinib (NCT05668988), furmonertinib (NCT05607550), etc. For G719X/L861Q/S768I mutations, first-generation EGFR-TKIs are ineffective, but second/third-generation ones work: afatinib (FDA-approved 2018), osimertinib (ORR 50%–55%), mefatinib (ORR 85.7%, NMPA breakthrough therapy 2023). Ongoing trials include furmonertinib (NCT05548348) and sutetinib (NCT05168566).
Perioperative Treatment with EGFR-TKIs
In perioperative settings, EGFR-TKIs are validated. The EVIDENCE study showed icotinib prolonged DFS (47.0 vs. 22.1 months; HR 0.36, p<0.0001), NMPA-approved for II-IIIA 期 adjuvant therapy in Jun 2021. The ADAURA study confirmed osimertinib improved DFS (65.8 vs. 21.9 months; HR 0.23), FDA-approved for IB-IIIA 期 adjuvant therapy in Dec 2020. Phase 2 trials of gefitinib, erlotinib, osimertinib, etc., as neoadjuvant therapy show promise; phase 3 trials (gefitinib NCT03203590, osimertinib NCT04351555) are ongoing.
Mechanisms of EGFR-TKI Resistance
Resistance is divided into primary (e.g., EGFR exon 20 insertions) and secondary. Secondary resistance includes on-target (EGFR amplification, T790M/C797S mutations, etc.) and off-target mechanisms (MET/HER2/FGFR alterations, RAS–MAPK/PI3K/AKT/mTOR pathway activation, EMT, SCLC transformation).
Post-Resistance Treatment Strategies
Resistance to first/second-generation EGFR-TKIs occurs in 9.2–14.7 months (main mechanism: T790M mutation). Third-generation EGFR-TKIs inhibit 19del/L858R/T790M mutations but develop resistance in 18.9–22.1 months (main mechanism: C797S mutation). Several fourth-generation EGFR-TKIs are in development (BBT-176, BLU-945, etc.). For other resistance mechanisms (MET amplification, RET/ROS1/ALK fusion, BRAF V600E mutation), combining EGFR-TKIs with targeted agents shows benefits. The ORIENT-31 study (sintilimab + bevacizumab + chemotherapy, PFS 6.9 vs. 4.3 months; HR 0.46, p<0.0001) and HARMONi-A study (evoralimab + chemotherapy, PFS 7.06 vs. 4.80 months; HR 0.46, p<0.0001) were NMPA-approved in May 2023 and 2024, respectively.
Summary
EGFR-TKIs have revolutionized EGFR-mutant NSCLC treatment, significantly improving OS and quality of life. However, challenges like resistance, optimal combination strategies, and maintenance duration remain. Further research is needed to refine therapies for precise, individualized treatment. The review was published in Volume 139, Issue 7 of the Chinese Medical Journal on April 05, 2026.
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Reference
DOI: 10.1097/CM9.0000000000004016
About Prof . Yuankai Shi from National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College
Member of the advisory committee of the New Drug Evaluation, National Medical Products Administration, China.
International Adversary Board member of The Lancet Oncology (2017.11-2020.12).
He was the principal investigator or participant for over 400 clinical trials and related research projects of anti-cancer drugs and completed the pivotal registration trials for 15 domestic anti-cancer new drugs or biosimilars. He has published over 470 articles in medical journals.
Highly Cited Chinese Researchers by Elsevier in 2020, 2021, 2022, and 2023.
The World’s Top 2% Scientists in 2021, 2022, 2023, and 2024.
The Editor in Chief of Cancer Pathogenesis and Therapy .
Funding information
This work was supported by grants from Chinese National Major Project for New Drug Innovation (No. 2017ZX09304015), National Natural Science Foundation of China (No. 81972805), and Major Project of Medical Oncology Key Foundation of Cancer Hospital Chinese Academy of Medical Sciences (No. CICAMS-MOMP2022006).
Chinese Medical Journal
Literature review
Not applicable
Epidermal growth factor receptor tyrosine kinase inhibitor for the treatment of non-small cell lung cancer in the past 30 years (1997-2026)
5-Apr-2026