Receptor Tyrosine Kinase Fusion-Mediated Resistance to EGFR TKI in EGFR-Mutant NSCLC: A Multi-Center Analysis and Literature Review

Authors

Yang Xia
Kaiwen Wang
Jing Zhao
Zhaohui Arter
Yongchang Zhang
Jiaqi Zhou
Yuefei Lu
Liang Zeng
Robyn Du
Jennifer A Owens
Yasir Y Elamin
Carl M Gay
Ferdinandos Skoulidis
Anne S Tsao
Charles Lu
Tina Cascone
Don L Gibbons
Jianjun Zhang
Olivia Chen
Kevin K S Mok
Misako Nagasaka
Wen Li
John V Heymach
Sai-Hong Ignatius Ou
Molly Li
Xiuning Le

Publication Date

4-1-2025

Journal

The Journal of Thoracic and Cardiovascular Surgery

DOI

10.1016/j.jtho.2024.11.027

PMID

39622411

Abstract

Introduction: Drug resistance remains a major clinical challenge in EGFR-mutant NSCLC tumors owing to pathway reactivation, pathway bypass, and pathway indifference resistance mechanisms to evade tyrosine kinase inhibitor (TKI) suppression. Fusion of receptor tyrosine kinases (RTKs), such as RET, ALK, and FGFR3, has been reported to mediate EGFR TKI resistance. Given the rarity of these fusions and the heterogeneous nature of the condition, no prospective clinical trials evaluated the incidence, safety, and therapeutic benefit of dual EGFR-RTK inhibition.

Methods: We queried clinical databases from multiple institutions to identify patients who had RTK fusions detected on next-generation sequencing testing results from tissue or blood at five institutions: the Second Affiliated Hospital Zhejiang University School of Medicine, Hunan Cancer Hospital, Prince of Wales Hospital Chinese University of Hong Kong, Chao Family Cancer Center, and the University of Texas MD Anderson Cancer Center from March 1, 2016, to September 30, 2023. The data analyzed included objective response rate (ORR) to treatment post RTK fusion detection, duration of treatment, and safety. A comprehensive literature search was conducted to identify patients with RTK fusion as the primary resistance mechanism in EGFR-mutated NSCLC patients.

Results: Twenty-seven patients were identified to be eligible in the analysis. ALK fusions were most reported (42.9%), followed by RET fusions (35.7%). Fifteen patients received dual TKI after fusion detection and nine received fusion targeting single TKIs. The median time on treatment was 169 days or 5.8 months (35-1050 d). ORR by the Response Evaluation Criteria in Solid Tumors in the evaluable 25 patients was 24% and the disease control rate was 80%. In 14 evaluable patients who received dual TKI therapy, ORR by the Response Evaluation Criteria in Solid Tumors was 21.4%, and the disease control rate was 78.6%. No new toxicities were observed with dual EGFR-RTK inhibition. In the literature review, after pooling 291 patients from 59 studies, RET fusions were the most common (50.0%), followed by BRAF (13.3%), ALK (13.3%), FGFR (10%), NTRK (5.3%), EGFR (1.7%), ROS1 (1.3%), MET (1%), and ERBB (0.7%).

Conclusion: The emergence of RTK fusions is one of the mechanisms of bypass resistance of EGFR TKI. Dual inhibition of EGFR-RTK was safe and efficacious in patients with targetable RTK fusion after progression to EGFR TKIs.

Keywords

Humans, Carcinoma, Non-Small-Cell Lung, Protein Kinase Inhibitors, Lung Neoplasms, ErbB Receptors, Drug Resistance, Neoplasm, Mutation, Male, Female, Middle Aged, Oncogene Proteins, Fusion, Aged, Receptor Protein-Tyrosine Kinases, EGFR, NSCLC, RTK fusions, Resistance mechanisms

Published Open-Access

yes

Recommended Citation

Xia, Yang; Wang, Kaiwen; Zhao, Jing; et al., "Receptor Tyrosine Kinase Fusion-Mediated Resistance to EGFR TKI in EGFR-Mutant NSCLC: A Multi-Center Analysis and Literature Review" (2025). Faculty, Staff and Student Publications. 4434.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/4434