Receptor tyrosine kinase fusion-mediated resistance to EGFR-TKI in EGFR-mutant NSCLC: a multi-center analysis and literature review

Abstract

Background: Drug resistance remains a significant challenge in EGFR-mutant NSCLC tumors engage due 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 heterogenous 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 NGS 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 (MDACC) 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 patient cases with RTK fusion as 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 cases received dual TKI after fusion detection, 9 received fusion targeting single TKIs. Median time on treatment was 169 days (35 - 1050, 5.8 months). ORR by RECIST in the evaluable 25 cases was 24% and disease control rate (DCR) was 80%. In 14 evaluable patients who received dual TKI therapy, ORR by RECIST was 21.4% and DCR 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: 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 post progression on EGFR TKIs.

Keywords: EGFR; RTK fusions; resistance mechanisms.