The influence of ROS1 fusion partners and resistance mechanisms in ROS1-TKI-treated non-small cell lung cancer...

Area of Science:

• Oncology
• Molecular Biology
• Clinical Research

Background:

• Limited data exists on clinical outcomes in ROS1-fusion positive non-small cell lung cancer (NSCLC) stratified by fusion partner and resistance mechanisms.
• ROS1 rearrangements are rare drivers in NSCLC, necessitating understanding of treatment efficacy and resistance patterns.

Purpose of the Study:

• To analyze clinical outcomes in ROS1-fusion positive NSCLC patients treated with tyrosine kinase inhibitors (TKIs).
• To investigate the impact of different fusion partners and acquired resistance mutations on TKI treatment response.
• To compare real-world TKI efficacy with findings from clinical trials.

Main Methods:

• A retrospective cohort study of 56 ROS1-fusion positive NSCLC patients.
• Fusion partners identified using FISH or NGS.
• Clinical data, including TKI treatment (crizotinib, lorlatinib), response rates, progression-free survival, and resistance mutations, were analyzed.

Main Results:

• Crizotinib showed a 55% objective response rate (ORR) and 5.3 months median progression-free survival (mPFS).
• Brain metastases and prior chemotherapy increased progression risk.
• Lorlatinib had a 28% ORR and 3.7 months mPFS; resistance mutations (G2032R, L2026M) were identified in non-responders.
• Fusion partners did not influence crizotinib outcomes.
• Real-world TKI efficacy was lower than reported in clinical trials.

Conclusions:

• Fusion partners did not impact crizotinib efficacy in ROS1+ NSCLC.
• Lorlatinib demonstrated limited efficacy against on-target resistance mutations.
• Real-world data suggests lower TKI effectiveness in ROS1+ NSCLC compared to clinical trials.
• Clinical and molecular factors significantly influence treatment response in this patient population.