Abstract 87P
Background
ALK rearrangements occur in 3–5% of NSCLC cases. ALK tyrosine kinase inhibitors (TKIs) have revolutionized treatment, improving outcomes. Next-generation sequencing (NGS) enables comprehensive genomic profiling, uncovering additional alterations in pathways such as DNA repair, epigenetic regulation, and cell cycle that may influence resistance and disease progression.
Methods
We performed a retrospective analysis of 74 patients (pts) treated at Fondazione IRCCS Istituto Nazionale dei Tumori in Milan between 2013 and 2024. Clinical and pathological data were collected. NGS OCAPlus DNA/RNA was undertaken in 29 patients (pts). Survival rates were estimated using Kaplan-Meier curves.
Results
The cohort had a male majority (55.4%); the median age was 59 years. Most were never smokers (59.5%); adenocarcinoma histology was present in 93.3% of pts. ECOG Performance Status (PS) was mainly 0–1 (93.3%). 70 pts (94.6%) received first-line ALK TKIs, predominantly Alectinib (71.6%). At a median follow-up of 31 months (mo), median Overall Survival was not reached (95% CI: 87.7–NR). Median Progression-Free Survival with first-line TKIs was 66.3 mo (95% CI: 23.2–NR), while the overall response rate was 87.8% (95% CI: 78.1–94.2). Among patients who underwent NGS OCAPlus testing, the most frequently altered pathways were categorized: DNA repair (14 patients, 48.7%), epigenetic regulation (10 patients, 34.4%), cell cycle (9 patients, 31.0%), cell adhesion and extracellular matrix (9 patients, 31.0%), and enzymatic metabolism and oxidative stress (5 patients, 17.2%). Tissue and liquid biopsies at disease progression were performed in 22 pts of the whole cohort (29.7%). Resistance mechanisms were identified in 16.2% of pts, primarily on-target mutations (mainly I1171N and G1202R with 5.4% each), followed by histologic transformation to LCNEC in 3 pts (4.0%) and MET amplification in 1 pt (1.3%).
Conclusions
Our findings highlight the prevalence of genetic alterations in pathways such as DNA repair and epigenetic regulation among ALK-rearranged NSCLC patients. These alterations may provide insights into resistance mechanisms and guide future therapeutic strategies to improve patient outcomes.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.