"Variant matters": the impact of ALK fusion subtypes on progression and response in non-small-cell lung cancer-data from clinical practice from Polish centers.

BACKGROUND

For patients with advanced non-small-cell lung cancer (NSCLC) who have anaplastic lymphoma kinase (ALK) gene rearrangements, targeted therapy with ALK inhibitors (ALKi) is now regarded as the standard of care. The main objective of the study was to identify ALK gene fusion variants in the study population and determine the frequency of occurrence of individual variants. In addition, overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) were evaluated with regard to specific variants.

METHODS

We conducted a retrospective analysis of 61 patients with lung adenocarcinoma with detected ALK gene fusion variant determined in next-generation sequencing (NGS) treated between 2019 and 2022 at the Department of Lung and Thoracic Tumours of the National Cancer Institute in Warsaw and the Department of Pneumonology, Oncology, and Allergology of the Medical University of Lublin. Patients were treated with crizotinib, alectinib, or brigatinib.

RESULTS

On the 61 tumours analyzed, variant 1 was the most common in the study group (37.7% of patients), followed by variants 2 and 3, found with similar frequency in the study population (in 27.9% and 21.3% of patients, respectively). Disease stabilization occurred slightly more often in patients with variant 1, and progressive disease (PD) slightly more often in patients with variant 3 of the ALK gene fusion. The patients with variant 2 of the ALK gene fusion gene had a significantly lower risk of progression compared to those with other variants of this gene, with a median PFS that was not reached (NR) vs. 24 months; hazard ratio (HR) =0.3509; 95% confidence interval (CI): 0.1498-0.8291; P=0.02. Patients with variant 3 of the ALK fusion gene had a significantly higher risk of death in comparison to patients with other variants of the ALK fusion gene-median OS was 31 vs. 58 months; HR =2.5204; 95% CI: 1.0234-6.2071; P=0.044.

CONCLUSIONS

Our results highlight the high efficacy of ALKi in achieving disease control (DC) in patients with ALK-positive NSCLC, regardless of the specific fusion variant or treatment regimen. However, the subtle differences in stable disease (SD) and PD rates among fusion variants suggest that genetic profiling may be useful in predicting the durability of response.