Fusion isoform multiplicity and impact on treatment outcomes in ALK-rearranged non-small cell lung cancer with next-generation tyrosine kinase inhibitors.

BACKGROUND: ALK-rearranged non-small cell lung cancer (NSCLC) reported controversies regarding the impact the ALK-fused genes on treatment outcome. Fusion isoforms are structural variants of the same fusion transcript. Recent evidence suggests that the presence of multiple isoforms within a single tumor is associated with reduced response to crizotinib. Whether ALK fusion isoforms affect treatment with next-generation ALK-tyrosine kinase inhibitors (TKIs) remains to be determined. METHODS: This analysis retrospectively involved 89 advanced ALK-rearranged (ALK + ) NSCLC patients treated with next-generation TKIs in first-line setting in five French centers from 2006 to 2023 and with RNA-seq routinely performed. We used multivariate Cox regression models to identify potential correlations between the presence of isoform multiplicity, other clinical factors, and PFS. RESULTS: ALK + patients with multiple isoforms (n = 38, 42.7 %) showed a significantly shorter median PFS compared to patients with a single isoform (multiple:14.6 months; single: 27.1 months, HR 0.58 0.33-1.02, p = 0.0499). The multivariate analysis reported that multiple isoforms and PD-L1 ≥ 50 % expression were independently negatively associated with PFS. Exploratory analyses did not identify ALK fusion-v3 variant as independently associated with shorter PFS. Eight of the 9 patients with emergent ALK p.G1202R mutation at disease progression had multiple isoforms. Subsequent biopsies performed in 19 patients at progression revealed that isoform profiles changed during treatment course. CONCLUSION: This analysis confirmed the presence of multiple isoforms in ALK-rearranged NSCLC and patients with multiple isoforms treated with next-generation TKIs reported a shorter PFS. Improved knowledge in isoform complexity would be required to provide more personalized therapeutic approaches to ALK+- NSCLC patients.