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.