ALK Inhibitor Response in Novel and Fusion-Positive Lung Cancers: Case Report.

[BACKGROUND] fusion-positive NSCLC is driven by a range of fusion partners, most often . The clinical impact, oncogenicity, and resistance mechanisms of rare, noncanonical fusions remain underexplored. We describe two previously unreported fusion partners in NSCLC and explore the potential mechanisms of resistance in each case, including on-target and bypass mutations, as well as the use of next-generation sequencing (NGS) testing on cerebrospinal fluid (CSF) as a useful tool.

[CASE PRESENTATION] We report two patients with metastatic NSCLC harboring novel and fusions. Both patients achieved marked partial responses to first-line alectinib, confirming the oncogenic and actionable nature of the fusions. The patient with fusion developed leptomeningeal disease after 27 months; CSF NGS revealed persistent fusion and newly acquired deletion. The patient with fusion, following durable responses to alectinib and lorlatinib, relapsed with detection of on-target kinase domain mutations (F1174V, I1171N) and amplification on progression.

[CONCLUSIONS] These cases expand the landscape of noncanonical fusions in NSCLC which are responsive to approved ALK TKIs and offer insights into oncogenic and resistance mechanisms. Comprehensive molecular workup, including RNA-based NGS, is essential for detecting rare but actionable ALK rearrangements and optimizing therapeutic strategy. NGS of CSF was a valuable tool for the detection of clinically suspected leptomeningeal disease and disease monitoring.