ALK Inhibitor Response in Novel ZFPM2::ALK and TRIM24::ALK Fusion-Positive Lung Cancers: Case Report
Year: 2025
Type: article
Study design: Case Report
Abstract: Background ALK fusion-positive NSCLC is driven by a range of fusion partners, most often EML4::ALK . The clinical impact, oncogenicity, and resistance mechanisms of rare, noncanonical ALK fusions remain underexplored. We describe two previously unreported ALK 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 ZFPM2::ALK and TRIM24::ALK fusions. Both patients achieved marked partial responses to first-line alectinib, confirming the oncogenic and actionable nature of the fusions. The patient with ZFPM2::ALK fusion developed leptomeningeal disease after 27 months; CSF NGS revealed persistent fusion and newly acquired CDKN2A/B deletion. The patient with TRIM24::ALK fusion, following durable responses to alectinib and lorlatinib, relapsed with detection of on-target ALK kinase domain mutations (F1174V, I1171N) and MYC amplification on progression. Conclusions These cases expand the landscape of noncanonical ALK 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.
Authors: Charles Hsu, Mohamed Yakoub, Michael Offin, Juliana Eng, Alexander Drilon, Soo-Ryum Yang
Institution: Memorial Sloan Kettering Cancer Center
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,000
OpenAlex ID: W4416527879