Durable response to ALK inhibition in low-allele-frequency SPTBN1-ALK-rearranged gastric cancer followed by lineage plasticity-mediated resistance: a case report.

BACKGROUND: ALK rearrangements are rare in gastric cancer, and their therapeutic relevance remains poorly defined. While ALK inhibitors have demonstrated efficacy in lung cancer and other malignancies, data in gastric tumors are limited.

CASE PRESENTATION: We report a 52-year-old woman with metastatic gastric adenocarcinoma harboring a rare SPTBN1-ALK fusion detected at a low variant allele frequency (0.65%). The tumor was negative for HER2 amplification, microsatellite instability, and PD-L1 expression. After failure of chemotherapy combined with immunotherapy, treatment with the ALK inhibitor iruplinalkib resulted in rapid clinical improvement and a durable partial response lasting approximately 14 months. Serial next-generation sequencing at progression demonstrated enrichment of the fusion-positive clone (variant allele frequency increased to 5.94%), accompanied by expansion of TP53-mutant alleles and acquisition of additional genomic alterations. Subsequent histologic transformation to small-cell neuroendocrine carcinoma was observed, with loss of RB expression and markedly elevated Ki-67. No canonical ALK kinase domain resistance mutations were detected, suggesting a non-on-target resistance mechanism.

CONCLUSIONS: This case highlights that even low-allele-frequency ALK fusions may have important clinical relevance in gastric cancer and may identify patients who could benefit from ALK-targeted therapy. It also illustrates the dynamic evolutionary trajectory of oncogene-driven tumors under therapeutic pressure, with histologic transformation to small-cell neuroendocrine carcinoma that may reflect lineage plasticity. Comprehensive genomic profiling and longitudinal molecular monitoring may facilitate the identification of rare actionable alterations and improve understanding of resistance mechanisms in advanced gastric cancer.