Objective:

To report a case of a patient with metastatic gastric adenocarcinoma harboring a rare SPTBN1–ALK fusion and to explore the therapeutic relevance of ALK inhibitors in such cases, particularly given the rarity of this fusion.

Approach:

• Case Presentation: A 52-year-old woman with metastatic gastric adenocarcinoma was treated with the ALK inhibitor iruplinalkib after failing chemotherapy and immunotherapy, resulting in a durable partial response lasting approximately 14 months.
• Progression Analysis: At progression, there was an increase in the fusion-positive clone's variant allele frequency and histologic transformation to small-cell neuroendocrine carcinoma, indicating lineage plasticity.

Key Findings:

• The SPTBN1–ALK fusion was detected at a low variant allele frequency but was clinically relevant.
• The patient experienced significant clinical improvement with ALK-targeted therapy.
• Histologic transformation to small-cell neuroendocrine carcinoma occurred at progression, indicating lineage plasticity and the dynamic nature of the tumor.

Interpretation:

This case highlights the potential clinical relevance of low-allele-frequency ALK fusions in gastric cancer, emphasizing the need for comprehensive genomic profiling.

Limitations:

• The rarity of ALK rearrangements in gastric cancer limits generalizability and understanding of their clinical implications.
• The case study design does not provide broader population-level data.

Conclusion:

Comprehensive genomic profiling and longitudinal monitoring may enhance the identification of rare actionable alterations in advanced gastric cancer.