Clinical benefit of various HER2-directed regimens in gastrointestinal malignancies: a retrospective cohort study

BACKGROUND: Multiple drugs targeting the human epidermal growth factor receptor-2 (HER2) have shown clinical activity in gastrointestinal (GI) cancers. How to best integrate these various options in clinical practice alongside conventional therapy, however, is unclear. METHODS: We assessed the clinical outcomes of 103 patients with advanced HER2-altered GI malignancies who received ≥ 1 line of anti-HER2 therapy at our institution between 2010 and 2023. RESULTS: Next-generation sequencing (NGS) detected an ERBB2 amplification in 66% (27/41) of tumors that were HER2 + by IHC/ISH. Conversely, all patients with ERBB2 amplification were HER2 + by IHC. In the second-line and beyond, trastuzumab plus pertuzumab had the longest median time to treatment discontinuation (7.9 months), followed by trastuzumab deruxtecan (5.0 months). Among 25 patients who received ≥ 2 anti-HER2 agents, 24% had more durable clinical benefit to their second-line HER2 therapy compared to their first, as measured by the growth modulation index. CONCLUSIONS: Multimodal HER2 testing is needed to accurately identify candidates for HER2-targeted treatment, as NGS alone misses a significant proportion of cases. Patients who develop resistance to one anti-HER2 agent may still achieve benefit from subsequent HER2-directed regimens. Early and serial treatment with HER2-directed agents should be considered for patients with HER2 + GI cancers.