[Recent Advances in the Treatment of HER2-Altered Solid Tumors]

Between 2024 and early 2026, HER2-directed oncology has rapidly evolved from a strategy confined to HER2-overexpressing malignancies to a histology-agnostic framework that accommodates diverse HER2 alterations, including amplification/overexpression, low-ultralow protein expression, and activating ERBB2 mutations. Antibody-drug conjugates (ADCs), led by trastuzumab deruxtecan, have established clinically meaningful activity across multiple solid tumors in HER2 IHC 3+ populations and have further expanded into HER2-low and ultralow expression settings, supporting the concept of HER2 as a biological continuum rather than a binary biomarker. In parallel, combination approaches integrating anti-HER2 ADCs with immune checkpoint inhibitors have shown encouraging signals in selected tumor types, underscoring potential immunomodulatory contributions of HER2 targeting. For ERBB2 tyrosine kinase domain (TKD) -activating mutations-particularly in non-small cell lung cancer-highly selective oral tyrosine kinase inhibitors (TKIs) have produced substantial response rates with favorable tolerability, consolidating mutation-defined therapy as a distinct clinical paradigm alongside protein expression-driven strategies. In gastroesophageal adenocarcinoma, treatment options beyond trastuzumab-based regimens continue to diversify: ADC-based standards in later lines are being complemented by next-generation HER2 antibodies, including recent phase Ⅲ evidence supporting anbenitamab after prior trastuzumab exposure, which may further inform sequencing decisions. Collectively, these advances highlight an emerging precision model in which therapeutic selection and rational sequencing are guided by integrated assessment of HER2 protein expression, ERBB2 genomic status, prior HER2-directed exposure, and toxicity risk (notably ADC-associated interstitial lung disease). Standardization of high-fidelity diagnostic workflows-spanning IHC/ISH quality assurance, re-biopsy when feasible, and context-appropriate use of circulating tumor DNA-will be essential to ensure consistent patient identification and to enable optimal deployment of ADCs, TKIs, and antibody-based therapies across histologic boundaries.