HER-2 amplification

P3, N=3380, Not yet recruiting, UNICANCER

P2, N=30, Not yet recruiting, Sun Yat-sen University

P1, N=27, Recruiting, Institut Paoli-Calmettes | Trial completion date: Feb 2026 --> Mar 2027 | Trial primary completion date: Mar 2025 --> Mar 2027

P=N/A, N=500, Not yet recruiting, Shengjing Hospital

We position this regulatory axis within the broader landscape of established resistance mechanisms and emerging therapeutic strategies, including antibody-drug conjugates, kinase inhibitors, and rational combination approaches. By integrating canonical resistance pathways with transcriptional regulation, this review provides a balanced perspective on how downstream regulatory processes may influence therapeutic response in HER2-positive gastric cancer.

We dissect the mechanistic underpinnings and clinical performance of foundational regimens such as FOLFOX, FOLFIRI, and CAPOX, and analyze how key driver alterations, including RAS/RAF mutations, HER2 amplification, MSI/MMR status, and VEGF-mediated angiogenesis, influence disease progression and therapeutic selection...Emerging advances such as KRAS G12C inhibitors, multi-kinase angiogenesis modulators, antibody-drug conjugates, ribosome biogenesis inhibitors, AI-guided therapeutic algorithms, and ctDNA-based monitoring are also discussed. By integrating mechanistic insights with clinical evidence, this review offers a structured framework to better understand current treatment paradigms and future directions in biomarker-driven precision therapy for colon cancer.

P1, N=51, Recruiting, National Cancer Institute (NCI) | Trial completion date: Mar 2026 --> Mar 2027 | Trial primary completion date: Mar 2026 --> Mar 2027

P2, N=65, Completed, SOLTI Breast Cancer Research Group | Recruiting --> Completed

Copy number-based oncogene dominance may suggest tumor dependence and response to HER2-targeted therapy, highlighting a potential novel biomarker in HER2-positive gastric cancer.

In the past few years, targeted therapeutic modalities such as antibody-drug conjugates (ADCs), particularly trastuzumab deruxtecan (the first agent to be granted FDA approval for HER2-mutant NSCLC), alongside selective tyrosine kinase inhibitors (TKIs), including zongertinib and sevabertinib, have demonstrated robust systemic efficacy and notable intracranial penetration. This comprehensive review delineates the molecular landscape and clinical phenotypes of HER2-altered NSCLC, synthesizes interim and mature data from ongoing clinical trials evaluating anti-HER2 therapies, and critically examines efficacy and safety results from different classes of targeted agents. Further research is crucial to uncover potential mechanisms of resistance in NSCLC with HER2 mutations and define sequencing or combinatorial strategies pertinent to optimizing individualized patient management.

These molecular tools have the potential to change how CRC is managed by earlier detection and more precise predictive biomarkers. However, large-scale validation and clinical standardization are still crucial for their extensive utilization.