Global evolution of HER2-targeted clinical trials across solid tumors: Shifts in tumor representation, biomarker definitions, therapeutic modalities, and geographic leadership.

Abstract

e23085 Background: HER2 has expanded from a breast-restricted biomarker to a pan-tumor therapeutic target, driven by advances in antibody–drug conjugates, next-generation TKIs, refined HER2-low assays, and recognition of HER2 mutations. Despite this rapid evolution, the global landscape of HER2-directed clinical trials spanning tumor types, biomarker categories, therapeutic modalities, and geographic trends remains undefined. A comprehensive mapping is needed to clarify these shifts and guide next-generation HER2-targeted development and global trial design. Methods: A landscape analysis of interventional HER2-targeted trials was performed using ClinicalTrials.gov harmonized with AACT (cutoff December 2024). Trials were identified using HER2/ERBB2 terms, HER2-low and HER2-mutant criteria, and HER2-directed agents (trastuzumab, pertuzumab, T-DM1, T-DXd, tucatinib, neratinib, lapatinib, pyrotinib, poziotinib). Extracted variables included tumor type, phase, biomarker definitions, therapeutic modality, sponsor, design architecture, and geographic distribution. Temporal trends from 2005–2024 were assessed. Results: Across 1,327 HER2-targeted trials, early development was dominated by breast cancer (> 50% before 2015). After 2020, breast trials fell to 28%, while studies in other tumors expanded sharply gastric (14%), lung (12%), colorectal (11%), biliary (6%), and gynecologic (5%). HER2-mutant trials increased from < 1% to 17%, driven by mutation-focused TKIs. HER2-low trials rose to 22% after the success of T-DXd. Therapeutically, ADCs showed the fastest growth, increasing from 6% of trials in 2010 to 41% in 2024. Monoclonal antibody regimens decreased from 48% to 19%. TKI development concentrated heavily in Asia, which now conducts 63% of global TKI trials. Randomized trials increased from 12% to 31%, and HER2–immunotherapy combinations from 2% to 18%. Industry sponsored 59% of trials, academic groups 31%, and government programs 10%. Global activity expanded from 17 countries pre-2010 to 59 countries by 2024. Conclusions: The global HER2-targeted trial landscape has shifted dramatically from a breast-focused, monoclonal-antibody era to a broad, biomarker-driven, and therapeutically diverse ecosystem across many solid tumors. Three major trends stand out: (1) rapid growth of HER2-low and HER2-mutant trial programs(2) ADCs becoming the dominant driver of HER2 drug development (3) Asia emerging as the global leader in TKI innovation. These shifts highlight the need for clearer biomarker standards, especially for HER2-low, and for coordinated development of pan-tumor HER2-directed strategies. This comprehensive mapping helps define priorities for the next generation of HER2-targeted therapies and reflects the rapidly evolving global geography of HER2 innovation.