Genomic landscape of <i>ERBB3</i> alterations in 5,416 metastatic solid tumors: Real-world evidence regarding biomarker-agnostic ADC strategies.

3090 Background: While ERBB2 (HER2) is a well-established therapeutic target, the clinical significance and genomic landscape of ERBB3 (HER3) across diverse solid tumors are less defined. As HER3 emerges as a critical mediator of resistance and a target for novel antibody-drug conjugates (ADCs), characterizing its genomic alterations in a real-world setting is essential to refine therapeutic positioning. Methods: We analyzed clinical next-generation sequencing (NGS) data (Illumina TSO 500 or Oncomine Comprehensive Assay Plus) from 5,416 patients with metastatic solid tumors at a single tertiary center (Samsung Medical Center) between 2019 and 2025. ERBB3 alterations were categorized into mutations (SNVs/indels, VAF ≥2%) and amplifications (copy number [CN] ≥4). Results: ERBB3 alterations were identified in 12.9% (697/5,416) of patients. The prevalence was overwhelmingly driven by mutations (12.3%), while amplifications were rare (0.6%). The highest mutation frequencies were observed in: Urothelial carcinoma, 18.2%; Malignancy of unknown origin, 16.3%; and Biliary tract cancer, 15.7%. The most frequent variants were K498I (Domain IV) and R1127H (C-terminal tail). Known oncogenic hotspots (V104, A232V, G284R, E928G) were present but not dominant. Notably, the ERBB3-mutated cohort exhibited high co-mutation rates with canonical drivers: TP53 (66%), APC (35%), and KRAS (31%). In common GI cancers, ERBB3 mutations frequently co-occurred with APC and KRAS, suggesting they often act as "passenger" or secondary events rather than primary drivers. High-level amplifications (CN ≥8) were rare (&lt;0.1%) and appeared in isolated cases across various histologies. Conclusions: ERBB3 alterations are relatively common (12.9%) in metastatic solid tumors but are characterized by a diverse mutational landscape rather than focal amplifications. The high frequency of co-occurring canonical drivers suggests that HER3 primarily functions as a resistance hub or facilitator in these tumors. These real-world data provide a strong genomic rationale for biomarker-agnostic ADC strategies (targeting HER3 protein expression) rather than mutation-specific approaches in most ERBB3-altered solid tumors.