Efficacy and Safety of Human Epidermal Growth Factor Receptor 2 (HER2) Antibody-Drug Conjugates in Solid Tumors Harboring Non-tyrosine Kinase Domain ERBB2 Mutations: A Systematic Review.

ERBB2 (HER2) gene mutations are established oncogenic drivers across a wide range of solid tumors. While therapeutic development has primarily focused on alterations within the tyrosine kinase domain (TKD), ERBB2 mutations also occur in non-TKD regions, including the extracellular, transmembrane, juxtamembrane, and C-terminal domains. The clinical efficacy and safety of HER2 antibody-drug conjugates (ADCs) in tumors harboring non-TKD ERBB2 mutations remain incompletely characterized. We conducted a systematic review in accordance with the PRISMA 2020 guidelines. PubMed, Embase, and Web of Science were searched for clinical studies reporting outcomes of HER2 ADC therapy in adult patients with solid tumors harboring non-TKD ERBB2 mutations. Eligible studies included phase II non-randomized trials, observational studies, case series, and case reports. Data were extracted on tumor type, mutation domain, ADC regimen, efficacy outcomes, and safety, with particular attention to interstitial lung disease (ILD)/pneumonitis. Nine studies were included, comprising five phase II non-randomized clinical trials and four case-based studies. Non-TKD ERBB2 mutations were most frequently located in the extracellular domain (56 reported cases), followed by the transmembrane/juxtamembrane domains (26 cases), while C-terminal alterations (15 cases) were less commonly reported. Trastuzumab deruxtecan was the most frequently administered ADC and demonstrated objective tumor responses across multiple tumor types, with the most consistent activity observed in tumors harboring extracellular and transmembrane/juxtamembrane domain mutations. In contrast, evidence supporting efficacy in C-terminal domain mutations was limited and derived mainly from case-based reports. ILD/pneumonitis was reported in a subset of patients, including grade ≥3 events, but no ILD-related fatal events were reported among patients with non-TKD ERBB2 mutations. Current clinical evidence indicates that HER2 ADCs can provide meaningful antitumor activity in selected solid tumors harboring non-TKD ERBB2 mutations, particularly those involving the extracellular and transmembrane/juxtamembrane domains. However, treatment benefit appears heterogeneous across mutation domains and less consistent than that reported for canonical TKD alterations, and interpretation is limited by study heterogeneity and the lack of mutation-domain-stratified outcome reporting. Prospective studies with mutation-domain-stratified designs are warranted to better define the role of HER2 ADCs in non-TKD ERBB2-mutated malignancies and to inform precision treatment strategies.