P1/2, N=90, Not yet recruiting, Canwell Biotech Limited

Patients meeting IHC 0 with membrane staining (HER2-ultralow) criteria may benefit from HER2-targeted therapies such as trastuzumab deruxtecan...These findings highlight potential challenges of identifying HER2-ultralow expression and suggest the need for enhanced pathologist training, adherence to best practices, and integration of digital pathology and artificial intelligence solutions. Trial Registration: ClinicalTrials.gov_identifier: NCT03734029.

This case provides preliminary evidence that T-DXd may achieve deep and durable intracranial responses even in heavily pretreated patients with active BMs, including those previously treated with WBRT and T-DM1. The exceptional duration of response observed in this case appears to exceed historical expectations and warrants further investigation in this high-risk population.

Recent advances in molecular profiling and the development of HER2-directed ADCs have fundamentally reshaped the therapeutic relevance of HER2 in UC, enabling activity even in tumors with heterogeneous or low expression of HER2. This comprehensive narrative review synthesizes current knowledge on HER2 biology in UC, addresses challenges in biomarker assessment, critically appraises the evolving clinical trial landscape of HER2-directed ADCs, explores the interaction between HER2 and other oncogenic alterations and discusses mechanisms of resistance with future directions for HER2-targeted strategies in UC.

Disitamab Vedotin achieved durable partial response (> 8 months PFS) in advanced HER2 2+/FISH- bladder cancer after first-line chemo-immunotherapy progression. This case provides real-world evidence that disitamab vedotin may benefit HER2 2+/FISH- patients, supporting broader HER2 testing and treatment consideration in this subset.

AI-assisted HER2 IHC scoring significantly improves interobserver consistency and provides quantitative support that helps address key limitations of conventional categorical HER2 assessment.

P1/2, N=380, Recruiting, BioNTech SE | Trial completion date: May 2029 --> Aug 2029 | Trial primary completion date: May 2028 --> Aug 2029

Discordance between HercepTest® and 4B5 is frequent and clinically consequential, leading to reclassification based on 4B5 that affects eligibility assessment in a substantial subset of patients. These findings highlight the need for careful interpretation of HER2 results in real-world reassessment and increased awareness of diagnostic variability in HER2-low classification.

The HER2CLIMB trial demonstrated the benefit of tucatinib, trastuzumab and capecitabine (TTC) in human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer (ABC). Treatment discontinuation due to toxicity occurred in 7.4% of participants; there were no treatment-related deaths. In this national real-world cohort, TTC demonstrated clinically meaningful activity and was not associated with any new safety signals in HER2-positive ABC, including patients previously exposed to T-Dxd and those with brain metastases.

Multiplexed imaging showed broad but heterogeneous HER2 expression across tumor states in both cases; in the MYCN-amplified tumor, this occurred alongside EGFR/MAPK-enriched proliferative niches, whereas the ZFTA-RELA tumor showed more diffuse organization without strong coupling of EGFR and proliferation. These findings provide early clinical evidence supporting HER2-directed ADCs in ependymoma and highlight the value of integrated molecular and spatial profiling in interpreting therapeutic response in rare CNS tumors.

P2, N=120, Recruiting, Dana-Farber Cancer Institute | Trial completion date: Jun 2028 --> Jun 2030 | Trial primary completion date: Jun 2026 --> Jun 2028

The temporal relationship between molecular and radiologic findings observed here suggests potential value for earlier detection of disease activity, although whether such lead time translates into improved clinical outcomes requires prospective validation. The findings support prospective evaluation of this approach, including the ongoing TROPHY trial investigating this therapeutic approach.