Enhertu (fam-trastuzumab deruxtecan-nxki)

First-generation ADCs, such as Gemtuzumab ozogamicin, demonstrated the proof of concept but suffered from high immunogenicity, poor selectivity, and heterogeneous drug-antibody ratios. Second-generation ADCs introduced stable linkers and humanized antibodies, exemplified by Ado-trastuzumab emtansine (T-DM1), which targets the HER2 receptor in breast cancer...Third-generation ADCs, including Trastuzumab deruxtecan and Sacituzumab govitecan, incorporate site-specific conjugation, higher drug-to-antibody ratios, and potent payloads capable of inducing bystander killing even in tumors with low antigen expression...In conclusion, ADCs exemplify the convergence of molecular biology, immunology, and medicinal chemistry in the pursuit of precision oncology. Their progressive evolution from concept to clinic not only validates Ehrlich's century-old vision but also heralds a new therapeutic era in which cancer treatment achieves unprecedented specificity, efficacy, and improvement in patient outcomes.

Initial systemic therapy with doxorubicin achieved stable disease at three months. Based on the genomic findings identified following comprehensive genomic profiling, the patient was subsequently enrolled in the DESTINY-PanTumor02 clinical trial and transitioned to treatment with trastuzumab deruxtecan targeting the human epidermal growth factor receptor 2 (HER2) alteration...It illustrates the marked radiologic and clinicopathologic heterogeneity of IMT and emphasizes the importance of comprehensive histopathologic and molecular evaluation to guide management in aggressive disease variants. Close collaboration across cross-disciplinary diagnostic specialties is essential for the assessment and treatment of rare, multi-organ conditions.

However, with the development of resistance, the tumor microenvironment shifted to an immunosuppressive state, characterized by reactivation of transforming growth factor-beta signaling and upregulation of programmed cell death protein-1 (PD-1). These findings provide novel insights into mechanisms underlying T-DXd resistance and highlight potential therapeutic targets for overcoming T-DXd resistance in GC.

In patients with BCBM, T-DXd-associated ILD/pneumonitis occurred in 10% of patient and frequently necessitated treatment modification. Although no fatal ILD was observed, the high discontinuation rate underscored the imperative for vigilant monitoring and protocol-guided management to mitigate pulmonary toxicity while preserving intracranial efficacy.

P1, N=48, Suspended, National Cancer Institute (NCI) | Recruiting --> Suspended

Approximately 40 % of young women with luminal HER2-negative breast cancers have HER2-low or ultralow disease. These findings highlight the importance of accurately assessing HER2 expression in YWBC to identify candidates for emerging HER2-targeted therapies such as trastuzumab deruxtecan.

P=N/A, N=50, Not yet recruiting, Shanghai Sixth People's Hospital; Shanghai Sixth People's Hospital

P=N/A, N=46, Not yet recruiting, The Affiliated Hospital of Inner Mongolia Medical University; The Affiliated Hospital of Inner Mongolia Medical University

P4, N=120, Not yet recruiting, Tianjin Cancer Hospital Airport Hospita; Tianjin Cancer Hospital Airport Hospita

P4, N=200, Not yet recruiting, The First Affiliated Hospital of Jinzhou Medical University; The First Affiliated Hospital of Jinzhou Medical University

The broad aims of this paper are: (a) To draw attention to some of the challenges associated with identifying whether patients have HER2-low metastatic breast cancer (mBC), in an environment where healthcare professionals have previously only needed to determine whether mBC is HER2-positive and therefore likely to respond to traditional HER2-targeted therapies; and (b) to indicate, where possible, what might be done to help overcome specific challenges in this regard. Advice regarding the management of specific T-DXd-related side effects of interest, including interstitial lung disease and pneumonitis, left ventricular dysfunction and emesis, is also offered.

T-DXd efficacy appears consistent across different age groups, although elderly patients showed reduced OS. Higher BMI was associated with improved PFS but increased toxicity. While DDIs did not affect survival outcomes, they influenced specific adverse events. Our results reinforce the efficacy and favorable safety profile of T-DXd in a broad real-world population, including patients with polypharmacy or comorbidities, while highlighting that personalized monitoring and supportive care strategies may be particularly beneficial for elderly patients and those with higher BMI.