Enhertu (fam-trastuzumab deruxtecan-nxki)

P2, N=702, Recruiting, West German Study Group | Active, not recruiting --> Recruiting | N=402 --> 702 | Trial completion date: Jun 2029 --> Sep 2030 | Trial primary completion date: Jun 2025 --> Jun 2030

Our findings revealed that statin use significantly enhanced the efficacy of T-DXd in both a preclinical HER2-negative rat model and patients with HER2-positive mBC. Prospective clinical trials are warranted to validate these observations.

In these studies, trastuzumab deruxtecan, a HER2-targeted ADC, demonstrated notable intracranial responses in patients with active CNS disease, suggesting that CNS barriers are dynamically remodeled within the tumor microenvironment to permit drug access...By integrating emerging clinical evidence with key pharmacological determinants and tumor-associated microenvironmental changes, this review delineates the mechanisms governing ADC activity in brain metastases and identifies critical factors underlying intracranial response. Collectively, these insights provide a mechanistic framework to guide the rational design of next-generation ADCs and optimize therapeutic strategies for patients with advanced CNS involvement.

DS-8201 demonstrates potential as one of the effective salvage therapies following RC48 failure in HER2 altered solid tumors, showing significantly better disease control and a distinct, manageable toxicity profile. These findings highlight the importance of selecting personalized ADCs based on molecular subtypes and toxicity factors and provide a basis for future, larger-scale prospective studies.

Conventional chemotherapy and first-generation antibody-drug conjugates (ADCs), such as ado-trastuzumab emtansine (T-DM1), were limited by non-specific cytotoxicity, heterogeneous drug-antibody ratios, linker instability, and insufficient bystander killing, yielding modest efficacy in heavily pretreated populations...Clinically, trastuzumab deruxtecan demonstrated meaningful progression-free survival benefit in HER2-low metastatic breast cancer, while enfortumab vedotin reduced mortality risk in platinum- and immunotherapy-refractory urothelial carcinoma, establishing ADC efficacy across solid tumor histologies...Trastuzumab deruxtecan carries a 15.4% incidence of interstitial lung disease, including fatal events, and sacituzumab govitecan is associated with grade 3 or higher neutropenia in approximately 51% of patients. Furthermore, next-generation ADCs are not resistance-proof, with antigen downregulation, payload efflux, and impaired internalization emerging as clinically relevant escape mechanisms. Biomarker-driven patient selection, rigorous toxicity monitoring, and prospective trials addressing resistance will be essential to realizing the full and durable potential of this drug class.

Durvalumab plus T-DXd demonstrated clinically relevant efficacy for first-line treatment of metastatic HR-negative, HER2-low breast cancer, with no unexpected toxicities observed. ClinicalTrials.gov identifier: NCT03742102 .

P1/2, N=55, National Institutes of Health, National Cancer Institute, Division of Cancer Treatment and Diagnosis

P2, N=100, Not yet recruiting, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University

P1, N=108, Active, not recruiting, Daiichi Sankyo | N=78 --> 108 | Trial completion date: Jun 2026 --> May 2030 | Trial primary completion date: Jun 2026 --> May 2030

Antibody-drug conjugates (ADCs), led by trastuzumab deruxtecan, have established clinically meaningful activity across multiple solid tumors in HER2 IHC 3+ populations and have further expanded into HER2-low and ultralow expression settings, supporting the concept of HER2 as a biological continuum rather than a binary biomarker...In gastroesophageal adenocarcinoma, treatment options beyond trastuzumab-based regimens continue to diversify: ADC-based standards in later lines are being complemented by next-generation HER2 antibodies, inclu ding recent phase Ⅲ evidence supporting anbenitamab after prior trastuzumab exposure, which may further inform sequencing decisions. Collectively, these advances highlight an emerging precision model in which therapeutic selection and rational sequencing are guided by integrated assessment of HER2 protein expression, ERBB2 genomic status, prior HER2-directed exposure, and toxicity risk (notably ADC-associated interstitial lung disease). Standardization of high-fidelity diagnostic workflows-spanning IHC/ISH quality assurance, re-biopsy when feasible, and context-appropriate use of circulating tumor DNA-will be essential to ensure consistent patient identification and to enable optimal deployment of ADCs, TKIs, and antibody-based therapies across histologic boundaries.

Higher FLOT2 expression in nine HER2 amplified cell lines correlated with a higher T-DM1 IC50 in vitro , and breast cancer patients with high FLOT2 expression had worse survival when receiving either T-DXd (16.2 months (m) vs 18.3 m, p=0.04) or T-DM1 (38.0 m vs 41.3 m, p=0.1) in real-world Caris Life Sciences data. In conclusion, FLOT2 regulates the internalization and cytotoxicity of T-DM1 mediated by Cbl-dependent ubiquitination of HER2. Zoledronic acid disrupts the HER2/FLOT2 interaction, therefore increasing the internalization and cytotoxicity of T-DM1, providing proof of principle that a small molecule inhibitor of the HER2/FLOT2 interaction can enhance the activity of the HER2-targeting ADC.

She was treated with a methylprednisolone taper, budesonide and infliximab, resulting in resolution of symptoms. In this case, colitis was successfully managed with corticosteroids and infliximab, allowing for safe re-challenge at a reduced dose. This case highlights the importance of recognizing and managing rare toxicities associated with antibody-drug conjugates to optimize their safe use in ovarian cancer treatment.