Enhertu (fam-trastuzumab deruxtecan-nxki)

P1, N=138, Active, not recruiting, AstraZeneca | Trial completion date: Dec 2025 --> Jun 2026

Emerging evidence indicates that sequential ADC use can be effective despite some cross-resistance, especially when distinct payload mechanisms are employed. Clinical use should consider payload type, timing, and breast cancer subtype, but toxicities remain critical for decision-making. Research providing insights into resistance mechanisms and biomarkers is needed for personalized approaches.

P=N/A, N=60, Recruiting, Blokhin's Russian Cancer Research Center

P1, N=36, Not yet recruiting, National Cancer Institute (NCI) | Initiation date: Dec 2025 --> Mar 2026

Our study demonstrates that in potential NSCLC beneficiaries of T-DXd therapy, HER2 expression is underestimated in biopsy samples and metastatic lesions compared to resected and primary sites. This heterogeneity holds great significance for guiding clinical sample selection.

Across these variants, integration of morphology with targeted immunohistochemistry and molecular testing (including p53, MMR status, POLE) is essential for accurate classification, risk stratification. HER2 overexpression and/or amplification occurs in 25-30% and HER2 testing has become a standard biomarker for selecting patients with recurrent or advanced disease for trastuzumab, and more recently trastuzumab-deruxtecan therapy.

Alterations in FGFR3, commonly found in the luminal-papillary molecular subtype associated with low response to immunotherapy, are the target of erdafitinib. Enfortumab vedotin, which targets Nectin-4 (expressed in >95% of urothelial carcinomas), is approved for patients who progress after chemotherapy and/or immunotherapy...Sacituzumab govitecan, an antibody-drug conjugate directed against Trop-2, is effective in basal, luminal and stroma-rich subtypes but not in neuroendocrine carcinomas. In addition, therapies developed for HER2-positive breast cancer have shown efficacy in urothelial carcinoma, with recent data from the DESTINY pan-tumour phase II trial leading to FDA approval of trastuzumab deruxtecan for HER2-overexpressing metastatic urothelial carcinoma. This paper is a comprehensive review of the molecular pathology of bladder cancer, highlighting advances in molecular classification, biomarkers and personalized therapies. The transition from morphology-based classifications to combined morphological and molecular approaches, with therapeutic implications, is also addressed.

T-DXd is potentially a safe and effective treatment option for older patients with HER2-low breast cancer and for those with impaired ADL. Further accumulation of cases and investigations of long-term outcomes are warranted.

Conversely, T-DXd administered due to the presence of HER2-low showed excellent effectiveness. Performing a re-biopsy is crucial due to the possible loss of estrogen receptors, which would require a change in therapeutic strategy no longer based on endocrine therapy. In cases that remain luminal, knowledge of the mutational profile may help to offer patients novel targeted treatments.

In patients with high-risk, residual invasive HER2-positive breast cancer, postneoadjuvant T-DXd resulted in a significantly higher likelihood of invasive disease-free survival than T-DM1; toxic effects were mainly gastrointestinal and hematologic. An important identified risk of T-DXd is interstitial lung disease, which requires appropriate monitoring and management. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Breast05 ClinicalTrials.gov number, NCT04622319.).

AI-assisted interpretation improved observer agreement (Kappa: 0.703 vs. 0.610 in non-amplified cases) and reduced ambiguous immunohistochemistry (IHC) 2+/0 assignments. These findings delineate distinct clinicopathological characteristics of HER2-ultralow/null tumors, highlight HER2 IHC reproducibility challenges, and validate AI as an effective tool for standardizing scoring to optimize patient selection for T-DXd therapy.

Antibody-drug conjugates (ADCs), particularly trastuzumab deruxtecan (T-DXd), have markedly improved survival and also exert antitumor effects through immune activation...Tumor vaccines and genomics-driven targeted drugs, such as trastuzumab-α-amanitin conjugates, hold promise in reactivating antitumor immunity. This review summarizes current progress in immunotherapy for HER2 low-expressing TNBC, with emphasis on ADCs, combination regimens, and emerging precision strategies, aiming to inform future research and clinical application.