Enhertu (fam-trastuzumab deruxtecan-nxki)

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.

The incidence of ILD with T-DXd in the real-world setting was similar to that observed in clinical trials, indicating no new ILD-related safety signals. Further investigation of the identified factors may offer insights into ILD incidence in high-risk populations.

pDuFLOT and pSOX are potential regimens among senior patients with resectable gastric cancer. At this moment, pDuFLOT may be globally used while pSOX should better be applied among East Asian countries. CadCAPOX, SuCAPOX, PemCAPOX and NiCAPOX are considered as potential first-line regimens among HER2-negative senior patients. CadCAPOX and SuCAPOX are probably more fit for East Asian patients currently, while NiCAPOX may be better applied among Western countries and PemCAPOX has the potential of worldwide application. SuCAPOX is a potential regimen among HER2-negative/PD-L1-positive senior patients, while PemCAPOX may also be considered. Currently, standard CAPOX or FOLFOX regimen may still be available for HER2-negative senior patients with CLDN18.2, FGFR2b or MET positivity. Meanwhile, among HER2-positive senior patients, TraCAPOX is still considered to be available. Regarding first-line maintenance treatments, RamP is a potential regimen among HER2-negative or non-specific senior patients, especially those from Western countries. As second-line regimens, FruP and RamP may be potentially available among East Asian and worldwide HER2-negative senior patients respectively, while T-DXd has the potential of global application among HER2-positive counterparts. Concerning third-line or subsequent regimens, T-DXd is potentially available among HER2-positive senior patients, especially from East Asian countries. Among HER2-negative or non-specific patients, RamIRI is a potential regimen, especially among East Asian patients, while nivolumab and regorafenib may still be available at this moment. Meanwhile, nivolumab and other parallel regimens already recommended by guidelines are still potentially available among HER2-negative/CLDN18.2-positive senior patients. As the first network meta-analysis on this topic, our conclusions may not only provide potential supplements for current guidelines, but also reveal the necessity and directions for future clinical and mechanism researches, especially because of the underpowered subgroup data and exploratory nature of regional applicability.

This review summarizes a range of ADCs targeting tumor-associated antigens in ovarian cancer, including mirvetuximab soravtansine (MIRV), trastuzumab deruxtecan (T-DXd), datopotamab deruxtecan (Dato-DXd), sacituzumab tirumotecan (SKB-264), PF-06664178, anetumab ravtansine (BAY 94-9343), BMS-986148, DMOT4039A, RC88, lifastuzumab vedotin (DNIB0600A), upifitamab rilsodotin (ABBV-181), ZW220, DMUC4064A, and sofituzumab vedotin (DMUC5754A). The ADCs hold significant potential to reshape the treatment landscape for ovarian cancer by providing targeted therapeutic options. Further research is required to optimize patient selection, address resistance mechanisms, and improve safety profiles.

However, T-DXd increased the risks of interstitial lung disease (relative risk &lsqb;RR] = 13.832; P < 0.001), decreased left ventricular ejection fraction (RR = 2.247; P < 0.001), anemia, nausea, vomiting, decreased appetite, and alopecia; neutropenia and diarrhea risks were comparable between groups. These findings highlight T-DXd's survival benefits and toxicity profile warranting monitoring.

Recent trials demonstrate encouraging outcomes with ADC such as Enfortumab Vedotin (EV), Sacituzumab Govitecan (SG), Trastuzumab Deruxtecan (T-DXd), and Disitamab Vedotin (DV) in UC, improving response rates and Progression-Free Survival (PFS). In RCC, ADC against ENPP3, CD70, and TIM-1 show durable responses in early trials, though challenges such as dose-limiting toxicities require further investigation. Overall, this review underscores ADC as a transformative approach in uro-oncology, highlighting ongoing advancements in combination strategies and biomarker-driven applications to refine therapeutic outcomes and expand treatment options for these challenging malignancies.