Kadcyla (ado-trastuzumab emtansine)

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.

These bidirectional changes indicate a metabolic coupling between tumor and circulation, driven by differential utilization and excretion processes during T-DM1 response. Collectively, our findings demonstrate that T-DM1 elicits coordinated local and systemic metabolic reprogramming, providing mechanistic insights into its antitumor activity and the metabolic coupling between tumor and circulation.

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.

Concurrent T-DM1 and RT was generally well tolerated. However, RP appeared more frequent in patients with pulmonary comorbidities and larger PTV, warranting careful selection and prospective validation.

P=N/A, N=10, Recruiting, Guangzhou Institute of Respiratory Disease

Kaplan-Meier survival curve and Cox regression model was used to analyze the effect of different levels of NLR and LDH before T-DM1 treatment on the survival of patients. Elevated NLR and LDH were associated with poor PFS and OS. Future data are needed to validate and update our results.

Recent therapeutic advances have focused on overcoming resistance through platinum agents, PARP inhibitors, immune checkpoint blockade, post-neoadjuvant escalation with capecitabine or trastuzumab emtansine, and emerging antibody-drug conjugates. This review summarizes the advancement of chemotherapy in breast cancer.

P1/2, N=181, Recruiting, Boehringer Ingelheim International GmbH

In the context of the Chinese health system, none of the three alternative regimens-pyrotinib plus capecitabine, T-DM1, and T-DXd-demonstrated cost-effectiveness relative to lapatinib plus capecitabine at the current WTP threshold.

P3, N=1635, Active, not recruiting, Daiichi Sankyo | Trial completion date: Dec 2030 --> Jun 2028 | Trial primary completion date: Dec 2025 --> Jul 2025

T-DM1 shows dose-dependent hepatotoxicity, while cytochrome P450 3A4 (CYP3A4) inhibitors may increase hepatic accumulation of trastuzumab deruxtecan (T-DXd). Trastuzumab mainly induces hepatocellular and cholestatic injury, whereas T-DM1 involves both HER2-dependent and independent pathways. Diagnosis relies on causality assessment, and most cases are reversible with liver function monitoring and timely dose adjustment.

P3, N=562, Not yet recruiting, SWOG Cancer Research Network