Kadcyla (ado-trastuzumab emtansine)

P3, N=1615, Active, not recruiting, Jiangsu HengRui Medicine Co., Ltd. | Recruiting --> Active, not recruiting

P3, N=228, Recruiting, GeneQuantum Healthcare (Suzhou) Co., Ltd.

P2, N=2175, Active, not recruiting, ECOG-ACRIN Cancer Research Group | Trial primary completion date: Oct 2026 --> Oct 2027

Overall, the available real-world evidence supports the clinical effectiveness of tucatinib-based therapies in HER2+ MBC, including heavily pretreated populations, patients with prior exposure to T-DXd, and those with brain metastases. However, gaps remain in the real-world data regarding the safety profile of tucatinib and its impact on health-related quality of life in routine clinical practice.

P3, N=228, Active, not recruiting, Yingen Biopharmaceutical (Suzhou) Co., Ltd. | -> Active, not recruiting | Phase classification: PN/A --> P3

This case provides preliminary evidence that T-DXd may achieve deep and durable intracranial responses even in heavily pretreated patients with active BMs, including those previously treated with WBRT and T-DM1. The exceptional duration of response observed in this case appears to exceed historical expectations and warrants further investigation in this high-risk population.

P2, N=48, Active, not recruiting, Carey Anders, M.D. | Trial primary completion date: Apr 2026 --> Nov 2026 | Trial completion date: Jul 2026 --> Nov 2027

Concerning treatment, in advanced HER2-positive, Non-Squamous NSCLC tumors, the first-line treatment is Platinum-based + Pemetrexed chemotherapy, with or without immunotherapy, because no HER2-targeted antibody therapy has yet been approved for initial treatment. After progression, HER2-targeted antibody-drug conjugates like Trastuzumab-Deruxtecan and Ado Trastuzumab-Emtansine may offer patients clinical benefits. New HER2-selective tyrosine kinase inhibitors, such as zongertinib and sevabertinib, have shown promising results, including patients previously treated with antibody-drug conjugates (ADCs). Recent advances, including next-generation ADCs such as SHR-A1811 and A166, and bispecific antibodies, such as zenocutuzumab for NRG1 fusion-positive disease, which are also expanding treatment options. Overall, advances in diagnostics and new targeted therapies are changing how HER2-altered NSCLC is treated and are helping to make care more personalized.

Treatment response was the main determinant of progression, while baseline inflammatory markers offered modest complementary prognostic value. These findings may aid patient selection for T-DM1, particularly in settings with limited access to trastuzumab deruxtecan.

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.