P1/2, N=103, Recruiting, Chia Tai Tianqing Pharmaceutical Group Nanjing Shunxin Pharmaceutical Co., Ltd. | Trial completion date: Dec 2025 --> Dec 2029 | Trial primary completion date: May 2025 --> May 2027

Combining palbociclib, trastuzumab, and ET was safe and improved significantly PFS, compared to TPC in previously treated HER2-positive, PAM50 luminal A/B ABC patients.

P2, N=400, Recruiting, UNICANCER

P=N/A, N=384, Recruiting, AstraZeneca | Trial completion date: Nov 2025 --> Apr 2026 | Trial primary completion date: Nov 2025 --> Apr 2026

The treatment resulted in a complete response, with a tolerable side effect profile and ongoing treatment-free survival. Our case adds to the literature suggesting clinical benefit of the use of Trastuzumab-deruxtecan in HER2-positive tumors, and underscores the importance of molecular testing for patients with rare tumor subtypes.

P2, N=56, Recruiting, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University

We evaluated two ADCs with a shared antibody framework: trastuzumab linked to the microtubule inhibitor monomethyl auristatin E (T-MMAE) and the topoisomerase inhibitor deruxtecan (T-DXd). The secondary anti-tumor response mediated by memory CD8+ T cells were crucial for the formation of immunological memory induced by both ADCs. Therefore, our findings reveal that, after ADC-mediated tumor cytotoxicity, different ADC payloads elicit distinct immunological responses characterized by varying levels of myeloid cell activation within the TME.

P4, N=120, Not yet recruiting, Tianjin Medical University Cancer Institute and Hospital

Our study indicates that patients emerge from T-DXd treatment with highly refractory disease. These findings highlight the urgent need for optimized treatment strategies and novel therapeutic options for this patient population.

Among increasingly personalised strategies, particular promise is shown by HER2-targeted therapies for HER2-positive malignancies (e.g. trastuzumab deruxtecan). Additionally, targeting TP53 wild-type tumours with selinexor, as well as addressing AKT and DNA repair pathways in both uterine carcinomas and sarcomas (i.e. AKT inhibitor and poly(ADP-ribose) polymerase inhibitor combinations), represents key advancements. Furthermore, anti-angiogenic and immune checkpoint inhibitor combinations hold significant promise for future therapeutic strategies.

However, recent research has led to the development of antibody-drug conjugates (ADCs), such as trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd), with the latter showing promising results in treating these patients. In this context, the interplay between miRNAs and HER2-targeted therapies, particularly their modulation of common essential genes and signaling pathways, could reshape HER2-low therapy strategies to transform current practices aimed at improving the overall patient outcomes. Therefore, this review aims to elucidate the mechanisms underlying current HER2-targeted therapy and explore a potential crosstalk with miRNAs, ultimately serving as a guide for the development of personalized therapeutic strategies.

Results from a recent Phase 3 clinical trial (DESTINY-Breast04) established the efficacy of the antibody-drug conjugate, trastuzumab deruxtecan (T-DXd) in patients with metastatic breast cancer with immunohistochemistry (IHC) score 1+ or 2+ and without in situ hybridization amplification, defining a new category of metastatic breast cancer known as human epidermal growth factor receptor 2 (HER2)-low...The panel recommended robust standard operating procedures to overcome these challenges. The central point of discussion was to implement clear guidelines, careful supervision of pre-analytical and analytical issues, and specialized training for accurate HER2 testing that would help select patients eligible for novel therapies.