Enhertu (fam-trastuzumab deruxtecan-nxki)

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.

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.

Regarding the conjugation type, only trastuzumab deruxtecan, labetuzumab govitecan, sacituzumab govitecan, BYON3521, and SYD1875 used homogeneous conjugation. An interesting observation was that for some ADCs, TAA expression was higher in normal tissue than in the tumor. In summary, our analysis highlights that only a limited number of ADCs incorporate payloads with favorable physicochemical properties and that several ADCs currently under development target TAAs with higher expression in normal tissues than in the corresponding tumors.

P1/2, N=792, Recruiting, Hoffmann-La Roche | N=580 --> 792 | Trial completion date: May 2028 --> Sep 2030 | Trial primary completion date: May 2028 --> Sep 2030

P1/2, N=210, Active, not recruiting, Hoffmann-La Roche | Trial completion date: Oct 2026 --> Jul 2026 | Trial primary completion date: Oct 2025 --> Jul 2026

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

P=N/A, N=50, Active, not recruiting, Nagoya City University | Enrolling by invitation --> Active, not recruiting

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.