Week 1, June 2025: Recent Progress: Antibody-Drug Conjugates in Oncology

Antibody-drug conjugates (ADCs) couple the specificity of monoclonal antibodies with the cytotoxic potency of chemotherapeutic agents. Recent advances have been reported in both hematologic and solid tumors, with next-generation ADCs overcoming limitations of traditional therapies through improved targeting, linker technologies, and payload selection.

Targeting CD123: Pivekimab Sunirine in BPDCN

This Monday, the University of Texas MD Anderson Cancer Center reported a new antibody-drug conjugate showing promising safety and response rates for patients with rare blood cancer, blastic plasmacytoid dendric cell neoplasm (BPDCN). According to data from a Phase I/II study, pivekimab sunirine (PVEK), achieved an overall response rate of 85% and complete response rate of 70% as frontline treatment in newly diagnosed patients with BPDCN. PVEK is an ADC directed against CD123, an interleukin-3 receptor α subunit consistently overexpressed in BPDCN. With a high-affinity anti-CD123 monoclonal antibody conjugated to a potent cytotoxic payload via a cleavable linker, PVEK enables targeted intracellular delivery of its drug component following receptor-mediated endocytosis. Compared to earlier agents such as tagraxofusp-erzs, which used a fusion toxin approach, PVEK’s ADC format allows for improved pharmacokinetics and a potentially broader therapeutic window.

DB-1310 Demonstrates Early Efficacy in EGFR-Mutant and Refractory Solid Tumors

Meanwhile, DB-1310, a HER3-targeted antibody-drug conjugate, exhibited promising early clinical activity in patients with advanced solid tumors resistant to standard therapies, particularly in those with EGFR-mutant non-small cell lung cancer (NSCLC). DB-1310 is a novel ADC comprised of a humanized anti-HER3 IgG1 monoclonal antibody, cleavable peptide linker, and DNA topoisomerase I inhibitor. In a first-in-human, ongoing Phase I/IIa study led by researchers from UCLA, DB-1310 produced objective responses in 44% of EGFR-mutant NSCLC patients and achieved a median progression-free survival of 7 months with a median overall survival of 18.9 months.

Trodelvy-Keytruda Combination in Frontline TNBC 

Further along in the clinical research phase, new Phase III data from the ASCENT-04 trial have positioned Gilead Sciences’ sacituzumab govitecan (Trodelvy), a TROP2-targeted ADC, as a potential new standard-of-care in PD-L1–positive metastatic triple-negative breast cancer (TNBC). Trodelvy delivers the cytotoxic payload SN-38 to cancer cells, where it inhibits topoisomerase I and induces cell death by disrupting DNA replication. The combination of Trodelvy with Merck’s PD-1 inhibitor pembrolizumab (Keytruda) significantly reduced the risk of progression or death by 35% compared to the Keytruda plus chemotherapy control arm, extending median progression-free survival to 11.2 months versus 7.8 months. In a competitive ADC landscape, Trodelvy faces emerging challenges from agents such as Kelun-Biotech’s sacituzumab tirumotecan and AstraZeneca’s Datroway.

Novel ADC Trastuzumab Rezetecan as HER2-Targeted Therapy for NSCLC 

Just this week, China’s NMPA-National Medical Products Administration approved Hengrui Pharma Co.,Ltd's trastuzumab rezetecan, a novel HER2-targeted ADC, for adult patients with unresectable locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring activating HER2 mutations who have received prior systemic therapy. The approval was based on the pivotal HORIZON-Lung study, which reported a confirmed objective response rate of 74.5% and a median progression-free survival of 11.5 months, substantially outperforming conventional treatments. Beyond its established efficacy in lung cancer, trastuzumab rezetecan has demonstrated clinical advances across multiple tumor types, with eight additional indications.