Initial results from Daiichi Sankyo's first-in-human phase 1/2 trial of DS-3939 demonstrated promising clinical activity in patients with previously treated advanced solid tumors refractory to standard treatment. The data, presented at the 2025 European Society for Medical Oncology (ESMO25), marks the first clinical presentation for the sixth DXd antibody drug conjugate from Daiichi Sankyo's oncology pipeline.
DS-3939 is a specifically engineered, potential first-in-class tumor-associated mucin-1 (TA-MUC1) directed DXd antibody drug conjugate discovered and being developed by Daiichi Sankyo. TA-MUC1 is a tumor-specific transmembrane glycoprotein that is overexpressed in most human epithelial cancers, making it a promising target for cancer therapy. Currently, there are no TA-MUC1 directed medicines approved for any type of cancer.
Trial Design and Patient Population
The dose escalation part of the phase 1/2 trial enrolled 64 patients with advanced solid tumors, including 16 with non-small cell lung cancer (NSCLC), 12 with pancreatic ductal adenocarcinoma, nine with urothelial carcinoma, eight with ovarian cancer, seven with biliary tract cancer, seven with colorectal cancer and five with breast cancer.
Patients received a median of three prior therapies (range, 1-17) for locally advanced/metastatic disease, with more than one-third receiving prior topoisomerase I inhibitor treatment (n=24; 37.5%). As of the data cut-off on August 1, 2025, 15 patients (23.4%) were still being treated with DS-3939.
Safety Profile
The safety and tolerability of DS-3939 was evaluated at increasing dose levels from 1.0 mg/kg to 10.0 mg/kg. The most common treatment-emergent adverse events (TEAEs) of any grade in >20% of patients were nausea (60.9%), vomiting (35.9%), fatigue (28.1%), anemia (26.6%), constipation (26.6%), decreased appetite (23.4%), diarrhea (23.4%) and decreased neutrophil count (23.4%).
Grade 3 or higher TEAEs occurred in 46.9% of patients (n=30) and the most common (>2%) included decreased neutrophil count (15.6%), anemia (10.9%), pneumonitis (4.7%) and decreased platelet count (3.1%). Three dose-limited toxicities were observed, including one grade 3 anemia needing transfusion (4.0 mg/kg dose), one grade 3 abdominal pain (6.0 mg/kg dose) and one grade 4 decreased platelet count (8.0 mg/kg dose).
Treatment-related interstitial lung disease (ILD)/pneumonitis occurred in 10.9% (n=7) of patients. The majority of ILD events were low grade (grade 2 [n=6 or 9.4%]) with one grade 3 (n=1 or 1.6%) event as determined by an independent adjudication committee. Following the data cut-off of August 1, 2025, two ILD events were adjudicated as grade 5 and two additional ILD events are pending adjudication.
Efficacy Results
Preliminary efficacy results were reported across dose levels from 1.0 mg/kg to 10.0 mg/kg of DS-3939. One confirmed complete response was observed in a patient with ovarian cancer and 10 confirmed partial responses were seen in patients with ovarian cancer (n=5), NSCLC (n=4) and breast cancer (n=1).
Thirty-nine cases of stable disease were observed in patients with NSCLC (n=11), urothelial carcinoma (n=8), pancreatic ductal adenocarcinoma (n=6), colorectal cancer (n=5), biliary tract cancer (n=4), breast cancer (n=3) and ovarian cancer (n=2) after a median follow-up of 8.8 months (range, 0.6-22.9).
Expert Commentary
"These initial results are encouraging for patients with advanced solid tumors where treatment options remain limited once standard therapies are no longer effective," said Manish R. Patel, MD, Director of Drug Development, Florida Cancer Specialists and Sarah Cannon Research Institute. "Enrollment continues into the dose expansion part of the trial to help us better understand the potential role DS-3939 may play in treating numerous types of advanced solid tumors."
Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo, noted: "These first-in-human results offer preliminary evidence that targeting the novel tumor antigen TA-MUC1 may be a promising treatment approach for multiple types of cancer. Additionally, these results represent the sixth antibody drug conjugate from the pipeline of Daiichi Sankyo with encouraging early phase data further demonstrating the portability of our DXd antibody drug conjugate technology to new tumor targets."
Next Steps
The two-part, multicenter, open-label, first-in-human phase 1/2 trial continues with dose expansion cohorts to further assess the safety and efficacy of DS-3939. The trial will evaluate safety endpoints, including dose-limiting toxicities and adverse events, and efficacy endpoints, including objective response rate, disease control rate, duration of response, time to response, progression-free survival and overall survival. Pharmacokinetic and biomarker endpoints also will be assessed.
The trial is ongoing and enrolling patients across multiple tumor types at sites globally, including Asia, Europe and North America.
