The B7-H4-targeting antibody-drug conjugate (ADC) puxitatug samrotecan (AZD8205) has demonstrated promising efficacy and manageable safety in patients with advanced or metastatic endometrial cancer, according to updated results from the phase 1/2a BLUESTAR study presented at the 2025 Society of Gynecologic Oncology Annual Meeting on Women's Cancer.
The investigational therapy showed objective response rates (ORRs) of 34.6% and 38.5% in evaluable patients treated at 2.0 mg/kg (n=26) and 2.4 mg/kg (n=26) dose levels, respectively. Disease control rates at 12 weeks were similarly impressive at 80.8% (95% CI, 60.6%-93.4%) and 84.6% (95% CI, 66.1%-95.6%).
"Puxitatug samrotecan is an exciting new ADC targeting B7-H4, which is expressed in approximately 73% of endometrial cancers," explained lead study author Stephanie Gaillard, MD, PhD, director of Gynecologic Cancer Trials at Johns Hopkins School of Medicine. "It showed promising efficacy across a range of B7-H4 expression and in patients who had been previously treated with immunotherapy."
With median follow-up of approximately 4 months in both cohorts, the median progression-free survival (PFS) was 7.0 months in both the 2.0 mg/kg group (95% CI, 4.5-9.0) and the 2.4 mg/kg group (95% CI, 5.5-9.2).
Study Design and Patient Characteristics
The BLUESTAR first-in-human study enrolled 65 patients with advanced or metastatic endometrial cancer who were assigned to receive puxitatug samrotecan at either 2.0 mg/kg (n=30) or 2.4 mg/kg (n=35) once every three weeks.
All participants were at least 18 years old with measurable disease per RECIST 1.1 criteria and had experienced disease progression on standard-of-care therapy. Importantly, all tumors expressed B7-H4 as confirmed by immunohistochemistry, and no patients had previously received a topoisomerase 1 inhibitor.
The patient population had a median age of 62-65 years across the two cohorts, with most patients being White (56.7-68.6%) or Asian (22.9-33.3%). All patients had an ECOG performance status of 0 or 1, indicating good functional capacity.
Most patients had received prior platinum-based chemotherapy (91.4-96.7%), and a substantial proportion had previously been treated with PD-(L)1 inhibitor immunotherapy (62.9-63.3%). The median number of prior treatment regimens was 1.0 in the lower-dose cohort and 1.5 in the higher-dose group.
The study included patients with various histologic subtypes of endometrial cancer, including endometrioid (22.9-23.3%), serous (14.3-23.3%), carcinosarcoma (11.4-16.7%), and clear cell (0-6.7%). A significant proportion (30.0-40.0%) had tumors classified as "other" histologic subtypes.
Median B7-H4 expression was similar between the two cohorts at 57.5% and 55.0%, respectively.
Safety Profile and Adverse Events
The majority of treatment-related adverse effects (TRAEs) were gastrointestinal and hematologic in nature, consistent with the mechanism of action of topoisomerase 1 inhibitors.
"Hematologic toxicities were managed with dose delays, reductions, or use of growth factors and transfusions if needed," Dr. Gaillard noted. "There was no febrile neutropenia in these cohorts; anti-emetic prophylaxis as primary therapy was introduced post-escalation for management of nausea."
Grade 3 or higher TRAEs occurred in 40.0% and 34.3% of patients in the 2.0 mg/kg and 2.4 mg/kg cohorts, respectively. The most common severe adverse events included anemia (16.7-20.0%), neutropenia (20.0%), leukopenia (3.6-10.0%), and diarrhea (0-17.1%).
Notably, no treatment-related adverse events led to treatment discontinuation, suggesting that the safety profile is manageable with appropriate supportive care.
Future Directions
Based on these encouraging results, Dr. Gaillard announced plans for further development of the drug: "A global phase 3 study of puxitatug samrotecan versus physician's choice of chemotherapy is planned for patients with B7-H4-positive endometrial cancer whose disease has progressed following prior platinum and immunotherapy."
Endometrial cancer is the most common gynecologic malignancy in developed countries, with limited treatment options for patients with advanced or recurrent disease who have progressed on standard therapies. The development of targeted therapies like puxitatug samrotecan represents an important advancement in addressing this unmet medical need.
The BLUESTAR study results suggest that targeting B7-H4 with an antibody-drug conjugate may offer a new therapeutic approach for patients with endometrial cancer, particularly those who have exhausted standard treatment options.
