Puxitatug Samrotecan Demonstrates Efficacy, Manageable Safety in Advanced/Metastatic Endometrial Cancer

Puxitatug samrotecan (AZD8205)—a B7-H4–targeting topoisomerase 1 inhibitor antibody-drug conjugate (ADC)—demonstrated preliminary efficacy and a manageable safety in patients with advanced or metastatic endometrial cancer, according to updated results from the phase 1/2a BLUESTAR study (NCT05276548) presented at the 2025 SGO Annual Meeting on Women’s Cancer.1

Among evaluable patients treated with puxitatug samrotecan at 2.0 mg/kg (n = 26) and 2.4 mg/kg (n = 26), the objective response rates (ORRs) were 34.6% and 38.5%, respectively; the respective 12-week disease control rates were 80.8% (95% CI, 60.6%-93.4%) and 84.6% (95% CI, 66.1%-95.6%).

At a median follow-up of 4.1 months (range, 1.2-12.7) for the 2.0-mg/kg cohort and 4.0 months (range, 0-12.5) for the 2.4-mg’kg cohort, the median progression-free survival was 7.0 months (95% CI, 4.5-9.0) and 7.0 months (95% CI, 5.5-9.2), respectively.

“Puxitatug samrotecan is an exciting new ADC targeting B7-H4, which is expressed in approximately 73% of endometrial cancers. Puxitatug samrotecan showed promising efficacy across a range of B7-H4 expression and in patients who had been previously treated with immunotherapy, with an ORR of [34.6%] and [38.8%], ” lead study author Stephanie Gaillard, MD, PhD, director of Gynecologic Cancer Trials and co-director of Development Therapeutics/Phase I Clinical Trials Program at Johns Hopkins School of Medicine in Baltimore, Maryland, explained in her presentation.

BLUESTAR Study Design and Patient Demographics

A total of 65 patients with advanced or metastatic endometrial cancer were enrolled in the BLUESTAR first-in-human phase 1/2a study evaluating puxitatug samrotecan.

Patients were assigned to 1 of 2 dose cohorts: 2.0 mg/kg (n = 30) or 2.4 mg/kg (n = 35) once every 3 weeks.1,2 All enrolled patients were at least 18 years of age with measurable disease per RECIST 1.1 criteria and prior progression on standard-of-care therapy.1 Notably, all tumors expressed B7-H4 as confirmed by immunohistochemistry, and no patients had previously received a topoisomerase 1 inhibitor.

The median age at enrollment was 62 years (range, 52-78) in the 2.0-mg/kg cohort and 65 years (range, 47-81) in the 2.4 mg/kg cohort. Most patients were White (56.7%; 68.6%) or Asian (33.3%; 22.9%) across the two cohorts. ECOG performance status was 0 or 1 in all patients, with 50.0% and 57.1% of patients, respectively, having an ECOG status of 0.

The median number of prior treatment regimens was 1.0 (range, 1-2) in the 2.0-mg/kg cohort and 1.5 (range, 1-5) in the 2.4-mg/kg cohort. Most patients had received prior platinum-based chemotherapy (96.7%; 91.4%), and a substantial proportion had previously been treated with a PD-(L)1 inhibitor (63.3%; 62.9%).

Regarding histologic subtypes, patients had endometrioid (2.0 mg/kg, 23.3%; 2.4 mg/kg, 22.9%), serous (23.3%; 14.3%), carcinosarcoma (16.7%; 11.4%), and clear cell (6.7%; 0%) disease. Notably, 30.0% and 40.0% of patients in the respective cohorts had tumors classified as "other" histologic subtypes.

The median B7-H4 expression was 57.5% in the 2.0-mg/kg cohort and 55.0% in the 2.4-mg/kg cohort.

Safety Findings and Future Analysis

The majority of treatment-related adverse effects (TRAEs) were gastrointestinal and hematologic in nature.

“Hematologic toxicities were managed with dose delays, reductions, or use of growth factors and transfusions if needed,” Gaillard noted. “There [was] no febrile neutropenia in these cohorts; anti-emetic prophylaxis as primary therapy was introduced post-escalation for management of nausea.”

Additionally, 40.0% and 34.3% of patients in the 2.0-mg/kg and 2.4 mg/kg cohorts, respectively, experienced grade 3 or higher TRAEs. The most common included anemia (16.7%; 20.0%), neutropenia (20.0%; 20.0%), leukopenia (10.0%; 3.6%), and diarrhea (0%; 17.1%). No TRAEs led to treatment discontinuation.

“A global phase 3 study of puxitatug samrotecan vs physician’s choice of chemotherapy is planned for patients with B7-H4–positive endometrial cancer whose disease has progressed following prior platinum and immunotherapy,” Galliard concluded.

References

1. Gaillard S, Guo R, Finkelstein K, et al. Safety and preliminary efficacy of puxitatug samrotecan (AZD8205) in patients with endometrial cancer: a first-in-human Phase 1/2a study. Presented at: 2025 SGO Annual Meeting on Women’s Cancer; March 14-17, 2025; Seattle, WA. Abstract 933087
2. A phase I/​IIa study of AZD8205 given alone or in combination with anticancer drugs, in participants with advanced or metastatic solid malignancies. Clinicaltrials.gov. Updated February 21, 2025. Accessed March 15, 2025. https://clinicaltrials.gov/study/NCT05123482