Puxitatug Samrotecan Elicits High Response Rate in Select Endometrial Cancers

Puxitatug samrotecan (Puxi-Sam, AZD8205), a B7-H4-directed antibody-drug conjugate (ADC) with a topoisomerase 1 inhibitor payload, produced a confirmed objective response rate (ORR) of 47.1% and a median progression-free survival (PFS) of 7.2 months in patients with B7-H4-expressing recurrent or progressive endometrial cancer treated at the 2.4 mg/kg dose level, according to findings form the phase 1/2a BLUESTAR study (NCT05123482) presented at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting.¹

In an analysis of 51 patients enrolled in the endometrial cohort who had received both prior platinum-based chemotherapy and prior anti-PD-1/PD-L1 therapy, the confirmed ORR climbed to 60.6% with a median PFS of 7.1 months. These findings supported an FDA Breakthrough Therapy Designation (BTD) for puxitatug samrotecan in patients with B7-H4-selected recurrent or progressive endometrial cancer after prior platinum and immunotherapy. The ADC also produced a 24.4% confirmed ORR at the same dose level in patients with heavily pretreated platinum-resistant ovarian cancer.

"Puxi-Sam demonstrates antitumor activity in patients with B7-H4-expressing ovarian cancer and endometrial cancer, but particularly compelling efficacy is seen in patients with endometrial cancer," lead investigator Linda Mileshkin, MD, of the Peter MacCallum Cancer Centre in Melbourne, Australia, said when she presented the data. “The 60.6% response rate in the BTD-supporting subgroup represents a really clinically meaningful benefit for this group of patients at a time of limited treatment options.”

B7-H4 is a member of the B7 family of immunoregulatory proteins that is highly expressed on a substantial proportion of ovarian and endometrial cancers but only minimally expressed on normal tissue, making it an attractive ADC target. Puxitatug samrotecan is designed to deliver a topoisomerase 1 enzyme inhibitor payload selectively to B7-H4-expressing tumor cells.

How was BLUESTAR designed and who enrolled?

BLUESTAR is a phase 1/2a, first-in-human, open-label study evaluating intravenous puxitatug samrotecan administered every 3 weeks as monotherapy in patients with B7-H4-positive advanced or metastatic solid tumors. B7-H4 positivity was defined as at least 25% tumor cell staining by central immunohistochemistry.

The endometrial cancer expansion cohort included patients dosed at 2.0 mg/kg (n = 42) and 2.4 mg/kg (n = 51). The platinum-resistant ovarian cancer expansion cohort included patients dosed at 1.6 mg/kg (n = 33) and 2.4 mg/kg (n = 45). Platinum resistance was defined as progression during or within 6 months after the last platinum dose, with at least 2 prior platinum lines. Eligible patients had an ECOG performance status of 0 or 1 and had received prior standard-of-care therapy. The primary endpoint was the incidence of adverse events, with key secondary endpoints focused on ORR, duration of response (DOR), disease control rate (DCR), PFS, and overall survival. The data cutoff for the current analysis was January 30, 2026.

In the endometrial cancer cohort at 2.4 mg/kg, the median age was 65.0 years (range, 34-81). Overall, 58.8% had endometrioid histology, 25.5% had serous histology, 9.8% had carcinosarcoma, and 2.0% had clear cell histology. The median number of prior lines of therapy was 1 (range, 1-6), and 98.0% had received prior platinum-based chemotherapy with 64.7% having received prior anti-PD-1/PD-L1 therapy.

In the platinum-resistant ovarian cancer cohort at 2.4 mg/kg, the median age was 59.0 years (range, 35-74). Histology was serous for 68.9% of patients, with the next most common type listed as other (17.8%). The median number of prior lines of therapy was 2 (range, 1-6) with 100% having received prior platinum. More than half of patients (57.8%) had received a prior PARP inhibitor and 64.4% had received prior VEGF/VEGFR-targeted therapy.

How active was puxitatug samrotecan in endometrial cancer?

For those with endometrial cancer at the 2.4 mg/kg dose level (n = 51), puxitatug samrotecan elicited a confirmed ORR of 47.1% (95% CI, 32.9%-61.5%) and a 12-week DCR of 84.3% (95% CI, 71.4%-93.0%). The median DOR was 7.1 months (95% CI, 4.5-13.3), and the median PFS was 7.2 months (95% CI, 5.6-9.2). Activity was observed across endometrioid, serous, carcinosarcoma, and clear cell histologies, including in chemotherapy-refractory carcinosarcoma, Mileshkin said. Additionally, activity was seen across the full range of B7-H4 expression strata (25%-49%, 50%-74%, and ≥75% tumor cell staining).

At the lower 2.0 mg/kg dose level (n = 42), the confirmed ORR was 33.3% (95% CI, 19.6%-49.6%), the 12-week DCR was 71.4% (95% CI, 55.4%-84.3%), the median DOR was 6.0 months (95% CI, 4.9-9.7), and the median PFS was 5.7 months (95% CI, 4.5-8.3).

Is puxitatug samrotecan effective for platinum-resistant ovarian cancer?

In the platinum-resistant ovarian cancer cohort at 2.4 mg/kg (n = 45), the confirmed ORR was 24.4% (95% CI, 12.9%-39.5%) and the 12-week DCR was 64.4% (95% CI, 48.8%-78.1%). The median DOR was 7.0 months (95% CI, 4.0-14.8) and the median PFS was 5.7 months (95% CI, 4.1-9.5).

Responses were observed across histologies and B7-H4 expression levels. In the serous histology subgroup at the 2.4 mg/kg dose level (n = 31), the confirmed ORR was 22.6% (95% CI, 9.6%-41.1%) and the median PFS was 5.8 months (95% CI, 4.1-9.2). At the lower 1.6 mg/kg dose level across all ovarian cancer histologies (n = 33), the confirmed ORR was 12.1% (95% CI, 3.4%-28.2%), the median DOR was 5.8 months (95% CI, 2.8-NE), and the median PFS was 4.8 months (95% CI, 2.8-5.8). These findings demonstrate an exposure-response signal that informed selection of 2.4 mg/kg as the focus of further development, noted Mileshkin.

How well did patients tolerate puxitatug samrotecan?

Treatment-related adverse events (TRAEs) at the 2.4 mg/kg dose level of puxitatug samrotecan were dominated by nausea, which occurred for 52.9% of patients in the endometrial cohort and 68.9% in the ovarian cohort. These events were mostly low grade and managed with prophylactic antiemetic therapy.

The other common TRAEs with puxitatug samrotecan were primarily hematologic toxicities. In the endometrial cohort at 2.4 mg/kg, any-grade neutropenia occurred in 45.1% of patients (grade ≥3, 35.3%), any-grade anemia in 51.0% (grade ≥3, 29.4%), and any-grade asthenia/fatigue in 49.0% (grade ≥3, 5.9%). In the ovarian cohort at 2.4 mg/kg, any-grade neutropenia occurred in 68.9% (grade ≥3, 60.0%) and any-grade anemia in 62.2% (grade ≥3, 37.8%).

Treatment-related febrile neutropenia at the 2.4 mg/kg dose level occurred in 3.9% of patients with endometrial cancer and 11.1% of those with ovarian cancer. Treatment-related interstitial lung disease/pneumonitis was rare, occurring in 1.0% (3/292) of all patients treated across the BLUESTAR study.

Treatment discontinuation due to TRAEs was uncommon at the 2.4 mg/kg dose level: 2.0% in the endometrial cohort (1/51) and 6.7% in the ovarian cohort (3/45). Hematologic toxicities were generally managed with dose interruption, dose reduction, and growth factor support per investigator discretion, Mileshkin said.

What comes next for puxitatug samrotecan?

Based on these results, puxitatug samrotecan is now being evaluated in BLUESTAR-Endometrial-01 (NCT07044336), a global phase 3 study comparing the ADC with physician's choice of chemotherapy in patients with recurrent or progressive endometrial cancer who have progressed following platinum-based chemotherapy and anti-PD-1/PD-L1 therapy. The phase 1 BLUESTAR study continues to enroll patients to evaluate combination treatment strategies.

Reference

1. Mileshkin L, Gaillard S, Guo R, et al. Updated safety and efficacy of puxitatug samrotecan (Puxi-Sam, AZD8205) in patients with endometrial cancer (EC) or ovarian cancer (OC): phase 1/2a BLUESTAR study. J Clin Oncol. 2026;44(suppl 16):5515. doi:10.1200/JCO.2026.44.16_suppl.5515