Puxitatug Samrotecan Hits 60% Response Rate in Platinum- and IO-Pretreated Endometrial Cancer

The B7-H4–directed antibody-drug conjugate (ADC) puxitatug samrotecan (AZD8205) demonstrated promising antitumor activity in patients with recurrent or progressive endometrial cancer, according to updated findings from the phase 1/2a BLUESTAR study (NCT05123482) presented at the 2026 ASCO Annual Meeting.¹

At the 2.4 mg/kg dose level, the agent produced a confirmed ORR of 47.1% and a median PFS of 7.2 months in the overall endometrial cancer cohort, with responses climbing to 60.6% in the subgroup that had received both prior platinum-based chemotherapy and prior anti–PD-1/PD-L1 therapy. Those findings supported an FDA Breakthrough Therapy Designation (BTD) for puxitatug samrotecan in patients with B7-H4–selected recurrent or progressive endometrial cancer following prior platinum and immunotherapy. At the same dose level, the agent produced a confirmed ORR of 24.4% 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," said lead investigator Linda Mileshkin, MD, of the Peter MacCallum Cancer Centre in Melbourne, Australia. "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 an immunoregulatory protein in the B7 family that is highly expressed across a substantial proportion of ovarian and endometrial cancers while showing minimal expression on normal tissue, making it a favorable ADC target. Puxitatug samrotecan is engineered to selectively deliver a topoisomerase I inhibitor payload to B7-H4–expressing tumor cells.

Efficacy in Endometrial Cancer

At the 2.4 mg/kg dose level in the endometrial cancer cohort (n = 51), puxitatug samrotecan produced a confirmed ORR of 47.1% (95% CI, 32.9%-61.5%), a 12-week disease control rate (DCR) of 84.3% (95% CI, 71.4%-93.0%), a median duration of response (DOR) of 7.1 months (95% CI, 4.5-13.3), and a median PFS of 7.2 months (95% CI, 5.6-9.2). Responses were observed across endometrioid, serous, carcinosarcoma, and clear cell histologies — including in chemotherapy-refractory carcinosarcoma — and across all 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%), 12-week DCR was 71.4% (95% CI, 55.4%-84.3%), median DOR was 6.0 months (95% CI, 4.9-9.7), and median PFS was 5.7 months (95% CI, 4.5-8.3).

Efficacy in 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%), 12-week DCR was 64.4% (95% CI, 48.8%-78.1%), median DOR was 7.0 months (95% CI, 4.0-14.8), and median PFS was 5.7 months (95% CI, 4.1-9.5). In the serous histology subgroup at this dose level (n = 31), the ORR was 22.6% (95% CI, 9.6%-41.1%) and median PFS was 5.8 months (95% CI, 4.1-9.2). At the lower 1.6 mg/kg dose level (n = 33), the ORR was 12.1% (95% CI, 3.4%-28.2%), with a median DOR of 5.8 months (95% CI, 2.8-NE) and median PFS of 4.8 months (95% CI, 2.8-5.8). The dose-dependent activity across cohorts supported selection of 2.4 mg/kg for further development.

Safety

At the 2.4 mg/kg dose level, nausea was the most common treatment-related adverse event (TRAE), occurring in 52.9% of patients in the endometrial cohort and 68.9% in the ovarian cohort; events were predominantly low grade and managed with prophylactic antiemetics. Hematologic toxicities were the next most frequent: in the endometrial cohort, any-grade neutropenia occurred in 45.1% (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, any-grade neutropenia occurred in 68.9% (grade ≥3, 60.0%) and any-grade anemia in 62.2% (grade ≥3, 37.8%).

Febrile neutropenia occurred in 3.9% of patients with endometrial cancer and 11.1% of those with ovarian cancer at the 2.4 mg/kg level. Treatment-related interstitial lung disease/pneumonitis was rare, affecting 1.0% (3/292) of all patients across the full BLUESTAR study population. Treatment discontinuation due to TRAEs was uncommon: 2.0% in the endometrial cohort and 6.7% in the ovarian cohort. Hematologic toxicities were managed with dose interruption, dose reduction, and growth factor support per investigator discretion.

Study Design

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, with B7-H4 positivity 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 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 prior standard-of-care therapy. The primary end point was incidence of adverse events; key secondary end points included ORR, DOR, DCR, PFS, and overall survival. Data cutoff was January 30, 2026.

In the endometrial cohort at 2.4 mg/kg, median age was 65.0 years (range, 34-81); 58.8% had endometrioid histology, 25.5% serous, 9.8% carcinosarcoma, and 2.0% clear cell. The median number of prior lines was 1 (range, 1-6); 98.0% had received prior platinum and 64.7% prior anti–PD-1/PD-L1 therapy. In the ovarian cohort at 2.4 mg/kg, median age was 59.0 years (range, 35-74); 68.9% had serous histology. The median number of prior lines was 2 (range, 1-6); 100% had received prior platinum, 57.8% a prior PARP inhibitor, and 64.4% prior VEGF/VEGFR-targeted therapy.

Based on these results, puxitatug samrotecan is now being evaluated in the global phase 3 BLUESTAR-Endometrial-01 trial (NCT07044336), which is comparing the ADC against physician's choice chemotherapy in patients with recurrent or progressive endometrial cancer following platinum and anti–PD-1/PD-L1 therapy.

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