Puxitatug samrotecan (P-Sam), an investigational antibody-drug conjugate (ADC) targeting B7-H4-expressing tumors, showed promising efficacy in patients with advanced or metastatic endometrial cancer, according to results from the first-in-human phase I/IIa BLUESTAR study.
Among 52 evaluable patients, the group who received a 2 mg/kg dose of the topoisomerase I inhibitor had an objective response rate (ORR) of 34.6%, and the group receiving a dose of 2.4 mg/kg had an ORR of 38.5%, reported Stéphanie Gaillard, MD, PhD, of Johns Hopkins Sidney Kimmel Cancer Center in Baltimore, during the Society of Gynecologic Oncology annual meeting in Seattle.
Responses were observed across a range of B7-HR expression levels, as well as in patients who had received prior treatment with PD-1 or PD-L1 inhibitors.
The median progression-free survival was 7 months with both doses, with a median duration of response of 4.1 months with the 2-mg/kg dose, and 4 months with the 2.4-mg/kg dose.
The disease control rates at 12 weeks were 80.8% in the 2-mg/kg group and 84.6% in the 2.4-mg/kg group.
"P-Sam is an exciting new ADC targeting B7-H4, which is expressed in approximately 73% of endometrial cancers," Gaillard said at a late-breaking abstract session.
A phase III trial of P-Sam versus physician's choice of chemotherapy is planned that will include patients with B7-H4-positive endometrial cancer whose disease has progressed following platinum chemotherapy and immunotherapy.
Considering that it is expressed in nearly three-quarters of endometrial cancers, "B7-H4 seems like a great target," noted invited discussant Amanda Jackson, MD, of the University of Cincinnati.
Jackson was particularly impressed that patients with low B7-H4 expression -- ≥25% to <50% -- achieved a response with P-Sam, and that efficacy was seen in multiple histology types, "so I'm very excited to see what happens with the upcoming phase III study."
Gaillard explained that while B7-H4 has limited expression in normal tissue, it is highly expressed in several tumors, with the highest expression in endometrial cancer, making it an attractive target for an ADC. P-Sam demonstrated promising clinical activity in initial results from the first phase of the BLUESTAR study of heavily pretreated patients with advanced or metastatic solid tumors.
Expansion cohort studies are also ongoing in ovarian, breast, and biliary tract cancers.
For this study, eligible patients had advanced or metastatic endometrial cancer that progressed on prior platinum-based first-line therapy, a B7-H4-positive tumor as measured by immunohistochemistry, measurable disease by RECIST v1.1 criteria, and an Eastern Cooperative Oncology Group performance status of 0-1, and had not received a prior topoisomerase I inhibitor.
Patients received P-Sam 2 mg/kg (median age 62, 56.7% white) or 2.4 mg/kg (median age 65, 68.6% white) intravenously every 3 weeks until disease progression, unacceptable drug-related toxicity, or withdrawal of consent.
Almost all patients in the study (94%) had received prior platinum chemotherapy, while 63% had received a prior PD-1 or PD-L1 inhibitor.
Any-grade treatment-related adverse events (TRAEs) occurred in 83.3% and 85.7% of patients in the 2-mg/kg and 2.4-mg/kg groups, respectively, while TRAEs grade ≥3 occurred in 40% and 34.3%. Serious TRAEs occurred in 6.7% and 11.4% of the two groups.
TRAEs led to dose reductions in 10% and 14.3% of the 2-mg/kg and 2.4-mg/kg groups, respectively, but no treatment discontinuations occurred.
The most common TRAEs were gastrointestinal (nausea in 60% of patients overall), and hematologic (anemia in 40% of patients, and neutropenia in 36.7%).
At the time of data cutoff, treatment-related interstitial lung disease/pneumonitis was reported in three patients among the 259 enrolled across the entire BLUESTAR program.
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Mike Bassett is a staff writer focusing on oncology and hematology. He is based in Massachusetts.
Disclosures
The study was sponsored by AstraZeneca.
Gaillard reported relationships with AstraZeneca, BeiGene, Blueprint, Compugen, Pharma&, Immunogen, Tempest, Verastem, and Volastra.
Jackson reported relationships with Ethicon, Auris, AstraZeneca, OncLive, and Planned Parenthood.
Primary Source
Society of Gynecologic Oncology
Source Reference: Gaillard S, et al "Safety and preliminary efficacy of puxitatug samrotecan (AZD8205) in patients with endometrial cancer: a first-in-human phase 1/2a study" SGO 2025; Abstract LBA05.