Puxitatug Samrotecan Yields Responses With Manageable Safety in Pretreated HR+/HER2– Advanced Breast Cancer

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Treatment with puxitatug samrotecan (P-Sam; AZD8205), a novel B7-H4–targeting antibody-drug conjugate (ADC) with a topoisomerase I inhibitor payload, demonstrated a manageable safety profile and early antitumor activity in patients with previously treated, hormone receptor (HR)–positive, HER2-negative breast cancer, according to updated data from the ongoing phase 1/2a BLUESTAR trial (NCT05123482).1

Findings presented at the 2025 ESMO Breast Cancer Congress showed that treatment-related adverse effects (TRAEs) of any grade occurred in 96.9% of patients treated at a dose of 1.6 mg/kg (n = 32) and 96.6% of those treated with a 2.4-mg/kg dose (n = 29). Grade 3 or higher TRAEs were reported in 15.6% of patients in the 1.6-mg/kg cohort and 44.8% in the 2.4-mg/kg cohort. Serious TRAEs occurred in 3.1% and 10.3% of patients in the respective dose groups. TRAEs led to discontinuation of P-Sam in 1 patient (3.1%) in the lower-dose group and in 2 patients (6.9%) in the higher-dose group. Dose reductions due to TRAEs were required in 3.1% and 10.3% of patients in the 1.6-mg/kg and 2.4 mg/kg cohorts, respectively.

At a median follow-up of 4.2 months (range, 0-12.4) for the 1.6-mg/kg cohort and 4.4 months (range, 0-15.8) for the 2.4-mg/kg cohort, P-Sam generated an overall response rate (ORR) of 40.0% in the 1.6-mg/kg group (n = 30) and 29.6% in the 2.4-mg/kg group (n = 27). The disease control rate (DCR) at 12 weeks were 70.0% (95% CI, 50.6%-85.3%) in the 1.6-mg/kg cohort and 77.8% (95% CI, 57.7%-91.4%) in the 2.4-mg/kg cohort. The median progression-free survival (PFS) was 5.6 months (95% CI, 4.0-6.8) and 8.1 months (95% CI, 5.7–14.7), respectively.

"B7-H4 is a promising novel ADC target expressed in 45.4% of patients with HR-positive/HER2-negative breast cancer. P-Sam was well tolerated and had a manageable safety profile,” lead study author Richard Baird, MD, PhD, an academic medical oncologist at the Cancer Research UK Cambridge Cancer Centre, said in the presentation.

BLUESTAR Study Design and Baseline Characteristics

BLUESTAR is a first-in-human, multicenter, open-label phase 1/2a dose-escalation and -expansion trial evaluating the safety, tolerability, and preliminary efficacy of P-Sam in adult patients with advanced or recurrent solid tumors, including a dedicated cohort of patients with HR-positive/HER2-negative breast cancer.

Eligible patients in the breast cancer cohort were required to be at least 18 years of age with histologically confirmed HR-positive/HER2-negative advanced or recurrent disease and an ECOG performance status of 0 or 1. Patients needed to have documented disease progression on at least 1 prior endocrine therapy and not be candidates for additional endocrine therapy. Additionally, at least 1 prior line of chemotherapy was required. Additional inclusion criteria included B7-H4–positive tumors, defined as greater than 25% of tumor cells expressing B7-H4 per immunohistochemistry, and measurable disease per RECIST 1.1 criteria.

Dose escalation was conducted with P-Sam administered intravenously every 3 weeks across doses ranging from 0.8 mg/kg to 3.2 mg/kg. Patients enrolled in the breast cancer cohort received the agent at either 1.6 mg/kg or 2.4 mg/kg once every 3 weeks in the expansion phase.

Safety and the incidence of dose-limiting toxicities were the trial’s primary end points.2 Secondary end points included ORR, duration of response, PFS, DCR, overall survival, and pharmacokinetics.

Baseline Patient Demographics in the Breast Cancer Cohorts

The median age was 53.0 years (range, 35-79) in the 1.6-mg/kg cohort and 57.0 years (range, 38-73) in the 2.4-mg/kg cohort. The racial distribution showed that 40.6% of patients in the 1.6-mg/kg group and 51.7% in the 2.4-mg/kg group were White; Asian patients comprised 59.4% and 48.3% of these respective cohorts. An ECOG performance status of 0 was reported in 46.9% and 51.7% of patients, respectively. The majority of patients had histologically confirmed invasive ductal carcinoma not otherwise specified (1.6-mg/kg group, 84.4%; 2.4-mg/kg group, 82.8%). Invasive lobular carcinoma was observed in 6.3% and 10.3% of patients, respectively.

The median number of prior lines of chemotherapy was 3.0 (range, 0-7) for both cohorts. Most patients in both cohorts had prior exposure to CDK4/6 inhibitors (1.6-mg/kg cohort, 84.4%; 2.4-mg/kg cohort, 89.7%), prior anthracycline-based therapy (71.9%; 65.5%), and prior treatment with taxanes (81.3%; 69.0%).

The median percentage of tumor cells expressing B7-H4 was 67.5% (range, 25%-100%) in the 1.6-mg/kg cohort and 80.0% (range, 25%-100%) in the 2.4-mg/kg cohort.

Safety Findings Continued

Any-grade TRAEs occurring in at least 15% of patients included nausea (1.6-mg/kg group, 40.6%; 2.4-mg/kg group, 55.2%), asthenia or fatigue (31.3%; 41.4%), neutropenia (25.0%; 55.2%;), leukopenia (21.9%; 20.7%), anemia (15.6%; 31.0%), diarrhea (12.5%; 27.6%), and alopecia (9.4%; 27.6%). Notably, febrile neutropenia was observed in 3.3% of patients at the 2.4-mg/kg dose level.

Grade 3 or higher TRAEs in the 1.6-mg/kg cohort included neutropenia (3.1%), leukopenia (6.3%), and anemia (3.1%). In the 2.4-mg/kg cohort, grade 3 or higher TRAEs comprised asthenia or fatigue (3.4%), neutropenia (37.9%), leukopenia (10.3%), anemia (6.9%), and diarrhea (3.4%).

The most common TRAEs were gastrointestinal and hematologic. Hematologic toxicities were managed with dose delays, growth factors, transfusions, or treatment modification. Nausea was managed with antiemetic prophylaxis introduced post-escalation.

No treatment-related interstitial lung disease (ILD) or pneumonitis were reported. Across the broader trial population (n = 259), P-Sam–related ILD/pneumonitis was reported in 3 patients at grade 1 (n = 2) and grade 5 (n = 1).

References

1. Baird R, Chung W-P, Schmid P, et al. Puxitatug samrotecan (P-Sam, AZD8205) in patients with HR+/HER2– breast cancer: a first-in-human Phase 1/2a dose escalation and expansion study. Presented at: 2025 ESMO Breast Cancer Congress; May 14-17, 2025; Berlin, Germany. Abstract 300MO.
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 April 18, 2025. Accessed May 15, 2025. https://clinicaltrials.gov/study/NCT05123482