225AC-3BP-3940 Is Safe, Shows Activity in Heavily Pretreated Advanced Breast Cancer

Results showed that following treatment with 225AC-3BP-3940, 2 of 9 patients were alive at 13 and 26 months of follow-up; of the 7 patients who died, the median survival was 6 months.

Treatment with α-fractionated radiation therapy (FRT) with the Fibroblast activation protein (FAP)-binding peptide 225AC-3BP-3940 either alone or with β-emitters as TANDEM was well tolerated and elicited responses in patients with heavily pretreated metastatic breast cancer, according to findings of a retrospective analysis presented at the 2025 Society of Nuclear Medicine & Molecular Imaging Annual Meeting (SNMMI).

Results showed that following treatment with 225AC-3BP-3940, 2 of 9 patients were alive at 13 and 26 months of follow-up; of the 7 patients who died, the median survival was 6 months (range, 1-7). Of the 5 patients who were evaluable for response based on molecular imaging, 2 patients had a partial response, 1 had stable disease, and 2 had progressive disease.

“α-[fibroblast activation protein] radiotherapy with the binding peptide 225AC-3BP-3940 given as monotherapy or in TANDEM with beta-emitters is in our view, though data are limited, a valuable treatment option for heavily pretreated patients with metastatic breast cancer who have exhausted conventional therapies,” lead senior author Richard P. Baum, MD, PhD, professor of nuclear medicine at Curanosticum Wiesbaden-Frankfurt, the Center for Advanced Radiomolecular Precision Oncology in Wiesbarden, Germany, said in an oral presentation of the data. “Larger, prospective clinical trials are needed.”

Investigators theorized that radiomolecular medicine with radioligand therapy could have a role in patients with aggressive histopathological features, diffuse metastases that are resistant to systemic therapy and therefore a poor prognosis. Fibroblast activation protein (FAP)-directed radiopharmaceutical therapy with β- or α-emitting nuclides target the tumor microenvironment and tumor cells. FAP-α is a selective marker for cancer-associated fibroblasts that is expressed in the tumor microenvironment in 90% of tumors, as well as on select cancer cell surfaces.

In the retrospective analysis presented at the meeting, investigators sought to evaluate both acute- and long-term safety, efficacy, and survival outcomes with α-FRT with 225Ac-3BP-3940 both alone and with β-emitting Lutetium-177 or Yttrium-90 in patients with metastatic breast cancer treated under compassionate use following disease progression on standard treatments.

The analysis comprised prospective data collection, with 38 months of observation time between June 2021 and August 2024. FAP expression was determined via 68Ga-3BP-3940 PET/CT for eligibility to receive 3BP-3940 FRT. Patients then received premedication with 1000 mL of an intravenous jonosteril solution and were monitored both during and after 225Ac03BP-3940 injection; they also underwent SPET/CT scans in the event of TANDEM.

For safety, physicians examined acute adverse events (AEs) and long-term hematological, renal, and hepatic toxicities via Common Terminology Criteria for Adverse Events v5.0 criteria in 8 patients with at least 1 follow-up. Responses were assessed based on molecular imaging with THERCIST (68Ga-3BP-3940 PET/CT or SPET/CT).

The study population included 9 patients with advanced metastatic breast cancer between the ages of 37 to 75 years. Patients either had luminal A disease (n = 3), luminal B (n = 3), HER2-positive (n = 2), or triple-negative breast cancer (n = 1). All patients received prior chemotherapy, and other prior treatments included surgery (89%), hormonal therapy (78%), locoregional radiation (56%), denosumab (33%), bevacizumab (Avastin; 33%), CDK4/6 inhibitors (33%), trastuzumab (Herceptin; 22%), immune checkpoint inhibitors (22%), and β-FRT (177Lu-FRT or 90Y-FRT; 22%). One patient had a BRCA 2 mutation compared with 2 who were BRCA1/2 wildtype, and 6 patients were not assessed.

Four patients completed 1 cycle of treatment, 2 patients completed 2, and 3 patients completed 3 cycles. 225AC-3BP-3940 was given alone in 2 patients, combined with 177Lu-TANDEM in 13, or with 90Y TANDEM in 2 patients.

Regarding safety, grade 1 acute AEs consisted of nausea/emesis (n = 1) and lupus nephritis flare pain (n = 1), with Baum noting that the therapy was overall very well tolerated.

There were no long-term hematotoxicities at any grade; all reported hematological AEs were reported prior to FRT and reflected preexisting bone marrow impairment and were stable after treatment.

For patients with hepatic metastases, long-term nephrotoxicity comprised 1 case of grade 1 creatinine increase; there was also 1 case of grade 2 liver impairment that worsened to grade 3 (n = 1). There were no cases of grade 3/4 nephrotoxicity or hepatotoxicity, along with no cases of treatment discontinuation.

Reference

Perrone E, Ghai K, Eismant A, et al. A retrospective analysis of safety, efficacy and survival of metastatic colorectal cancer patients treated with Actinium-225 FAP-directed radiopharmaceutical therapy.J Nuclear Med. 2025;66(suppl 1):251921.