Dose-Escalation Results of 225Ac-J591 Plus 177Lu-PSMA-I&T

Scott Tagawa, MD, MS, FACP, and fellow researchers carried out a phase 1/2 trial investigating the combination of ²²⁵Ac-J591 with ¹⁷⁷Lu-PSMA-I&T (aka PNT2002). The study’s results will be presented at the American Society of Clinical Oncology 2023 Annual Meeting.

Eligible patients had progressive metastatic castration-resistant prostate cancer (mCRPC), 2 or more prior androgen receptor pathway inhibitors, prior chemotherapy (or unfit/refuse), and 1 or more lesions with a standardized uptake value greater than liver uptake.

A total of 18 patients were treated (6 at each dose level) with ¹⁷⁷Lu-PSMA-I&T (6.8 GBq), ²²⁵Ac-J591 (30, 35, or 40 KBq/kg), and up to 2 doses of combination testosterone replacement therapy 8 weeks apart, with ¹⁷⁷Lu-PSMA SPECT following each dose. Of the total patient group, 3 patients did not receive a second dose due to progressive disease or withdrawal.

The patient group had a median age of 70 years (range, 54-86 years) and a median prostate-specific antigen (PSA) level of 54.4 (range, 2.43-96.14). A total of 13 (72%) patients had bone metastases, while 9 (50%) had metastases in the lymph nodes, 2 (11%) in the liver, and 2 (11%) in the lungs.

The primary objectives of the study were dose-limiting toxicity (DLT) and a recommendation for phase 2 dosing. Phase 2 will test the proportion of patients obtaining a PSA decline greater than 50% (PSA50). DLT was defined as G4 myelosuppression lasting more than 1 week, grade 2 or higher nonhematologic adverse events (AE), or any grade-attributed AE delaying therapy over 3 weeks. Other end points included progression-free and overall survival, radiographic response rate, safety, circulating tumor cell (CTC) changes, patient-reported outcomes, PSMA imaging, and blood/tissue correlatives.

As of submission, 7 patients (39%) remain in the study, including 1 without progression at 16 months and another patient with undetectable PSA at 10 months. Follow-up is ongoing, where 17 (94%) patients have PSA decline, and 9 (50%) patients have a PSA over 50%. Of those with paired CTC counts, 4 of 5 (80%) converted from unfavorable to favorable CTC count, 4 of 8 (50%) from detectable to undetectable, and 1 of 2 (50%) remained undetectable. AEs included neutropenia, thrombocytopenia, anemia, pain flare, xerostomia, nausea, and fatigue.

The combination treatment of dual-PSMA targeting with mAb and SML is feasible, and a follow-up study is in progress. Efficacy will be tested further in the upcoming phase 2 portion of the study with ²²⁵Ac-J591 at 35 KBq/Kg and ¹⁷⁷Lu-PSMA I&T at 6.8 GBq.