(UroToday.com) At the 2023 ASCO annual meeting, Scott Tagawa presented results of the Phase I dose-escalation study of prostate-specific membrane antigen-targeted radionuclide therapy (PSMA-TRT) with alpha-radiolabeled antibody 225Ac-J591 and beta-radioligand 177Lu-PSMA I&T.
He set up the background for this study by noting that PSMA PET imaging is increasingly being utilized in all stages of prostate cancer evaluation and staging. PSMA has already been utilized as a target to generate a therapeutic response – with the approval of Pluvicto (based on the VISION trial data), PSMA targeted therapy has become an important adjunctive treatment in patients with mCRPC.
However, PSMA may be targeted by antibodies (mAb) or small molecules (SML), with different kinetics and biodistribution. mAb may have longer circulation time and marrow exposure, but have decreased access to luminal PSMA expression (e.g. salivary glands, intestine, kidney). In contrast, SML diffuses to all sites of PSMA expression and is then excreted. These differences are summarized below:
When looking at the radionuclide itself, alpha radionuclides emit more energy over shorter range vs beta. Pre-clinical data combining mAb and SML targeting supports synergy, with enhanced uptake and retention of SML.
Herein, the authors present phase I dose-escalation results of a phase I/II trial investigating combo 225Ac-J591 with 177Lu-PSMA-I&T (aka PNT2002).
Eligibility criteria include progressive mCRPC, ≥1 prior AR pathway inhibitor (ARPI), prior chemo (or unfit/refuse), ≥1 lesion with SUVmax >liver.
As for the radioactive Doses: 177Lu-PSMA-I&T (6.8 GBq); 225Ac-J591 (30, 35, or 40 KBq/kg), up to 2 doses of combo TRT 8 weeks (wks) apart with 177Lu SPECT following each dose.
Primary objective was evaluating dose-limiting toxicity (DLT) and recommended phase II dose; phase II will test the proportion of patients (pts) obtaining >50% PSA decline (PSA50). DLT defined as G4 myelosuppression lasting >1 wk, Gr>2 non-hematologic adverse event (AE), any Gr attributed AE delaying therapy >3 wks. Additional endpoints include progression-free and overall survival, radiographic response rate, safety, circulating tumor cell (CTC) changes, pt reported outcomes, PSMA imaging, blood/tissue correlatives.
For this phase, they recruited 18 patients (6 at each dose level). Full demographics detailed below:
18 pts treated (6 at each dose level); 3 did not receive the 2nd dose due to progressive disease or withdrawal.
2 of 6 pts with DLT at 40 KBq/Kg (Gr 2 or 3 thrombocytopenia delaying cycle 2 by >3 wk), but no DLT observed in other dose cohorts. Adverse events are summarized in the table below:
As of 5/1/2023, 5 pts remain on study, including 1 with an undetectable PSA at 13 months after 2 cycles of treatment. With follow up ongoing, 17 (94%) with PSA decline, 11 (61%) with PSA50. PSA response is summarized in the figures below:
Of those with paired CTC counts, 5 of 7 (71%) converted from unfavorable to favorable CTC count at 12 weeks, 5 of 11 (45%) from detectable to undetectable, 1 of 2 (50%) remained undetectable.
Based on this promising Phase 1 data, the authors conclude that the combination of dual-PSMA targeting with mAb + SML and alpha + beta is feasible and safe with follow up ongoing. Efficacy will formally be tested in the upcoming phase II portion of the study with 225Ac-J591 at 35 KBq/Kg and 177Lu-PSMA I&T at 6.8 GBq.
Clinical trial information: NCT04886986.
Presented by: Scott T. Tagawa, MD, MS, FACP is a Professor of Medicine and Professor of Medicine in Urology at Weill Cornell Medicine, and an Attending Physician at NewYork-Presbyterian – Weill Cornell Medical Center
Written by: Thenappan (Thenu) Chandrasekar, MD – Urologic Oncologist, Associate Professor of Urology, University of California, Davis, @tchandra_uromd @UCDavisUrology on Twitter during the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, Fri, June 2 – Tues, June 6, 2023.