1606P - Mature follow up of phase I dose finding trial of pembrolizumab (pembro) with AR inhibitors (ARI) and priming tumour-targeted radiation with anti-PSMA alpha emitter 225Ac-J591

Background

Immune checkpoint inhibition (ICI) rarely with efficacy in mCRPC. EBRT may help; PSMA targeted radionucleotides deliver radiation to multiple sites, alpha emitters cause double-stranded DNA breaks which may be immunogenic. ARI may increase PSMA and PD-L1 + radiosensitze. We hypothesize that alpha-PSMA (²²⁵Ac-J591) leads to release of neoantigens and improves response to ICI.

Methods

Eligibility: Progressive mCRPC by PCWG3 criteria (at least one prior ARPI, no chemotherapy in the mCRPC setting). Treatment: ARI of physician’s choice (enza/apa/darolutamide), pembro (pembro 400mg every 6 weeks), and single infusion of 225Ac-J591 at two different dose levels (65 or 80 KBq/kg). Primary endpoint; determination of recommended phase 2 dose (RP2D). Clinical parameters including PSA decline, PFS, OS, and PSMA-PET/CT were analyzed.

Results

Two cohorts: 6 at 65 KBq/kg, 6 at 80 KBq/kg, all with at least 1 prior ARPI (58% prior abi, 58% enza, 8% apa; 17% abi + ARI), 42% sip-T, 17% ¹⁷⁷Lu-PSMA. Median age 66.5, median PSA 7.75 ng/mL, 2 (17%) CALGB poor risk, 6 (50%) intermediate; 11 (92%) with bone metastases. With pembro, 7 (58%) received enza 3 (25%) apa, and 2 (17%) daro. No pt with MSI or high TMB (3 with germline BRCA2/CHEK2). No dose-limiting toxicity occurred and the RP2D was determined to be 80 KBq/Kg. A possibly delayed cytokine release syndrome of transient fever, thrombocytopenia, rash, and/or transaminitis occurred approx. 10 days after treatment in 58%. All patients had PSA decline, with 33% treated with 65 KBq/kg having >50% PSA decline and 67% in the 80 KBq/Kg group. All pts in the 65 KBq/kg group had progression (median PFS 5.4 months), whereas 50% in the 80 KBq/kg group completed 2 years of pembro and remain without progression. Median overall survival was 24 months in the 65 KBq/kg group, while 5 patients (83%) in the 80 KBq/kg group remain alive. Baseline median SUVmax whole body was 48.7 (55.5 in 66 KBq, 31.5 in 80 KBq) and the median SUVmean was 8.6 (similar in both groups).

Conclusions

The addition of ²²⁵Ac-J591 to pembro and ARI appears promising, with half of patients at 80 KBq/kg having durable response. The randomized phase II trial of pembro/ARI +/- ²²⁵Ac-J591 is ongoing (NCT04946370).

Clinical trial identification

NCT04946370.

Editorial acknowledgement

Legal entity responsible for the study

Scott T. Tagawa, Weill Cornell Medicine.

Funding

Weill Cornell Medicine, US Department of Defense, Merck.

Disclosure

D.M. Nanus: Financial Interests, Personal, Advisory Board: tELIX; Financial Interests, Personal, Invited Speaker: Janssen Oncology; Financial Interests, Personal, Other, DSMB Member: Genentech Roche; Financial Interests, Institutional, Coordinating PI, PI clinical trial: Exelixis; Financial Interests, Institutional, Local PI, Site lead clinical trial: Zenith Epigenetics. N.H. Bander: Financial Interests, Personal, Leadership Role: Convergent Therapeutics; Financial Interests, Personal, Licencing Fees or royalty for IP: Telix. S.T. Tagawa: Financial Interests, Personal, Advisory Board: Convergent Therapeutics, AIkido Pharma; Financial Interests, Personal, Other, Consultant: Ambrx, Telix Pharma, Blue Earth Diagnostics, POINT Biopharma, Myovant, Bayer, 4D Pharma, Gilead, Pfizer, Janssen, Astellas, AbbVie, Novartis, Seagen, Clarity, Merck, EMD Serono, Regeneron, Daiichi Sankyo; Financial Interests, Personal, Other, DSMB: Boston Scientific; Financial Interests, Personal, Stocks/Shares: AIkido Pharma; Financial Interests, Personal, Other, Patent co-inventor: Gilead; Financial Interests, Institutional, Advisory Board, Patent: Convergent Therapeutics; Financial Interests, Personal, Advisory Board, Patent: Convergent Therapeutics; Financial Interests, Institutional, Local PI: Medivation, Astellas, Janssen, Amgen, BMS, AstraZeneca, Bayer, Merck, Clovis, Seagen; Financial Interests, Institutional, Steering Committee Member: Gilead, Novartis, POINT Biopharma, Clarity, Ambrx, Promontory, Telix. All other authors have declared no conflicts of interest.