577O - PRINCE: Interim analysis of the phase Ib study of ¹⁷⁷Lu-PSMA-617 in combination with pembrolizumab for metastatic castration resistant prostate cancer (mCRPC)

Background

¹⁷⁷Lu-PSMA-617 (Lu-PSMA-617) is a radiolabelled small-molecule with established efficacy and safety in mCRPC, that delivers β radiation to tumours expressing PSMA. Pembrolizumab, an anti-programmed death 1 inhibitor, has modest single agent anti-tumour activity in mCRPC. We hypothesise that β radiation can induce tumour cell death that is potentially immunogenic, and that addition of pembrolizumab to Lu-PSMA-617 can improve responses. PRINCE aimed to evaluate the safety and efficacy of the combination of Lu-PSMA-617 and pembrolizumab.

Methods

mCRPC patients (pts) with high PSMA expression without discordant FDG avid disease on paired PSMA and FDG PET/CT scans received up to 6 cycles of Lu-PSMA-617 (6-8 GBq) every 6 weeks in conjunction with 200mg of pembrolizumab every 3 weeks for up to 2 years. Co-primary endpoints were safety and 50% PSA response rate (PSA50-RR). Secondary endpoints included PSA-progression-free survival (PSA-PFS), radiographic PFS (rPFS) and overall survival (OS).

Results

37 pts (median age 72 years; prior docetaxel 73%; prior androgen receptor targeted agent 100%) received a median of 4 cycles of Lu-PSMA-617 and 8 doses of pembrolizumab. Median follow up was 38 weeks. PSA50-RR was 73% (27/37 [95% CI: 56-86]) and 7/9 (78%) pts with RECIST measurable disease had a partial response. rPFS and PSA-PFS at 24 weeks were 64% (95% CI: 45-79) and 68% (95% CI: 50-81) respectively. Common treatment related adverse events (TRAE) (≥10%) were mainly Grade (G) 1-2 and included xerostomia (76%), fatigue (43%), diarrhoea (11%), rash (22%), nausea (24%), elevated ALT (11%), pruritus (19%), and bone pain (11%). Haematologic TRAE included G2-3 anaemia (8%), G1-2 thrombocytopenia (14%), and G1 neutropenia (3%). G3 immune related AEs affecting one pt each included mucosal pemphigus, myasthenia gravis, optic neuritis, pancreatitis, pneumonitis, nephritis, amylase elevation, type 1 diabetes, and colitis in 2 pts. 4 (11%) pts discontinued treatment due to toxicity.

Conclusions

The combination of Lu-PSMA-617 and pembrolizumab had promising activity. Toxicities were consistent with those of single agent Lu-PSMA-617 and pembrolizumab.

Clinical trial identification

NCT03658447.

Editorial acknowledgement

Legal entity responsible for the study

Peter MacCallum Cancer Centre.

Funding

This study was largely funded from a peer reviewed Victorian Cancer Agency Grant. We also received supplementary funding support from Merck Sharp and Dohme and Endocyte/Novartis.

Disclosure

S.K. Sandhu: Financial Interests, Institutional, Advisory Board, I have served on advisory boards for BMS. The contracts for my role are set up with the institution and the funds go to a research fund at Peter MacCallum Cancer Centre: Bristol Myer Squibb; Financial Interests, Institutional, Advisory Board, I have served on advisory boards for MSD. The e contracts for my role are set up with the institution and the funds go to a research fund at Peter MacCallum Cancer Centre: Merck Sharp and Dohme; Financial Interests, Institutional, Advisory Board, I have served on advisory boards for AstraZeneca. The contracts for my role as an advisor are set up with the institution and the funds go to a research fund at Peter MacCallum Cancer Centre: AstraZeneca; Financial Interests, Institutional, Advisory Board, I have served on advisory boards for Novartis. The contracts for my role as an advisor are set up with the institution and the funds go to a research fund at Peter MacCallum Cancer Centre: Novartis; Financial Interests, Institutional, Advisory Board, I have served on an advisory board for Merck Serono. The contracts for my service are set up with the institution and funds go into a research fund at the Peter MacCallum Cancer Centre: Merck Serono; Financial Interests, Institutional, Research Grant, My institution receives grant funding to run an investigator initiated trial that I lead: Novartis; Financial Interests, Institutional, Research Grant, My institution receives grant funding to run an investigator initiated trial that I lead: Genentech; Financial Interests, Institutional, Research Grant, My institution receives grant funding to run an investigator initiated trial that I lead: Amgen; Financial Interests, Institutional, Research Grant, My institution receives grant funding to run an investigator initiated trial that I lead: AstraZeneca; Financial Interests, Institutional, Research Grant, My institution receives grant funding to run an investigator initiated trial that I lead: Merck Serono; Financial Interests, Institutional, Research Grant, My institution receives grant funding to run an investigator initiated trial that I lead: Merck Sharp and Dohme; Non-Financial Interests, Principal Investigator, I am a principal investigator on several of Janssen sponsored studies and don't receive any renumeration for this: Janssen; Non-Financial Interests, Principal Investigator, I am a principal investigator on several Novartis sponsored studies and dont receive any renumeration for this: Novartis; Non-Financial Interests, Principal Investigator, I am a principal investigator on several of Genentech sponsored studies and don't receive any renumeration for this: Genentech; Non-Financial Interests, Principal Investigator, I am a principal investigator on several of Bristol Myer Squibb sponsored studies and don't receive any renumeration for this: Bristol Myer Squibb; Non-Financial Interests, Other, I serve on the Independent Safety and Data Monitoring committee for 2 of Novartis sponsored studies and dont receive any compensation for this: Novartis; Non-Financial Interests, Principal Investigator, I am the Priincipal Investigator for several AstraZeneca sponsored studies and am not remunerated for this: AstraZeneca; Non-Financial Interests, Other, I serve on the steering committee for several Janssen sponsored trials and i do not receive compensation for this: Janssen; Non-Financial Interests, Other, I serve on the steering committee for one AstraZeneca sponsored trial and I do not receive compensation for this: AstraZeneca; Non-Financial Interests, Other, I serve on the steering committee for one Genentech sponsored trials and I do not receive compensation for this: Genentech; Non-Financial Interests, Other, I serve on the steering committee for a Bristol Myer Squibb sponsored trial and I do not receive renumeration for this: Bristol Myer Squibb. A.M. Joshua: Financial Interests, Institutional, Advisory Board, Serving on an advisory board. Funds were paid to the institution: Merck, Sharpe & Dhome. L. Emmett: Financial Interests, Personal, Speaker’s Bureau: Astellas; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca; Financial Interests, Personal, Speaker’s Bureau: Janssen; Financial Interests, Personal, Speaker’s Bureau: Mundipharma; Financial Interests, Personal, Speaker’s Bureau: Clarity Pharmaceuticals. L. Spain: Financial Interests, Personal, Advisory Board, < 5000 Euro. Chaired the Advisory Board on irAEs and how to improve networking: Bristol Myers Squibb; Financial Interests, Personal, Invited Speaker, < 5000 Euro. Invited speaker at COSA (Australian conference): Bristol Myers Squibb; Financial Interests, Institutional, Principal Investigator, PROpel Study, PI for eastern Health: AstraZeneca; Financial Interests, Institutional, Principal Investigator, MDV3800-06 Study, PI for Eastern Health: Pfizer; Financial Interests, Institutional, Principal Investigator, IPATential 150 Study, PI for Eastern Health: Roche. L.G. Horvath: Financial Interests, Personal, Advisory Board, Honorarium donated back to Chris O'Brien Lifehouse (My hospital): Imagion Biosystems; Non-Financial Interests, Personal, Member of the Board of Directors, No payment received: ANZUP (Australia and New Zealand Urogenital and Prostate) Clinical Trials Group; Financial Interests, Personal, Stocks/Shares, Stock Options: Imagion Biosystems; Financial Interests, Personal, Stocks/Shares: My Emergency Doctor; Financial Interests, Institutional, Principal Investigator, AMG160 Phase I Study and AMG509 Phase I Study: Amgen; Financial Interests, Institutional, Principal Investigator, ATG-017 Study: Antagene; Financial Interests, Institutional, Advisory Role, Steering Committee Member, ENZAMET Study and ENZARAD Study: ANZUP; Financial Interests, Institutional, Advisory Role, Steering Committee Member, DASL-HiCAP Study ANZUP; Financial Interests, Institutional, Principal Investigator, AB928CSP0003 Study: ARCUS; Financial Interests, Institutional, Principal Investigator, 9785-CL-0335 (ARCHES) Study: Astellas; Financial Interests, Institutional, Research Grant: Astellas; Financial Interests, Institutional, Principal Investigator, BGB-A317 Study, BGB-283 Study, BGB-A317-290 Study: Beigene; Financial Interests, Institutional, Principal Investigator, JPCM Study: Eli-Lilly; Financial Interests, Institutional, Principal Investigator, XL184-021 Study: Exelixis; Financial Interests, Institutional, Principal Investigator, FPT155-001 Study: Five Prime; Financial Interests, Institutional, Principal Investigator, GSK204697 Study: GlaxoSmithKline; Financial Interests, Institutional, Principal Investigator, Galahad Study, ACIS Study, Prevalence Study: Janssen-Cilag; Financial Interests, Institutional, Principal Investigator, SHR3680-002 Study: Jiangsu Hengrui Medicines; Financial Interests, Institutional, Principal Investigator, MK7684-001 Study, MK3475-991 Study: Merck Sharp & Dohme; Financial Interests, Institutional, Principal Investigator, C344102 Study: Pfizer. M. Crumbaker: Financial Interests, Institutional, Principal Investigator: AstraZeneca; Financial Interests, Institutional, Principal Investigator: Merck Sharp & Dohme; Financial Interests, Personal, Advisory Role, Honorarium: Merck Sharp & Dohme; Financial Interests, Personal, Advisory Role, Honorarium: Pfizer. A. Anton: Financial Interests, Personal, Advisory Role, Honorarium: Amgen; Financial Interests, Personal, Advisory Role, Honorarium: Janssen; Financial Interests, Personal, Other, Travel: Amgen; Financial Interests, Personal, Invited Speaker, Travel: Astellas; Financial Interests, Institutional, Funding, Research funding: Amgen; Financial Interests, Institutional, Funding, Research funding: AstraZeneca; Financial Interests, Institutional, Funding, Research funding: Astellas; Financial Interests, Institutional, Funding, Research funding: Janssen; Financial Interests, Institutional, Funding, Research funding: Mundipharma. I.D. Davis: Financial Interests, Personal, Royalties, Authorship royalties for: Health Press; Financial Interests, Institutional, Principal Investigator, Institutional support for clinical research: Astellas; Financial Interests, Institutional, Principal Investigator, Institutional support for clinical research: AstraZeneca; Financial Interests, Institutional, Principal Investigator, Institutional support for clinical research: Bayer; Financial Interests, Institutional, Principal Investigator, Institutional support for clinical research: Bristol Myers Squibb; Financial Interests, Institutional, Principal Investigator, Institutional support for clinical research: Eisai; Financial Interests, Institutional, Principal Investigator, Institutional support for clinical research: Exelixis; Financial Interests, Institutional, Principal Investigator, Institutional support for clinical research: Janssen; Financial Interests, Institutional, Principal Investigator, Institutional support for clinical research: Merck Sharpe & Dohme; Financial Interests, Institutional, Principal Investigator, Institutional support for clinical research: Movember Foundation; Financial Interests, Institutional, Principal Investigator, Institutional support for clinical research: Pfizer; Financial Interests, Institutional, Principal Investigator, Institutional support for clinical research: Roche/Genetech; Non-Financial Interests, Institutional, Member of the Board of Directors, Director and Chair: ANZUP Cancer Trials Group; Non-Financial Interests, Institutional, Advisory Role, All honoraria and payments are made directly to ANZUP. No pass-through payment: Astellas; Non-Financial Interests, Institutional, Advisory Role, All honoraria and payments are made directly to ANZUP. No pass-through payment: AstraZeneca; Non-Financial Interests, Institutional, Advisory Role, All honoraria and payments are made directly to ANZUP. No pass-through payment: Bayer; Non-Financial Interests, Institutional, Advisory Role, All honoraria and payments are made directly to ANZUP. No pass-through payment: Bristol Myers Squibb; Non-Financial Interests, Institutional, Advisory Role, All honoraria and payments are made directly to ANZUP. No pass-through payment: Eisai; Non-Financial Interests, Institutional, Advisory Role, All honoraria and payments are made directly to ANZUP. No pass-through payment: Ipsen; Non-Financial Interests, Institutional, Advisory Role, All honoraria and payments are made directly to ANZUP. No pass-through payment: Janssen; Non-Financial Interests, Institutional, Advisory Role, All honoraria and payments are made directly to ANZUP. No pass-through payment: Merck/Pfizer; Non-Financial Interests, Institutional, Advisory Role, All honoraria and payments are made directly to ANZUP. No pass-through payment: Merck Sharpe & Dohme; Non-Financial Interests, Institutional, Advisory Role, All honoraria and payments are made directly to ANZUP. No pass-through payment: Roche. S. Williams: Financial Interests, Personal, Research Grant, Funding to perform laboratory work: Bristol Myers Squibb. R. Hicks: Financial Interests, Personal, Stocks/Shares: Telix Pharmaceuticals; Non-Financial Interests, Institutional, Advisory Role, Honorary Trustee. All honoraria is donated to the Peter MacCallum Cancer Centre: International Cancer Imaging Society; Non-Financial Interests, Institutional, Member of the Board of Directors, Honorary Director. All honoraria donated to the Peter MacCallum Cancer Centre: Neuroendocrine Cancer Foundation. M. Hofman: Financial Interests, Personal, Advisory Role: Janssen; Financial Interests, Personal, Advisory Role: Mundipharma; Financial Interests, Personal, Advisory Role: Astellas; Financial Interests, Personal, Advisory Role: Merck Sharp & Dohme; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Institutional, Sponsor/Funding, research grant: Advanced Accelerator Applications, A Novartis Company; Financial Interests, Institutional, Sponsor/Funding, research grant: Endocyte. All other authors have declared no conflicts of interest.