849PD - Preliminary results of a phase I/II dose-escalation study of fractionated dose 177Lu-PSMA-617 for progressive metastatic castration resistant prostate cancer (mCRPC)

Abstract

BackgroundPSMA is overexpressed in PC with limited expression in other organs. PC is radiosensitive with dose-response. Dose-fractionation allows delivery of higher total dose per cycle, may result in less radioresistance due to repopulation compared with doses 6-12 wks apart. Initial Ph I safety results of the dose-escalation portion of this study [ESMO 2018] were without DLT at all dose levels. MethodsEntry criteria: progressive mCRPC following at least 1 potent AR-targeted agent (e.g. abi/enza) and taxane (or unfit/refuse chemo) without limit of # prior therapies, adequate organ function, ECOG performance status 0-2. No preselection for PSMA expression. Treatment was a single cycle of fractionated dose 177Lu-PSMA-617 on D1 and D15. In the Ph I dose-escalation cohort, men received 7.4 to 22 GBq. In Ph II, a Simon 2 stage design enrolled pts at the 22.2 GBq dose level. Pre- and post-treatment 68Ga-PSMA11 PET/CT and post-treatment 177Lu-PSMA-617 imaging was performed in addition to standard serial CT and bone scans. Cellsearch CTC count at baseline and 12 wks. Results44 men (29 in Ph I, 15 in Ph II; total 21 at 22.2 GBq) with median age 69 (range 55-91), median PSA 182.97 (range 0.89-5541) were treated. 93% with bone, 45% nodal, 18% lung, 9% liver, 9% other visceral metastases. 55% with at least 1 prior chemo regimen, 52% >1 prior potent AR therapy, 27% with Ra223, 30% sip-T, 5% 177Lu-J591; 66% Halabi poor risk, 30% intermed risk. With follow up ongoing, 61% with >50% PSA decline (71.4% at 22.2 GBq), median overall survival 16 months (95% CI 11-NR). Of 26 with paired CTC counts, 57.7% decreased, 7.7% stable, 34.6% increased; 34.6% converted from detectable to undetectable at 12 weeks). 61.4% with all grade xerostomia, 29.5% fatigue, 25% thrombocytopenia, 25% anemia, 25% pain, 15.5% nausea. While not required for eligibility, all pts had some PSMA uptake in at least 1 site on PSMA PET, with 2.2% highest lesion SUV < liver SUV, 4.5% 1-2.5x, 13.6% 2.5-5x, and 79.5% highest lesion SUV > 5x liver. ConclusionsA single fractionated cycle of up to 22.2 GBq of 177Lu-PSMA-617 is safe, with encouraging early efficacy signals, even without selection for PSMA expression by imaging. A trend for dose-response was observed. Clinical trial identificationNCT03042468. Legal entity responsible for the studyWell Cornell Medicine. FundingWeill Cornell Medicine, Prostate Cancer Foundation, US Department of Defense, US National Institutes of Health, Endocyte. DisclosureS.T. Tagawa: Advisory / Consultancy, Research grant / Funding (institution): Endocyte. H. Beltran: Advisory / Consultancy: Endocyte. S. Vallabhajosula: Research grant / Funding (institution): Endocyte; Full / Part-time employment: NCM USA. O. Sartor: Research grant / Funding (institution): Endocyte. All other authors have declared no conflicts of interest.