ESMO 2019: Preliminary Results of a Phase I/II Dose-escalation Study of Fractionated Dose 177Lu-PSMA-617 for Progressive mCRPC

Barcelona, Spain ( PSMA is overexpressed in prostate cancer with limited expression in other organs. Furthermore, prostate cancer is radiosensitive with dose-response (PSA declines and OS); dose-fractionation allows delivery of higher total dose per cycle, which may result in less radio-resistance due to repopulation compared with doses 6-12 weeks apart. The initial phase I safety results of the dose-escalation portion of this study treating mCRPC with fractionated dose 177Lu-PSMA-617 were presented at ESMO 2018 and were without dose limiting toxicity at all dose levels. At the ESMO 2019 prostate cancer session Dr. Scott Tagawa and colleagues presented preliminary results of the phase I/II dose escalation study.

For this study, the entry criteria were progressive mCRPC following at least one potent AR-targeted agent (ie. abiraterone or enzalutamide) and taxane chemotherapy (or unfit/refused chemotherapy) without limiting the number of prior therapies, adequate organ function, and ECOG performance status 0-2. Treatment was a single cycle of fractionated dose 177Lu-PSMA-617 on day 1 and day 15. In the phase I dose-escalation cohort, men received 7.4 to 22 GBq. In phase II, a Simon 2 stage design enrolled patients 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. CTC counts were obtained at baseline and at 12 weeks.

There were 44 men (29 in phase I, 15 in phase II; a total of 21 patients at 22.2 GBq) enrolled with a median age of 69 (range 55-91) years, and median PSA of 183.0 ng/mL (range 0.89-5541). The metastatic burden was as follows: 93% to the bone, 45% to the lymph nodes, 18% to the lung, 9% to the liver, and 9% to other visceral organs. There 55% of patients with at least one prior chemotherapy regimen, 52% with more than one prior androgen receptor therapy, 27% who received prior Radium-223, 30% prior sipuleucel-T, and 5% prior 177Lu-J591. Among the enrolled, 66% were Halabi poor risk and 30% were intermediate risk. With follow up ongoing, 59.1% have had a >50% PSA decline (66.7% at 22.2 GBq), and 81.8% have experienced any PSA decline.

The median overall survival was 16.7 months (95% CI 11.2-NR). To date, there are 30 patients with paired CTC counts, 60.0% decreased, 10.0% stable, and 26.7% increased. Regarding adverse events, 61.4% with all grade xerostomia, 29.5% fatigue, 25% thrombocytopenia, 25% anemia, 25% pain, 15.5% nausea. While not required for eligibility, all patients had some PSMA uptake in at least one 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.

The authors concluded this presentation with the following concluding statements:

  • Dose escalation of 177Lu-PSMA-617 is safe to 22.2 GBq in a single cycle with fractionated dosing
  • In a population unselected for PSMA expression, there are promising early efficacy signals
  • Higher dose and higher baseline PSMA PET uptake associated with response and survival
  • While most have mild toxicity (especially pain flare and low-grade xerostomia), severe toxicity is rare
Clinical trial identification


Presented by: Scott T. Tagawa, MD, MS, Medical Oncology, NewYork-Presbyterian Hospital/ Weill Cornell Medical Center, New York, New York, USA

Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter: @zklaassen_md at the 2019 European Society for Medical Oncology annual meeting, ESMO 2019 #ESMO19, 27 Sept - 1 Oct 2019 in Barcelona, Spain