Lutetium-177 PSMA scanning for prostate cancer

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Published: 7 Oct 2019
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Dr Scott Tagawa - Weill Cornell Medicine, New York City, USA

Dr Scott Tagawa speaks to ecancer at ESMO 2019 in Barcelona about a phase I/II dose-escalation study of fractionated
dose Lutetium177-PSMA-617 for progressive metastatic castration resistant prostate cancer.

Initially he explains the premise behind using Lut-177 for PSMA, a good target for imaging in the tumour.

Dr Tagawa outlined the escalation given in this study, and the positive responses from the patient cohort. He then briefly touches upon the toxicities, which were manageable.

In prostate cancer PSMA is a cell surface antigen that’s present in the vast majority of tumours to some degree, so about 90% of tumours will have some element of PSMA on their cell surface. It may not be 100% of the cells within the tumour but typically when we do a PSMA scan most of the tumours will be visible. So we know it’s a target for imaging, we also know that prostate cancer is radiosensitive. So an area of cell surface targets, getting radionuclides to that area, lutetium-177 is an approved agent against somatostatin. A number of us have been looking at this in prostate cancer. We’ve been looking at lutetium in prostate cancer for a decade and a half but now with the advent of small molecules we’re able to do that with less myelosuppression.

That being said, there are very few prospective clinical trials and no-one, prior to this study, had ever done a dose escalation study. So we performed a phase I/II dose escalation study with an expansion phase II. Last year at ESMO 2018 we presented the dose escalation results where we essentially kept going up and up as high we had planned to 22.2GBq in a single cycle. We happened to fractionate the dose, give half and the other half on day 15 of cycle 1, as we had done that before with our monoclonal antibody J591. Essentially we did not see dose limiting toxicity in that phase I. We decided to stop escalation, that is, depending on the dose and schedule, that’s more or less the equivalent of three to four cycles of how it may be given in Australia or Germany.

What we’re presenting this year is a combined analysis of that cohort, which has longer follow-up, plus the phase II cohort which was additional patients at that 22.2GBq dose. So we’re presenting an analysis of 44 patients across different doses. Unlike many of the other targeted radionuclide therapy trials we were open in terms of enrolment so we did not require a scan to show positivity because in our minds that biomarker has never been proven to be predictive. So this is 44 patients that had scans at the beginning but we did not use that for actual criteria. Despite not knowing exactly what their PSMA expression prior to treatment is, the vast majority responded. So, approximately 82% across the different dose levels had a PSA decline; a little more than half had a significant PSA decline of at least 50%. If we look at what we consider the right dose, this 22.2GBq dose, it was 67%, about two-thirds, that had at least a 50% PSA decline. That was also associated with a circulating tumour cell control, so about 60% had a decline in circulating tumour cell count from baseline to twelve weeks with a respectable progression free and overall survival for a heavily pre-treated patient population.

Luckily, that was not at the cost of high grade toxicity. The majority of patients did have some treatment emergent adverse events, the most common was actually a pain flare. Around 80% had a pain flare, their baseline pain went up by self-reports over the first one or two weeks and then that tended to get better. And xerostomia, dry mouth, we know is an on-target off-tumour toxicity that’s potential because of PSMA expression in the salivary glands. Like the prospective Australian study we did see that in the majority; like most other reports it was mostly grade 1, temporarily happened within one or two weeks of the treatment and then tended to get better with time and usually resolved to baseline within a month or so.

So that looks quite promising and, in anticipation of this particular drug getting approved in the next year or two, we continue to work with dosing schedule. So we’ll hopefully have an optimised treatment when that drug is approved.