Comparing PSMA-617 and PSMA-I&T Radiopharmaceuticals for Prostate Cancer Therapy "Presentation" - Matthias Eiber
April 21, 2025
At the 2025 UCSF-UCLA PSMA Conference, Matthias Eiber compares PSMA-617 and PSMA-I&T radiopharmaceuticals. He notes both agents share binding motifs but differ in chelator properties and linker structures. Analyzing PSMAfore and SPLASH trials, he highlights SPLASH used approximately 40% less total activity with shorter median overall survival. Dr. Eiber presents dosimetry data indicating higher kidney doses with PSMA-I&T, and discusses emerging radio-hybrid ligands, particularly rhPSMA-10.1, which shows promising results with longer tumor retention and lower kidney doses.
Biography:
Matthias Eiber, MD, PhD, Department of Nuclear Medicine, Technical University of Munich (TUM), Munich, Germany
Biography:
Matthias Eiber, MD, PhD, Department of Nuclear Medicine, Technical University of Munich (TUM), Munich, Germany
Read the Full Video Transcript
Matthias Eiber: So I'm going to talk about PSMA-I&T versus PSMA-617. Is there a difference? And here are my conflicts of interests and especially emphasize my conflicts of interest, because Tom asked me to also talk about the RH PSMA ligands, the radio hybrid PSMA ligands. And as you see in the last line, I have a conflict of interest for them.
So let's start with PSMA-617 and PSMA-I&T, the chemistry. I think many of you know that they are used in many institutions. Development was nearly at a similar time. PSMA-617 was coming from Heidelberg. PSMA-I&T was coming from Munich. They share the same binding motifs. They are very similar. There are just a little differences. One difference is the chelator, which is a little bit differently charged for PSMA-I&T compared to 617, which makes it less lipophilic.
However, PSMA-I&T then has an larger linker, which increases lipophilicity again, so that this probably makes it up for the higher hydrophobic features regarding the chelator. So I think the question a lot of people are asking, are they equivalent? Are they different? And this is a question I try to approach from different angles during my talk, because fairly speaking, this is not very easy. There are no direct comparative clinical data. I think the closest you can get is look on PSMAfore and look on the SPLASH trials.
I don't have to explain you a lot about these talks, because Emmanuel yesterday really em explained us in length the trials, the design, the outcomes. So that was really a great talk. So the only thing I would like to cover here is trial design, very similar, or at least no substantial differences in side effects. There is only a substantial difference, and that was the dosing regime. So PSMA-4 using the usual six cycles every six weeks with 7.4 gigabecquerel activity level, compared to PSMA-I&T, eight weekly intervals with 6.8 gigabecquerels in only four cycles.
So if you add up the activity levels given, then you see in the SPLASH trial, it's approximately 40% less activity applied to the patient. If you look on median overall survival, it's in the lutetium PSMA arm for PSMAfore 12 months in 9.5 months in the PSMA, in the SPLASH trial. So there is, in fact, a difference.
What else is available in literature comparing both agents? There is one interesting matched pair comparison. This is a matched pair comparison from Germany, using data from Bonn, which have been using PSMA-617, and data from Würzburg, which have been using PSMA-I&T. And their matched pair analysis looked on 110 patients, 55 in each group. They looked on different features of the treatments. And as you can see in the red, the circled number of treatments per patient, cumulative activity, relatively similar, activity per cycle more or less the same, 6 gigabecquerel median dose. Side effect profile, relatively similar.
And also, if you look to the heart outcome parameter overall survival, you have a fairly similar outcome in overall survival of 12 months for I&T, 13 months of 617. And if you look on the Kaplan-Meier curves, you see the curves are more or less running in parallel. I also want to look on these agents from an dosimetry point of view. In the lower part of the slide, you see a table derived from the E and M, S and M procedure, EANM guideline. And in the upper part of the slide, you see a data from prospective trials and composing dosimetry for both agents. And you see a substantial difference with around 0.4 gray per gigabecquerel with lutetium PSMA-617 and 0.7 gray per gigabecquerel with I&T.
So this data, plus retrospective analysis, it looks like there is a higher dose to the kidney for I&T versus 617, which then was also one of the reasons why in PSMAfore or PSMA in SPLASH, lower activity level in total could be applied to the patient compared to PSMAfore. Is there also a role for improved PSMA ligands? And we will hear about this later in the session from different speakers. As I said, Tom asked me to talk about the radio hybrid PSMA ligands developed in Munich.
These are ligands, truly theranostic ligands, which you can label with F-18 using a silicone fluoride acceptor, as well as labeling with radio metals, for example, lutetium or actinium for a PSMA-RLT. I guess in the US, you know that one example of this class of agents, rhPSMA-7.3, has been approved as diagnostic PET agent named POSLUMA, and there are ongoing investigations of therapeutic ligands. They have been selected by the group around Professor Vester for balanced, rapid clearance and high tumor accumulation.
And the agents which are now under therapeutic development rhPSMA-10.1. What you could see here is first preclinical data, where in a mouse model, the performance of the different agents 617, I&T, and 10.1 have been compared. There are no big differences. There is a trend towards a little bit of a higher efficacy in 10.1 compared to the other agents. There are some early, very preliminary clinical data coming out from the Augsburg group around Constantin Lapa, and he is using 10.1 given these characteristics to rescue patients after failure of lutetium PSMA-I&T treatment.
And very recently this year, a case series of 10 patients have been published, and 10 patients who failed I&T who then underwent rhPSMA-10.1 treatment. 50% of the patients showed further PSA response and also 30% some imaging response. So there is some initial data of an higher efficacy of this agent. There is also here-- and I owe these slides to colleagues from Blue Earth therapeutics who are conducting a phase I, slash II clinical trials, phase I for safety and dosimetry.
And what they found in the phase I part is a very long, effective half life in tumors longer using 10.1, compared to 617, and also the absorbed dose in the kidney is significantly lower with 0.27 gray per gigabecquerel. And this is one of the reasons what I have outlined yesterday, that they are looking into this with changed or adapted protocols for treatment with higher and higher activity dose levels, and higher frequency in the phase II part of the trial. I also would shortly like to make a comment on the renal absorbed dose, whether it really matters. And I think it matters.
I know that this is a controversial topic in for 617. There are not many reports for renal toxicity. However, we are using lutetium PSMA-I&T in Munich since a lot of years. We are seeing increasingly number of patients, especially those with higher number of cycles 10 and more, with significant kidney toxicity. We have a few patients with complete kidney failure who are in the need of getting dialysis. And usually, the time to drop of the EGFR after treatment initiation is not before 12 to 20 months. So this is definitely something, which we should look into.
There are some indications that with the higher dose in I&T versus 617, this is more likely to be seen in this agent. And I want to conclude my personal view. And as I said, there are not many scientific data out. But this is what I read into this data so far, is both of 617 and I&T are very similar. There is a hint towards higher kidney dose in I&T. I think what we learned from PSMA-4 versus SPLASH, that activity level and probably also timing matters. And the second generation's PSMA ligands with the hope for further improvement of therapeutic efficacy. And I think we will more hear about this topic in Martin Pomper's talk just in a few minutes. Thanks a lot.
Matthias Eiber: So I'm going to talk about PSMA-I&T versus PSMA-617. Is there a difference? And here are my conflicts of interests and especially emphasize my conflicts of interest, because Tom asked me to also talk about the RH PSMA ligands, the radio hybrid PSMA ligands. And as you see in the last line, I have a conflict of interest for them.
So let's start with PSMA-617 and PSMA-I&T, the chemistry. I think many of you know that they are used in many institutions. Development was nearly at a similar time. PSMA-617 was coming from Heidelberg. PSMA-I&T was coming from Munich. They share the same binding motifs. They are very similar. There are just a little differences. One difference is the chelator, which is a little bit differently charged for PSMA-I&T compared to 617, which makes it less lipophilic.
However, PSMA-I&T then has an larger linker, which increases lipophilicity again, so that this probably makes it up for the higher hydrophobic features regarding the chelator. So I think the question a lot of people are asking, are they equivalent? Are they different? And this is a question I try to approach from different angles during my talk, because fairly speaking, this is not very easy. There are no direct comparative clinical data. I think the closest you can get is look on PSMAfore and look on the SPLASH trials.
I don't have to explain you a lot about these talks, because Emmanuel yesterday really em explained us in length the trials, the design, the outcomes. So that was really a great talk. So the only thing I would like to cover here is trial design, very similar, or at least no substantial differences in side effects. There is only a substantial difference, and that was the dosing regime. So PSMA-4 using the usual six cycles every six weeks with 7.4 gigabecquerel activity level, compared to PSMA-I&T, eight weekly intervals with 6.8 gigabecquerels in only four cycles.
So if you add up the activity levels given, then you see in the SPLASH trial, it's approximately 40% less activity applied to the patient. If you look on median overall survival, it's in the lutetium PSMA arm for PSMAfore 12 months in 9.5 months in the PSMA, in the SPLASH trial. So there is, in fact, a difference.
What else is available in literature comparing both agents? There is one interesting matched pair comparison. This is a matched pair comparison from Germany, using data from Bonn, which have been using PSMA-617, and data from Würzburg, which have been using PSMA-I&T. And their matched pair analysis looked on 110 patients, 55 in each group. They looked on different features of the treatments. And as you can see in the red, the circled number of treatments per patient, cumulative activity, relatively similar, activity per cycle more or less the same, 6 gigabecquerel median dose. Side effect profile, relatively similar.
And also, if you look to the heart outcome parameter overall survival, you have a fairly similar outcome in overall survival of 12 months for I&T, 13 months of 617. And if you look on the Kaplan-Meier curves, you see the curves are more or less running in parallel. I also want to look on these agents from an dosimetry point of view. In the lower part of the slide, you see a table derived from the E and M, S and M procedure, EANM guideline. And in the upper part of the slide, you see a data from prospective trials and composing dosimetry for both agents. And you see a substantial difference with around 0.4 gray per gigabecquerel with lutetium PSMA-617 and 0.7 gray per gigabecquerel with I&T.
So this data, plus retrospective analysis, it looks like there is a higher dose to the kidney for I&T versus 617, which then was also one of the reasons why in PSMAfore or PSMA in SPLASH, lower activity level in total could be applied to the patient compared to PSMAfore. Is there also a role for improved PSMA ligands? And we will hear about this later in the session from different speakers. As I said, Tom asked me to talk about the radio hybrid PSMA ligands developed in Munich.
These are ligands, truly theranostic ligands, which you can label with F-18 using a silicone fluoride acceptor, as well as labeling with radio metals, for example, lutetium or actinium for a PSMA-RLT. I guess in the US, you know that one example of this class of agents, rhPSMA-7.3, has been approved as diagnostic PET agent named POSLUMA, and there are ongoing investigations of therapeutic ligands. They have been selected by the group around Professor Vester for balanced, rapid clearance and high tumor accumulation.
And the agents which are now under therapeutic development rhPSMA-10.1. What you could see here is first preclinical data, where in a mouse model, the performance of the different agents 617, I&T, and 10.1 have been compared. There are no big differences. There is a trend towards a little bit of a higher efficacy in 10.1 compared to the other agents. There are some early, very preliminary clinical data coming out from the Augsburg group around Constantin Lapa, and he is using 10.1 given these characteristics to rescue patients after failure of lutetium PSMA-I&T treatment.
And very recently this year, a case series of 10 patients have been published, and 10 patients who failed I&T who then underwent rhPSMA-10.1 treatment. 50% of the patients showed further PSA response and also 30% some imaging response. So there is some initial data of an higher efficacy of this agent. There is also here-- and I owe these slides to colleagues from Blue Earth therapeutics who are conducting a phase I, slash II clinical trials, phase I for safety and dosimetry.
And what they found in the phase I part is a very long, effective half life in tumors longer using 10.1, compared to 617, and also the absorbed dose in the kidney is significantly lower with 0.27 gray per gigabecquerel. And this is one of the reasons what I have outlined yesterday, that they are looking into this with changed or adapted protocols for treatment with higher and higher activity dose levels, and higher frequency in the phase II part of the trial. I also would shortly like to make a comment on the renal absorbed dose, whether it really matters. And I think it matters.
I know that this is a controversial topic in for 617. There are not many reports for renal toxicity. However, we are using lutetium PSMA-I&T in Munich since a lot of years. We are seeing increasingly number of patients, especially those with higher number of cycles 10 and more, with significant kidney toxicity. We have a few patients with complete kidney failure who are in the need of getting dialysis. And usually, the time to drop of the EGFR after treatment initiation is not before 12 to 20 months. So this is definitely something, which we should look into.
There are some indications that with the higher dose in I&T versus 617, this is more likely to be seen in this agent. And I want to conclude my personal view. And as I said, there are not many scientific data out. But this is what I read into this data so far, is both of 617 and I&T are very similar. There is a hint towards higher kidney dose in I&T. I think what we learned from PSMA-4 versus SPLASH, that activity level and probably also timing matters. And the second generation's PSMA ligands with the hope for further improvement of therapeutic efficacy. And I think we will more hear about this topic in Martin Pomper's talk just in a few minutes. Thanks a lot.