Lutetium PSMA Beyond Six Cycles Extended Treatment and Re-Challenge Approaches "Presentation" - Matthias Eiber
April 15, 2025
At the 2025 UCSF-UCLA PSMA Conference, Matthias Eiber discusses lutetium PSMA therapy beyond six standard cycles. He distinguishes between extended treatment (continuous administration) and re-challenge treatment (restarting after progression), citing German data showing re-challenge produced better PSA responses and survival. Dr. Eiber presents alternative regimens including shortened intervals and higher treatment activities, highlighting ongoing prospective trials like RADIODOSE and Re-LuPSMA that show preserved efficacy with low toxicity.
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: Thanks, Tom, for the kind introduction. And chairman, Tom, thanks for the invitation to be here again at this amazing meeting. I would like to talk about lutetium PSMA beyond six cycles. Here are my conflicts of interest, and I would like to start what seems to be possible.
So in the literature, the case reports move up to 20 cycles. And I would like to show you two. There is just very recently one case report published by Hofman's group in Australia of a patient who received lutetium PSMA over more than four years, with a total of 20 cycles, 129 gigabecquerels of lutetium PSMA 617.
And this patient had no relevant side effects during the treatment. And it was still possible to expose this patient to cabazitaxel after lutetium PSMA was a failure. There is also another case report published by my colleague Andrew Gafita a few years ago. At that time, the patient has undergone 16 cycles of lutetium PSMA.
By the way, this is the only patient I have seen who had a complete remission, which you can see after the first four cycles he received. He received then additional courses of each four cycles-- and in the end also four additional cycles after the case has been published-- so it's, again, also 20 cycles in this patient.
He responded very well until the end, but then, he developed pleural lesions and refused any further treatment. So after more than five years-- after initiation of lutetium PSMA-- he died. In this patient, compared to a Michael's patient, we have seen a significant increase in creatinine level from 0.6 to 1.8 at the last cycle.
So as a short introduction, what means beyond 6x6. So there are two ways how to look on it. The one way is extended treatment-- treatment beyond six cycles. And this is what Wolfgang Fendler was already indicating.
There is the concept of continuous treatment, which means, you just continue the treatment after the six cycles, in comparison to re-challenge treatment-- which means, you finalized your six cycles. The patient responded well. Then, you do a therapy break. All of these patients, they progress during therapy break. And then, you start the treatment again.
But there is also the concept of alternative treatment regimes. So this is iteration to approve dosing and treatment regimes-- for example, higher treatment activities. The concept here is hit hard first or shorter treatment intervals. So this is the summary of literature regarding a treatment extension.
I would like to put emphasis on the largest evidence in literature. This is the German multicenter analysis, led by Wolfgang, who looked on 111 patients. Most of them were re-challenge treatments-- 68 compared to 43 patients.
Continuous treatment-- and you see in this retrospective analysis-- continuous treatment was done up to 10 cycles, whereas re-challenge treatment was even more than 13 cycles. And the patient, I've shown you from Munich-- the one with 20 cycles-- was also included.
What you can also see in this paper, the median time between stop after the first six cycles and the reinitiation was around seven months. And this is usually the time interval we see before patients are progressing during the therapy break.
If you look on side effects, there have been a rate of high-grade side effects, comparable to the initial treatment. If you look on anti-tumor response, there is a higher PSA decline in the re-challenge group, compared to continuous group-- because apparently, the patient with continuous treatment, they have been treated beyond the six cycles because they had no superb response in PSA and imaging.
However, both groups-- or the groups of continuous treatment and re-challenge treatment-- are in favor of the treatment group, with a median overall survival of 31.3 months. And apparently, the patient with re-challenge treatment lived longer than those with continuous treatment.
There have been also investigations on shorter treatment intervals. This is one body of evidence we generated in Munich, where we looked on patients treated in four weeks instead of six-weeks interval. We matched patients based on different criteria, not a very large retrospective analysis of 23 patients for each group.
We had slightly higher rates of adverse events in the four-week group-- also a tendency to better PSA response and longer PSA progression-free survival-- but similar overall survival in the group of four versus six weeks.
I guess many of you know this data for higher treatment activities, and this is the phase I dose escalation study done by Scott a few years ago-- and up to 22 gigabecquerels have been applied in two fractionated doses. And there were no dose-limiting toxicities. And also, in this cohort piece, PET was not used for treatment selection.
So there are novel approaches to be considered beyond applying six cycles in six-weeks interval. And what I summarize here is the dose scheming procedure from Blue Earth, phase I phase II clinical trial using a Munich compound-- the rhPSMA 10.1.
And in addition to the normal dosing regime, they have also implemented new dosing regimes-- one with a higher front-loading activity, where you apply a higher activity level before you go down to a usual activity level for maintenance-- and also a second arm where they look on higher frequency of treatments in three-week intervals before they, again, then go into a maintenance phase of the usual dosing regime, which we all know.
There are also prospective trials. And I think, Jeremie has already outlined them in his talk. There's the RADIODOSE trial, which is basically a trial which follows the continuous treatment principle. This is a trial with up to 12 cycles of lutetium and PSMA in patients who have to be stable, or declining PSA, or persistent PSA expression after cycle number six.
And there is also in UCLA a challenge study, the Re-LuPSMA study, which comprises patients after six cycles of lutetium PSMA, who progress in a therapy break and then can receive up to an additional six cycles.
So I want to conclude. I think lutetium PSMA shows preserved efficacy at continuous treatment and also at re-challenge at low toxicity. There are currently developments towards treatment extension. I think, it's usual that in a therapy break, you see progression within three to six months. There are prospective trials ongoing on this field.
In addition to that, novel dosing regimes-- for example, higher-activity levels or frequency-- might potentially enhance treatment response. We will see that, and we will also see some principle on this in tomorrow's dosimetry session. I think-- and this has been outlined also in a prior talk-- that here, especially in the investigation of side effects, it's very important-- what is my personal approach at in Munich for extended treatment?
Re-challenge is something we are increasingly doing, also using Pluvicto in the re-challenge setting. Continuous treatment now, as Pluvicto is approved, is getting much more difficult. So in the old days, we had the possibility to just continue-- which we now cannot do that way. But maybe, RADIODOSE and other studies might pave the way for this again in the future. Thank you very much for your attention.
Matthias Eiber: Thanks, Tom, for the kind introduction. And chairman, Tom, thanks for the invitation to be here again at this amazing meeting. I would like to talk about lutetium PSMA beyond six cycles. Here are my conflicts of interest, and I would like to start what seems to be possible.
So in the literature, the case reports move up to 20 cycles. And I would like to show you two. There is just very recently one case report published by Hofman's group in Australia of a patient who received lutetium PSMA over more than four years, with a total of 20 cycles, 129 gigabecquerels of lutetium PSMA 617.
And this patient had no relevant side effects during the treatment. And it was still possible to expose this patient to cabazitaxel after lutetium PSMA was a failure. There is also another case report published by my colleague Andrew Gafita a few years ago. At that time, the patient has undergone 16 cycles of lutetium PSMA.
By the way, this is the only patient I have seen who had a complete remission, which you can see after the first four cycles he received. He received then additional courses of each four cycles-- and in the end also four additional cycles after the case has been published-- so it's, again, also 20 cycles in this patient.
He responded very well until the end, but then, he developed pleural lesions and refused any further treatment. So after more than five years-- after initiation of lutetium PSMA-- he died. In this patient, compared to a Michael's patient, we have seen a significant increase in creatinine level from 0.6 to 1.8 at the last cycle.
So as a short introduction, what means beyond 6x6. So there are two ways how to look on it. The one way is extended treatment-- treatment beyond six cycles. And this is what Wolfgang Fendler was already indicating.
There is the concept of continuous treatment, which means, you just continue the treatment after the six cycles, in comparison to re-challenge treatment-- which means, you finalized your six cycles. The patient responded well. Then, you do a therapy break. All of these patients, they progress during therapy break. And then, you start the treatment again.
But there is also the concept of alternative treatment regimes. So this is iteration to approve dosing and treatment regimes-- for example, higher treatment activities. The concept here is hit hard first or shorter treatment intervals. So this is the summary of literature regarding a treatment extension.
I would like to put emphasis on the largest evidence in literature. This is the German multicenter analysis, led by Wolfgang, who looked on 111 patients. Most of them were re-challenge treatments-- 68 compared to 43 patients.
Continuous treatment-- and you see in this retrospective analysis-- continuous treatment was done up to 10 cycles, whereas re-challenge treatment was even more than 13 cycles. And the patient, I've shown you from Munich-- the one with 20 cycles-- was also included.
What you can also see in this paper, the median time between stop after the first six cycles and the reinitiation was around seven months. And this is usually the time interval we see before patients are progressing during the therapy break.
If you look on side effects, there have been a rate of high-grade side effects, comparable to the initial treatment. If you look on anti-tumor response, there is a higher PSA decline in the re-challenge group, compared to continuous group-- because apparently, the patient with continuous treatment, they have been treated beyond the six cycles because they had no superb response in PSA and imaging.
However, both groups-- or the groups of continuous treatment and re-challenge treatment-- are in favor of the treatment group, with a median overall survival of 31.3 months. And apparently, the patient with re-challenge treatment lived longer than those with continuous treatment.
There have been also investigations on shorter treatment intervals. This is one body of evidence we generated in Munich, where we looked on patients treated in four weeks instead of six-weeks interval. We matched patients based on different criteria, not a very large retrospective analysis of 23 patients for each group.
We had slightly higher rates of adverse events in the four-week group-- also a tendency to better PSA response and longer PSA progression-free survival-- but similar overall survival in the group of four versus six weeks.
I guess many of you know this data for higher treatment activities, and this is the phase I dose escalation study done by Scott a few years ago-- and up to 22 gigabecquerels have been applied in two fractionated doses. And there were no dose-limiting toxicities. And also, in this cohort piece, PET was not used for treatment selection.
So there are novel approaches to be considered beyond applying six cycles in six-weeks interval. And what I summarize here is the dose scheming procedure from Blue Earth, phase I phase II clinical trial using a Munich compound-- the rhPSMA 10.1.
And in addition to the normal dosing regime, they have also implemented new dosing regimes-- one with a higher front-loading activity, where you apply a higher activity level before you go down to a usual activity level for maintenance-- and also a second arm where they look on higher frequency of treatments in three-week intervals before they, again, then go into a maintenance phase of the usual dosing regime, which we all know.
There are also prospective trials. And I think, Jeremie has already outlined them in his talk. There's the RADIODOSE trial, which is basically a trial which follows the continuous treatment principle. This is a trial with up to 12 cycles of lutetium and PSMA in patients who have to be stable, or declining PSA, or persistent PSA expression after cycle number six.
And there is also in UCLA a challenge study, the Re-LuPSMA study, which comprises patients after six cycles of lutetium PSMA, who progress in a therapy break and then can receive up to an additional six cycles.
So I want to conclude. I think lutetium PSMA shows preserved efficacy at continuous treatment and also at re-challenge at low toxicity. There are currently developments towards treatment extension. I think, it's usual that in a therapy break, you see progression within three to six months. There are prospective trials ongoing on this field.
In addition to that, novel dosing regimes-- for example, higher-activity levels or frequency-- might potentially enhance treatment response. We will see that, and we will also see some principle on this in tomorrow's dosimetry session. I think-- and this has been outlined also in a prior talk-- that here, especially in the investigation of side effects, it's very important-- what is my personal approach at in Munich for extended treatment?
Re-challenge is something we are increasingly doing, also using Pluvicto in the re-challenge setting. Continuous treatment now, as Pluvicto is approved, is getting much more difficult. So in the old days, we had the possibility to just continue-- which we now cannot do that way. But maybe, RADIODOSE and other studies might pave the way for this again in the future. Thank you very much for your attention.