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Amir Iravani: And today, so the question that put for me is "Are we underdosing?" So this is my disclosure. And this is an outline of my talk. What is dose? How do we know we are not dosing properly the patient? Evidence of dose-response relationship? And how we can optimize the dosing?

So let's have a common understanding of what we mean by the dose and not raising our physicist eyebrows by talking about the dose. So in radiopharmaceutical therapy, when we talk about the dose, we're talking about the administered activity. So that's what we can manage, and that's what we can control by giving the administration activity.

And then, we'll have the drug which goes to the sites. It has a pharmacokinetics. And we have-- with the imaging, we are able to measure the activity over time, and then drive the radiation absorbed dose to the tumor and also all normal organs. So that's a different concept.

And then, it's completely different to the radiotherapy when the dose is prescribed, conformally, to a particular tumor. And also, we have to include also what we dose is-- we're talking about the dose scheme and treatment schedule. So the number of treatments and the interval between the treatments are also important factors in the patient response to treatment.

So I rephrase the question "Are we underdosing?" I don't know. But the question I would ask is "Are we optimally dosing the patients?" So the current status is we're giving a fixed administer activity at a fixed number of treatments at the fixed intervals of six weeks. And we're basically at the mercy of the tumor. And we're hoping for the best.

But our concept is basically ignoring a wide variability that we see in the volumes. For instance, the patient on the left side has got only one side of the disease. There's one rib lesion with a low volume of the disease. As we go, on the right side, we see a patient with a 3.3 liters of the disease. And we're still giving the same dose to each patient regardless of what volume of the disease they have, and also what level of expression, and how density of the tumor. Target expression is across the tumors.

We see a patient with a relatively moderate uptake or low uptake, similar to liver, to a patient with homogeneous to very high uptake. And are we not concerned that we may reach a point that we may not be saturating the tumor? And are the mass peptide of our is actually enough to treat all the lesions?

And also our treatments are not tailored to the disease biology. This actually case really struck me. This seems to be a patient we were predicted to have a good response to treatment. We see-- with the first cycle of treatment at three weeks, the PSA dropped. By six weeks, it came back. And again, we gave the treatment, PSA dropped, and again, came back a little bit. We gave it here, and at this point, when then we see the resistance is developed.

And is it because of we not optimize the dosing early on, and we basically increase the resistance to the disease? And we see it got worse and worse. And then, we had to give up, at some point, as the patient clinically progressed. So really, for this case, we didn't really-- our treatment didn't match with the rate that the tumor was repopulating.

So how do we know that the dosing is not optimal? So this is from Doctor Cohen from VISION Investigator. We see-- I mean, the benefit of the patient from Lutetium-PSMA is not even across the patient.

So when we look at the biomarkers, for instance, whole body tumor volume or body tumor SUV mean, we see there is a group of patients who actually benefit much than the other groups, which is only 25% of the patients in the highest quartile. Which actually that group brings the Kaplan-Meier curve for the entire group. So we see that six months of overall survival in this group, but only very modest improvement in the other groups, which is 75% of the patients, only two to three months.

And we know that the pretreatment PSMA PET correlates and with the post-treatment SPECT dosimetry. And when we look at the lesion-based analysis, for instance on the right side, this is a dosimetry study from Peter Mac phase II trial led by late Doctor Violet. We see there is a trend for the highest lesions and they have a better chance of PSA response. But there is a lot of overlap as well.

When we go to the whole body tumor volume and whole body dosimetry, we see a better trend, but is still there is a lot of overlap between responders and non-responders. And Doctor Hofman, multiple times, kind of implied here that we may be OK-- or to predict which patients may not respond like that-- what dose level there is actually the treatment might be futile.

But above that, we're not really good to predict the responders. So dose-response relationship-- there is a dose-response relationship. But at the moment, with the current dose scheme, it's far from perfect.

And studies have also shown that the early cycles of treatments are important. So it's not that every cycle has the same weight. The earlier cycles are more important as we see the drop in the dosimetry in the lesions as we go. But this is most relevant in the patients who actually respond, which is kind of intuitive. But the question is how we can early on make more patients to have a deeper response earlier during the course.

And for instance, we see these are the four different groups of patients. But if we can bring the patient from the bottom three to top one to have a deeper response earlier, that's an opportunity to basically have a response.

And this is, I think, one of the very interesting studies, which is done by Doctor Tagawa and from Weill Cornell. And they, basically-- one of the few only studies that they did, basically, increase the administrative activity in a short space and in the short intervals at dose-dense approach, but from 100 milligrams at day 1 and day 15 to 300. And even at the 300 by 2 weeks interval, they did not see a dose-limiting toxicities.

And interestingly, even in the patient who are unselected based on the PSMA PET, there is a high PSA response in this group, and very encouraging PFS, and overall survival, only with two doses, and similar to the VISION group, and very limited, and very acceptable toxicities we see here with the anemia and the rate of 12% which is similar to the VISION group.

So the question is, how are we going to leverage this information to basically optimize our treatment and also leveraging the biology? And this where it came from-- from UK, Doctor De Bono.

And it is a preclinical study, basically, showing that the ionizing radiation is in fact upregulates PSMA expression in a dose-dependent fashion. In a three cell lines, we see when they irradiated with the different dose schemes of 3 grays to 12 grays, they actually with the Western blots and the densitometric analysis, we see increased PSMA expression, which lasts three days or even longer.

So the question if dose-intense treatments, in fact, we could improve the outcome of the patient. So this is the subject of the study that we are now open and UCLA, UCSF is going to be joining here. So we basically select the patients based on their biomarkers of the PSMA expression. And we try to improve the outcome of the patient who have lower PSMA expression by dose enhancing the treatment early on. And so to see whether we could improve their outcome.

So in conclusion, the current concept of fixed treatment schedule, basically, ignores the wide variability we see in the volume, we see in the target expression and tumor biology. And although there seems to be a dose-response relationship, it's far from perfect. A lot to be understood in that space. And there is an opportunity, at the moment, I think, to improve the outcome by early intensification and using adaptive strategies to improve the outcome.

Thank you very much.