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Hello and welcome to Noon Conference,

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You can also sign up for a free trial of our premium membership to get access to

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hundreds of case-based micro-learning courses across all key radiology

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subspecialties. Today we are honored to welcome Dr.

0:40

Steven Roe for a lecture entitled Current Radiopharmaceutical Theranostic

0:45

Applications in Nuclear Medicine. Dr.

0:47

Roe completed his medical degree and a PhD in chemistry at the University of

0:52

Michigan before undertaking residency training in diagnostic radiology and

0:57

nuclear medicine at Johns Hopkins. Hopkins.

0:59

He spent seven years on the faculty at Johns Hopkins before recently moving to

1:03

the University of North Carolina,

1:05

where he continues his research in molecular imaging of GU oncology.

1:10

At the end of the lecture, please join Dr.

1:12

Roe in a live q and a session where he will address questions you may have on

1:15

today's topic.

1:16

Please remember to use the q and a feature to submit your questions so we can

1:20

get to as many as we can before our time is up. With that,

1:24

we are ready to begin today's lecture. Dr. Roe, please take it from here.

1:28

Alright. Thank you so much. It's, uh,

1:30

really a pleasure to to be joining you today. I am down here in, uh,

1:33

in beautiful North Carolina, and, uh, it's, uh, uh,

1:37

just a great day to talk about, uh, radiopharmaceuticals and, and theranostics.

1:41

The, the last time I was here a couple of months ago, which, uh,

1:44

some of you may have also been at, we, we were focused on,

1:47

on prostate specific membrane, antigen and its use in prostate cancer, uh,

1:51

mostly on the diagnostic side, although we talked a little bit about the, the,

1:53

the potential theranostic applications. Uh,

1:57

today we're going to more broadly look at, at Theranostics. Uh,

2:00

we'll start out with a, a brief discussion of, uh,

2:04

the sort of I 1 23 I 1 31 M I B G pair for, uh,

2:08

metastatic pheochromocytomas and paragangliomas. Uh,

2:12

we'll segue from that. I, I think rel hopefully smoothly, uh,

2:16

into somatostatin receptor expressing tumors, uh,

2:19

which can include paras and pheos. Uh, but we think of more, uh,

2:23

today in terms of midgut neuroendocrine tumors. Um,

2:27

so things like pancreatic neuroendocrine tumors or al neuroendocrine tumors,

2:32

uh, and the use of the gallium dotatate, uh, lutetium 1 77 dotatate,

2:37

uh, theranostic pair where we're,

2:39

we're gonna leverage lutetium instead of I 1 31, uh,

2:42

to deliver our beta particles. And then, uh, from there, we'll,

2:46

we'll head back to the prostate cancer realm because of course,

2:48

P ssm a theranostics is really going to be the kind of the high volume, uh,

2:53

driver of, of theranostics, uh, worldwide, uh,

2:56

just because of so many men that,

2:58

that have prostate cancer and the percentage of them that will eventually

3:01

progress, uh, to me,

3:03

metastatic disease that would be amenable to treatment with, with psm,

3:06

a targeted theranostics. And, uh, and we will, uh, and, and again, we will,

3:11

uh, we'll talk about sort of a, uh, uh, a little bit about the diagnostics,

3:14

which is gonna be both F 18 and gallium 68 labeled radio tracers. Uh,

3:19

and then our, uh, current regulatory approved, um,

3:23

they're not therapeutic agent in prostate cancer,

3:26

which is also gonna be LUTETIUM 1 77 labeled. Um, and the fact that,

3:30

uh, there, there are other things in the pipeline, uh,

3:33

that prostate cancer is kind of driving that, because again, it's so common.

3:37

And so, we'll, we'll touch on maybe some of the emerging ideas that are,

3:41

that are there for what happens when patients, uh,

3:43

don't respond to the current theranostics. And, uh, and what do we,

3:47

what do we have sort of in the, in the hopefully near future that,

3:51

that may be able to help those patients, uh,

3:56

broadly? Uh, we'll, we'll, we'll, again, uh, may, maybe I can,

3:59

I can reset here just so we're all on the same page. So, uh,

4:02

theranostics fundamentally comes down to the use of a targeted diagnostic

4:06

radiotracer, um, that shows us that a a given target is expressed,

4:12

or that a given tumor has an affinity for, for the diagnostic agent,

4:17

and that implies that the therapeutic agent will,

4:21

will also be effective. Uh, so it's a, so there's our, there's our,

4:25

the origin of our word theranostic. Uh,

4:28

it's really an example of precision medicine as at its finest.

4:30

We are figuring out how to get the right agent to the right patient,

4:35

uh, at the right point in, in the treatment of their disease.

4:39

And in some ways, this is nothing new. We've been using iodine 1 23,

4:43

iodine 1 31 since at least the fifties, uh, for treatment of thyroid cancer. Uh,

4:48

but it's really coming into its own now that we have things that, uh,

4:51

that aren't just sort of iodine. They're, they're designed molecules, uh,

4:56

that had big medicinal chemistry programs behind them to really try to optimize

5:00

them and allow us to, to mo most effectively treat patients.

5:03

And the approved agents, uh, again, are for pheochromocytoma, paraganglioma,

5:07

mid gutter or endocrine tumors and prostate cancer. Uh,

5:11

when I tend to say approved, I, I often mean us, uh,

5:14

food and drug administration approved I practice in the us. That's,

5:17

that's what I'm most familiar with. Uh,

5:19

there may be various agents used around the world that, uh, uh, that, uh,

5:23

either within a regulatory framework or potentially outside of a regulatory

5:27

framework, uh, in,

5:29

in situations where there may be compassionate use doctrines at work.

5:34

So, let's, let's jump right in and, and talk about, uh, uh,

5:37

pheochromocytomas and paragangliomas. This is, uh, uh,

5:41

this is often our, uh, our tumor of sort of 10 percents, right?

5:46

So 10% are bilateral in the adrenals, 10% are extra adrenal,

5:51

10% are malignant. Uh,

5:52

and I think there's a whole bunch of other 10 percents that approximately apply

5:56

to, uh, to, to pheochromocytomas. Uh,

5:59

this used to be something that nuclear medicine had a very important role in the

6:02

di in the initial diagnosis of, and we'll look at a couple of examples of that.

6:06

But quite honestly, uh, uh, magnetic magnetic resonance angiography,

6:10

CT angiography, uh,

6:11

have gotten so good that they often do a great job of characterizing these

6:15

tumors. And I think that from a purely diagnostic standpoint,

6:19

in terms of a primary tumor characterization,

6:22

nuclear medicine has taken a little bit less of a, a prominent role in that. Uh,

6:27

and here's an example of a, uh, a right adrenal pheochromocytoma,

6:30

incredibly avidly enhancing. Uh, as you can see, just on an art, this is a, uh,

6:35

an early arterial phase, and this tumor is just enhancing like crazy.

6:39

So that's very characteristic of, of our pheochromocytomas when,

6:44

uh, uh,

6:44

when nuclear medicine was maybe doing a little bit more on the diagnosis of,

6:48

of the primary end and perhaps, uh, uh, perhaps also pointing for,

6:53

for how we're gonna move into a theranostic paradigm in, in this disease. Uh,

6:58

we were using a lot of I 1 23 m i bg. Uh, this, of course,

7:01

has a normal bio distribution, so we should expect it to,

7:04

you should expect to see it in the salivary glands, variably, but often, uh,

7:08

fairly intensely in the heart, liver, spleen, kidneys, adrenals,

7:12

it can have uptake in brown fat. Uh, there's, uh,

7:15

clearance through both the colon and through the urinary system.

7:18

And then there's also a very variable, uh, physiologic activity in other, uh,

7:22

in other normal structures. But this is of course, why,

7:27

why we, uh, why we would make use of it, uh, is that it can identify,

7:32

um, pheochromocytomas and paragangliomas with high with,

7:38

I would say moderate contrast maybe. Uh, on, on the axial here,

7:41

it looks like fairly high contrast, so that you can see on the plane are the,

7:43

the uptake isn't, uh, uh, doesn't sort of knock your socks off the way,

7:46

maybe a targeted pet radiotracer might. Uh, but nonetheless, uh, this,

7:51

this does, this does still have a role. And I, I, I still, uh,

7:54

I still see cases where perhaps M r I wasn't determined or, uh, couldn't make a,

7:59

a definitive diagnosis. And we wanna try another non-invasive approach. Um,

8:03

I 1 23 might be g might might still have a, uh, might still have a role there.

8:08

Uh, but again, th this, this talk is mostly about theranostics and we,

8:12

and we wanna focus on that. So when a, a pheo or a para goes bad,

8:16

and it begins to metastasize, uh, which is not a common phenomenon,

8:20

but does happen, uh,

8:22

we can still do whole body staging with I 1 23, my bg.

8:27

I would say this, this is becoming a, again,

8:29

a less common thing that we might do out. Of course, uh,

8:32

many of these tumors will have F D G uptake.

8:35

Many of these tumors will have dotatate uptake,

8:37

which we'll talk about in a little while. Uh, but nonetheless, I want,

8:40

i i 1 23 of my BG can still provide us, uh,

8:43

facile whole body staging of a, of a metastatic phe.

8:50

And that gets us to what we can potentially do then with that, uh,

8:53

in the theranostic space, which is to, instead of using I 1 23 M I B G,

8:57

we can use high specific activity I 1 31 M I B G, uh,

9:02

which is, uh, marketed in the US under the trade name azedra. Uh,

9:06

and it's f d a approved for,

9:07

for therapy of what is admittedly a very rare disease. Now,

9:10

this is so rare that I, I think the, uh,

9:13

the economics of sort of producing azedra and administering azedra

9:18

have, have started to curtail its use to the point that, uh,

9:22

that my understanding is this won't be commercially available for much longer.

9:26

Uh, but that doesn't mean it didn't have an important role to play, and that it,

9:30

uh, hasn't, again, kind of pointed us in a, in a good direction. This was, uh,

9:34

uh, this was one of the early approved Theranostic agents, and it is, uh, um,

9:40

and it, it has helped, uh, at least a handful of patients, uh, with what is a,

9:45

uh, not only a rare disease, but typically a very symptomatic disease, uh,

9:50

and a disease that is almost inexorably progressive.

9:54

These patients, uh, often have, uh,

9:57

horribly labile and difficult to control, uh, blood pressure, uh,

10:01

just like a patient who may have a primary and non-malignant pheochromocytoma.

10:06

And the phase two trial that actually led to f d a approval, uh,

10:09

was specifically based around, uh, or had a,

10:14

a primary endpoint of actually decreasing the number of, uh,

10:17

anti-hypertensive medications that patients required, uh,

10:20

that primary endpoint was, was met and, and hence that the agent was approved.

10:25

Uh, but, uh, that really, uh, sort of leaves us to, I guess, question, you know,

10:29

would there, would there be overall survival advantages? Um, you know,

10:34

does this improve patient's quality of life? We think it, we think it does.

10:37

We think those things are probably true. Uh,

10:39

but those were not specifically tested in a pivotal, pivotal clinical trial, uh,

10:43

prior to the approval of azedra.

10:47

There are patients that do have very, very nice objective responses to, uh, uh,

10:51

to this agent. Uh, this is a, a slide from my, my colleague, Dr. Lil Sone, uh,

10:56

who's the, uh, nuclear Medicine Division director at Johns Hopkins. And, uh,

11:00

this was a, a patient that participated in, uh, in a clinical trial, uh,

11:05

prior to approval. Uh, you can see here,

11:07

there's an arterially enhancing lesion in the left lobe of the liver. Uh,

11:10

that lesion becomes less enhancing and distinctly smaller, uh,

11:14

12 months after therapy with, with azedra.

11:17

So this patient has had an objective response, at least in this one lesion. Uh,

11:21

but that, uh, that wasn't either with the clinical trial,

11:24

was testing and may not be an overly common thing that we, we see in patients.

11:28

Uh, but what we, what we really hope to do is abrogate their use of

11:34

anti-hypertensives, and hopefully by that,

11:36

improve their symptomatology and quality of life. Now, as I noted,

11:41

uh, a couple of slides ago,

11:43

commercial availability of edra going forward isn't necessarily something

11:48

that's, that's gonna be guaranteed. Uh, and it, it, again, it makes sense.

11:52

This is such a rare disease that, uh, that it's hard to,

11:55

hard to have just this incredibly expensive sort of niche or boutique, uh,

12:00

therapeutic for it. But, uh, but I,

12:04

I remain hopeful that what we'll eventually be,

12:06

be doing is identifying those patients with metastatic paras or fiss,

12:09

whose tumors expressed somatostatin receptors. This, again, is, uh,

12:15

is a nearly universally expressed in well differentiated,

12:19

uh, midget neuroendocrine tumors, uh,

12:22

tends also to be expressed in other kinds of neuroendocrine tumors,

12:25

although pot, potentially to lesser degrees. Uh,

12:28

we've long leveraged somatostatin receptor expression for

12:33

the diagnostic end of things. So, uh,

12:35

folks on the call may remember Indian one 11 Pentre or Trea Scan, uh,

12:40

which for, for decades was, was used in the, uh, in the evaluation of, uh,

12:44

somatostatin receptor expressing tumors. I think pretty much, uh,

12:48

pretty much everywhere, uh, worldwide, or at least many places, uh,

12:52

around the world, have, uh, now gone to Gallium 68 dotatate, um,

12:57

a very similar molecule, only labeled with a PET radio tracer, uh, with,

13:02

with, and actually,

13:03

both agents have very high affinity specifically to sub subtype two,

13:07

the somatostatin receptors. And, uh, Dotatate provides very,

13:11

very high contrast, um, high spatial resolution imaging,

13:15

because it is a pet radiotracer. And, uh,

13:19

although you can use actually high doses of India one 11, uh, uh,

13:22

treat app pentre or REIO scan, uh, as a therapeutic,

13:26

that has really fallen out of favor. Uh, and we're, uh, uh,

13:30

pretty much universally using LUTETIUM 1 77 dotatate, uh, as, uh,

13:35

as a way to deliver, um, beta particles to, to tumors,

13:39

and hopefully control those tumors in that way. Uh, very briefly,

13:44

the, the Dotatate Biodistribution is, is seen here. Uh, I,

13:47

I present this because, we'll, we'll discuss a couple of pitfalls that, uh,

13:51

to interpretation that we just want to be aware of.

13:53

Generally not going to be an important thing when you've got a widely metastatic

13:57

patient who's gonna be, uh,

13:59

who's gonna be a candidate for LUTETIUM 1 77 dotatate. But again, we,

14:03

we do wanna be aware that not everything that has uptake on a DOTATATE scan is

14:07

necessarily a neuroendocrine tumor in terms of normal bio distribution. Uh,

14:12

pituitary gland, uh, salivary glands, thyroid, uh, spleen, uh,

14:17

adrenals, spleen and adrenals tend to be the hottest things on the scan. Uh,

14:20

kidneys are both, uh,

14:22

there's both binding to the kidneys and also filtering through the kidneys, uh,

14:26

pancreas, liver, and prostate.

14:30

So, uh, again, with, with paragangliomas of pheochromocytomas, uh, we,

14:34

we've had access to the I 1 23 M I B G I 1 31 M

14:39

I B G Theranostic pair. Uh, but, but hopefully, again,

14:43

we'll be able to transition some of these patients over to, uh,

14:47

to eventually the Gallium Dotatate Lutetium Dotatate Theranostic pair, um,

14:52

which would, which would currently be, uh, off-label use of,

14:55

of Lutetium Dotatate. But, uh,

14:59

but many of these patients do have smeta receptor expression on their tumors.

15:03

And so, here's an example of a patient, uh, who had a metastatic paraganglioma.

15:08

You can see on the I 1 23 M I B G planar imaging. Uh,

15:11

we see at least a couple of sites of abnormal uptake. Uh,

15:14

we see that much clearer on the gallium dotatate, uh, MIP image.

15:19

Now, in all fairness, the, uh, I 1 23 M I B G images as planar. It doesn't have,

15:24

it's not gonna have nearly as much information as, as the MIP image would. Uh,

15:28

but I, I think we do get a sense that the MIP image is just much cleaner. Uh,

15:32

it shows us subtle things that,

15:34

that I don't think we were ever gonna be able to find with, uh,

15:37

I 1 23 M I B G imaging. And, uh, on the CT scan,

15:41

things that may be very subtle or even a cult on ct, uh, we see those as having,

15:46

uh, very high uptake on the accompanying pet, uh, which again,

15:50

drives a very high contrast resolution for, for this,

15:53

this particular imaging agent. And here's a, uh, here's a patient. Uh,

15:58

this would certainly be a rare situation, uh, who had a, uh, familial, uh,

16:04

familial syndrome. She had a, uh,

16:06

SID eight dehydrogenase mutation that tended to drive the formation of,

16:09

of para gang gliomas. And, uh,

16:11

here you can see she has multiple sites of abnormal uptake in the neck and

16:15

perhaps extending down into the upper mediastinum. Uh, and again, these,

16:19

these lesions have, have incredibly high uptake on, on Gallium Dotatate PET

16:25

and Tate PET really should be probably subsuming a lot of things that we may

16:29

have, that we may have used, uh, M I B G or even other agents for. Uh,

16:35

and this is across the board in, in Pheos paras and,

16:38

and even Neuroblastomas that, uh,

16:40

that donate really has high sensitivity for, for these lesions.

16:45

And because Lutetium Dotatate has become so widespread, its application, uh,

16:50

again, identifying these patients that have high dotatate uptake allows us to

16:54

potentially put them down a pathway where they can hopefully have access to

16:57

that, that therapeutic agent. Uh, I think it's,

17:02

it's sometimes shocking how extensive patient's disease is if all they've had is

17:06

anatomic imaging prior to, prior to getting a dotatate pet. Uh, and some of,

17:11

and we do have to, I guess, I guess you could say,

17:13

have faith that Dotatate really is showing us, uh,

17:16

the true extent of disease here. I would say this, uh, sagittal, uh,

17:20

attenuation correction CT scan doesn't really show us anything that would lead

17:25

us to believe that this patient has widespread bone metastases from a midgut

17:29

neuroendocrine tumor. Uh, yet, uh, yet that is the case, as you can see in the,

17:33

uh, in Thesal PET and Fused PET CT images.

17:38

This said, I did, did want to touch on, on a, a little bit on the pitfalls of,

17:42

of gallium dotatate imaging. Uh, I think, uh,

17:45

I think every one of my trainees who has ever read their first gallium dotatate

17:49

scan, uh,

17:50

is always turned off by the fact that there's no brain uptake like there is with

17:52

F D G. And then there's this generally very intense uptake in the pituitary.

17:57

And so there's always, uh, there's always a,

17:59

a thought on their part that somehow this pituitary uptake must be abnormal.

18:02

That is an expected finding. Inflammatory conditions can have dotatate uptake.

18:07

Again, something we, we just need to be aware of. Uh, and here you can see a,

18:10

a patient who had biopsy proven, uh, pulmonary sarcoidosis, uh,

18:15

with at least moderate uptake in their mediastinal and hilar lymph nodes that,

18:20

uh, that is actually on target binding. So, um, thing, uh, various immune cells,

18:24

including macrophages, will express somatostatin receptor.

18:27

So this isn't sort of off target binding to something that isn't somatostatin

18:31

receptor. It just happens that they're, uh,

18:33

that inflammatory conditions can have somatostatin receptor, uh, expression.

18:38

And then, uh, uh, we wouldn't wanna mistake a, a,

18:41

a lenal for something like a peritoneal implant if we're doing, uh,

18:45

a staging examination on patients. Uh, the spleen, again, is, uh,

18:49

a very high uptake organ and spleen, uh, mirror that.

18:55

And then, uh, I, I would suppose I would be remiss not to mention the, what I,

18:59

what I think is probably the most famous pitfall of gallium deed imaging,

19:02

which is that the, uh, dorsal anga of the pancreas, uh,

19:06

the uncinate process primarily, uh,

19:09

has higher somatostatin receptor expression than the ventral ANGA does.

19:13

And so you will see up, you will see higher uptake, uh,

19:17

in many patients in the uncinate process.

19:19

It that can be relatively focal in mass. Like,

19:22

so it really is something to watch out for. Again,

19:25

maybe not for patients who are being selected for theranostics,

19:28

or we're usually looking at patients with relatively high volume metastatic

19:31

disease, but certainly in the interpretation of the scan, uh,

19:34

and the GALLATE scans, we wanna be aware of this. Alright, so that,

19:38

that all brings us to lutetium 1 77 dotatate, uh, in the us the,

19:43

the trade name for this agent is Lutera. Uh,

19:46

and that's often what we'll refer to it as in kind of day-to-day,

19:48

day-to-day in the clinic. Uh, it's, uh, uh, these,

19:52

these are patients who,

19:54

up until the advent of Lutera really had very little in the way of,

19:59

of reasonable therapeutic options.

20:01

They would typically be started on cold octreotide, um, which in its long,

20:06

long acting form is often called Sandostatin.

20:08

And it's a once monthly sort of depot injection that the patients get. Uh,

20:13

almost everyone will progress on that, and often in relatively short order.

20:18

And prior to the advent of lutetium dotatate, uh,

20:21

those patients would've gotten chemotherapy as as second line therapy.

20:25

Some still do, uh, although at least, uh,

20:28

in the US practices mostly switched to using lutetium dotatate as,

20:33

as the sort of second line agent.

20:35

I should note that is how the F D A approved it.

20:37

They did not approve it as a first line agent. So again, most patients will,

20:41

will still get octreotide cold octreotide as, as for their first agent.

20:45

And then upon failing that and progressing, uh, they'll,

20:48

they'll go on to lute to receive lutetium dotatate. Um, and so this,

20:53

uh, uh, there's really a number of studies that underlie this. Uh, but, uh,

20:57

but there's one that, that we'll, we'll focus on. So,

21:00

so at the meta analytic level, I think we, we knew that, uh,

21:03

lutetium dotatate and even other things like lutetium doda talk, uh,

21:08

lutetium, doda knock, uh, lots of, uh, lots of sort of variations on that theme,

21:13

uh, with essentially, uh, either the same or very similar, uh,

21:17

peptide components of the theranostic with, uh, with, um,

21:21

sort of different chelators for, for the lutetium. And again,

21:26

at the meta analytic level, we, we knew that this was working. There's, uh,

21:29

at this point, uh, gosh, probably 25 years of,

21:34

of generally retrospective data from, from the European experience with,

21:39

with this agent.

21:40

We know that some patients will have very long responses to this,

21:44

that treating patients repeatedly with this can be an option in,

21:47

in some scenarios. Uh, but the, uh,

21:50

the f d a approval in the US was really based on the netter one trial, uh,

21:55

which was a multicenter, uh, prospective phase three,

21:59

phase three pivotal clinical trial, uh, carried out at a number of sites,

22:03

primarily in, in North America and Europe. And the, uh,

22:08

what what certainly got the FDA's attention and,

22:11

and would've spurred the approval was that patients had an improved

22:16

progression-free survival and an improved overall survival,

22:21

uh, relative to, uh, relative to standard of care,

22:25

which was typically cold octreoscan or octreotide. So, uh,

22:30

cold octreotide. Now,

22:31

many of the patients getting dotatate will continue on their cold octreotide.

22:35

Uh, there's probably some anti-tumor efficacy with, with that agent.

22:41

And it also helps control symptoms.

22:44

And that's maybe something I haven't haven't emphasized up to this point,

22:47

but that we, we should talk about these pancreatic neuroendocrine tumors.

22:52

Uh, even, even sort of relatively indolent metastatic tumors. Uh,

22:57

many patients will have, uh, carcinoid syndrome, or they may have, uh,

23:02

release of various hormones that have profound effects on their quality of life.

23:07

Uh, you will, uh, you will meet patients who, uh, who have carcinoid syndrome,

23:12

who have, uh, such sort of difficulty, uh,

23:16

controlling their,

23:17

their bowels that they could basically never be far from a toilet.

23:22

And these patients become, uh, sort of, they, they,

23:26

it's almost like they'll never leave the house because they,

23:28

they can't leave the house 'cause they, they're just, uh, sort of on the,

23:32

on the toilet all day. That is a horrible quality of life.

23:36

And even if you can't necessarily, you know,

23:39

buy someone an improved overall survival, although again, uh, uh,

23:44

ate does that the, uh, uh,

23:47

you can potentially relieve their symptoms and give them back that quality of

23:51

life, uh, in addition to a little bit of quantity of life. But,

23:54

but a qual quality of life is a significant driver for,

23:57

for many of these patients. Now, there's more recent data, and I, uh, I won't,

24:02

won't dive too much into the weeds on it. That shows that, uh, that ultimately,

24:06

that ultimately, if you give it enough years, uh,

24:09

these Kaplan-Meier curves eventually come back together. And, and that simply,

24:13

that simply speaks to the fact that these patients do have a terminal illness,

24:16

and most of them will eventually progress and, and die from this illness. Uh,

24:21

but I, I don't think that takes away from the fact that at least out through the

24:24

follow-up period of the number one trial,

24:26

there was an improved overall survival, uh, and an improved progression,

24:30

and a significantly improved progression-free survival. And then many,

24:33

many patients will tell you just, uh, uh, really heartwarming stories about how,

24:38

uh, receiving this agent, uh, uh, really improve their,

24:42

their quality of life quite dramatically. Uh, and, uh,

24:47

I do wanna focus a little bit on, I guess, on the practical aspects of,

24:50

of the N one trial and what it means for what we do in clinic. So, again,

24:55

based on that trial, there was an F d A approval, and, uh, many of us are,

25:00

are using this in our, in our clinical practices now. Uh,

25:04

and the, uh, the things that I, that I think we should emphasize,

25:09

and when, when I talk to patients, the things I, I,

25:12

I tend to emphasize are that, uh, their tumors may not get any smaller. Uh,

25:16

there's actually only about 8% of patients will have a sort of resist 1.1

25:21

objective imaging response, uh, to the use of, uh, of Lutera.

25:27

Uh, which doesn't sound very good, but, uh, 70% of patients,

25:32

give or take, uh, we will, uh,

25:34

we'll have a good response and we'll have a progression-free survival interval

25:38

after, after using lutera.

25:40

So the objective response doesn't really track with what we see, uh,

25:43

in terms of, uh, um,

25:46

in terms of tumor control by this agent. Uh, so,

25:51

uh, so that, that's important. And many patients, uh, that I've seen, uh,

25:56

won't have an objective response or tumors will all stay kind of the same. Uh,

26:00

but again, that, that symptomatic relief that they, that they get, uh,

26:04

it is still, uh, still very satisfying to, to treat them. And the,

26:07

and the patients are very happy. There are toxicities associated with Lua.

26:12

They aren't necessarily toxicities. We would immediately, uh, uh,

26:16

we would immediately identify. But, uh,

26:20

there are hematologic toxicities, and in particular,

26:22

platelets seem to seem to be susceptible to, to dropping while on therapy with,

26:27

uh, with, uh, lutera. So, so we watch platelets, uh, very carefully. Uh,

26:33

ideally we like the platelets to kind of be above 75 when,

26:36

when we're treating patients. Of course,

26:38

it's even better if they're above a hundred. Uh, but, uh, uh,

26:41

many patients will have a, a little, little dip in their platelets.

26:44

It's very rare that a patient would actually need something like a platelet

26:46

transfusion. And then we also watch their renal function very carefully. Uh,

26:51

this isn't so much that we think that, that this,

26:53

that the amount of radioactivity they're gonna get is gonna lead to nephropathy

26:56

over the time course that these patients have to, to live. It's much more that,

27:01

uh, that if they take a hit to their renal function for some other reason,

27:04

and we have to remember, these are patients with generally, uh,

27:07

stage four and often widely metastatic disease. They're often frail.

27:12

Uh, they may not be, they may not be hydrating well on their own. These,

27:17

uh, if that renal function drops,

27:19

and particularly if it gets below a G F R of 30, uh, treating them with a,

27:24

um,

27:25

with 200 millicuries of a theranostic beta emitting radiopharmaceutical,

27:30

uh, that's primarily renally excreted, uh, will lead to,

27:35

uh, sort of added toxicities in other parts of the body.

27:37

So then your hematologic toxicities may, may really be ramped up.

27:41

So I have a pretty hard floor at, at a G F R of 30 below,

27:45

which I would be highly reluctant to treat a patient.

27:48

Maybe there would be a circumstance that would come along where I,

27:50

I would consider it. But, but generally that's, that's sort of the, uh, uh,

27:54

again, kind of a hard floor below, which I, I, I don't think we should go.

28:00

So, uh, let me, uh, lemme switch gears entirely then and,

28:03

and talk about kinda another success story within Theranostics. And again, one,

28:07

one that I believe would probably be of, of general interest to,

28:10

to the audience and,

28:13

and where things are going to get very interesting in terms of how we,

28:17

how we deliver theranostics, and how we, uh, uh, uh,

28:22

and how we move forward. Because, uh, up until now,

28:26

what we've been talking about are relatively rare diseases in the US are a few

28:30

thousand mid gotten or endocrine tumor patients a year. Um,

28:34

and so a a big academic center might,

28:37

might treat a couple to a few patients a month, uh, with,

28:41

with something like lutera. Whereas prostate cancer, uh,

28:46

worldwide, we're up over 1.2 million cases being diagnosed every year.

28:51

Uh, in the US alone, I think we're at about 280,000 a year.

28:56

The, uh, now many of those patients are gonna be cured by,

28:59

by surgery or by radia and or radiation.

29:02

But for those who go on to develop a metastatic and

29:07

lethal phenotype of prostate cancer, they,

29:11

they need systemic therapy. And that systemic therapy has traditionally sort of,

29:16

sort of gone through, uh, androgen deprivation, then, uh,

29:21

then either concurrent or followed by second generation anti-androgen agents

29:25

like abiraterone and enzalutamide,

29:27

and then eventually onto taxane based chemotherapies, uh,

29:30

which have also been sort of moved up further and further in,

29:33

in the course of the disease.

29:34

And some patients with relatively high volume metastatic disease will start a d

29:39

t and taxing based chemotherapy, uh, as their upfront, systemic,

29:43

systemic therapy, and as patients, uh, progress through and,

29:47

and fail those various therapies. Uh, P S M A, uh,

29:52

targeted theranostics is one way that, uh,

29:55

that those patients might continue to derive benefit from, uh,

29:58

from systemic therapy.

30:02

And while, while many, again,

30:04

many prostate cancer patients are cured early in the disease, um, it,

30:09

there's probably at least 40,000 patients a year in the US that are, uh,

30:13

or 40,000 patients right now that would be eligible for,

30:16

for treatment with A A P S psm, a the therapeutic. Um,

30:21

and all of a sudden we're, we're now in the tens of thousands.

30:24

And as clinical trials continue to read out positive for use of,

30:29

of P S M A therapeutics and, um, metastatic, uh,

30:33

hormone sensitive prostate cancer, uh, pre-chemo, the pre chemotherapy,

30:37

pre chemotherapy, hormone sensitive, uh,

30:41

perhaps even neoadjuvant therapy, as, as all of those things, uh,

30:45

start to start to come onto the table, uh,

30:48

that population just expands and expands. And quite honestly, my,

30:51

my main worry is are there enough nuclear medicine physicians and or

30:55

radiologists and or radiation oncologists that are interested in this to the

30:59

extent that, uh,

31:00

that we can get all of those patients treated with what is an efficacious and

31:04

well-tolerated therapy. So let me start with P S M A pet, uh,

31:08

because that's how we're gonna be selecting our patients.

31:10

And here where I talk about P S M A pet,

31:12

I'm kind of following the NCC N guidelines, look at it that, uh, that although,

31:17

uh, gallium p SMMA 11, uh,

31:19

has often been used to select patients in clinical trials for, uh,

31:23

for P S M A therapeutics that, uh, that, uh,

31:28

any P S M A targeted, uh, PET radio tracer, uh,

31:33

and in the US there's, there's now three approved. That's Gallium P SMMA 11, uh,

31:37

F 18 D C F P Y L, uh, and, uh, rh,

31:42

uh, P SMMA 11 F 18 RH p sm a, uh, 7.3, uh,

31:47

that, uh, that those,

31:48

that any of those radio tracers from the view of the N C C N can be used to

31:52

select patients. So we're gonna just take a,

31:54

a view that sort of all pssm a pet is the same, uh,

31:57

and I think that's a reasonable, reasonable way to approach it. Uh,

32:01

what we do know with psm, a pet, at least on the diagnostic side,

32:04

is that there's a moderate sensitivity,

32:06

very high specificity for preoperative nodal staging.

32:09

We know that there's a high detection efficiency for sites of biochemical

32:12

recurrence, and we believe we're effective for guiding,

32:15

guiding metastasis directed therapy in patients that have low volume metastatic

32:19

disease. But then the big thing is selecting patients for, uh, P S M A targeted,

32:23

uh, therapeutics, uh, very briefly,

32:27

here's a couple of patients with high risk prostate cancer being preoperatively

32:31

staged. Uh, we can see that, uh,

32:33

one of those patients truly does have localized disease. Uh, the other has, uh,

32:38

has unsuspected systemic disease, uh,

32:40

which we were able to pick up because of the high sensitivity of psm, a pet, uh,

32:45

for biochemical recurrence. We can find, uh,

32:47

small little local recurrences that, uh, uh, here shows up on M R I,

32:51

but certainly would not have shown up on ct. And obviously, uh, uh, being a,

32:55

a local soft tissue recurrence would not have shown up on bone scan

33:00

and then, uh, oligometastatic patients. So it, it may come,

33:04

there may come a time where we, where we do leverage, um, uh,

33:09

lutetium, uh, P S M A therapeutics for, um,

33:13

for patients with more limited volume metastatic disease.

33:17

Most of the patients we're seeing in clinical practice have high volume

33:19

metastatic disease. Uh,

33:22

and I think there's at least some thought that why not give these patients a

33:25

shot with external beam radiation therapy if they have low volume disease?

33:28

So this patient had only a solitary, uh,

33:31

solitary visible recurrence on P S M A PET did get SS B R T

33:36

and P S A became undetectable. Despite not starting systemic therapy.

33:41

Uh, we see patients we think might have been, uh,

33:44

might have been a candidate for, uh,

33:48

for metastasis directed therapy with limited volume of parent metastatic disease

33:52

on something like a bone scan who truly have widespread systemic disease.

33:56

And so this patient shouldn't get S B R T.

33:57

This is a patient who should be a candidate for, uh, for lutetium, uh,

34:02

PSM A therapy. There's a couple of different agents that, uh,

34:06

that have been pretty, pretty widely used worldwide. I think the, uh,

34:09

the one on the left here, lutetium PSM, A 6 1 7, uh,

34:11

has been the more widely used. And the two,

34:14

the two best clinical trials that have been done worldwide,

34:18

so far at least that have been published, uh, have been done with,

34:20

with PSMA 6 1 7. Uh, that's, uh, the trade name for that is Pluto in the us.

34:25

Uh, so we'll often just refer,

34:27

or we're sort of developing the habit to kind of refer to this as Pluto therapy,

34:31

presumably lutetium, PSMA I N t is going to be known as, as something different.

34:36

I think our expectation is that will be F d a approved, knock on wood,

34:39

hopefully the not too distant future. Uh, and that's, uh, uh, currently, uh,

34:44

currently the Pivotal clinical trial with that agent is, uh, I,

34:48

I believe is accrued out. Uh, and, but, but has not been read out yet.

34:54

Let me, uh, let me show you what, uh, I suppose amount to a whole lot of, uh,

34:59

of forest plots here. But, uh,

35:01

but I think each of them has an important point to make. And, uh, these are,

35:05

these are sort of at a meta analytic level,

35:07

although I'll show you data from the, uh, from the pivotal, uh, clinical trials.

35:12

I like the, I like this, uh, I like the sort of meta analytic data format, uh,

35:16

because it includes, uh, meta-analyses of all the, the toxicities. So, we'll,

35:21

we'll talk about that. And again, this really forms kind of a basis for,

35:24

for how I talk to patients who are, who are candidates for,

35:27

for receiving this therapy. So, uh, I will tell them that, uh,

35:31

in terms of an objective response rate, which is a P s a drop of at least 50%,

35:36

I expect a, somewhere around 40% of patients, uh,

35:40

who are metastatic castration resistant post-chemotherapy o

35:45

often post chemotherapy. But, uh,

35:47

but some of this data is with pre chemotherapy, metastatic castration resistant,

35:51

but all these PEs patients are metastatic castration resistant.

35:55

I expect 40% of those patients to have that 50% drop in P S A.

36:01

That is, uh, um, that doesn't sound all that great, I suppose.

36:06

Uh, right? It's less than 50%.

36:08

But these are heavily pretreated patients who get ve often seen taxane based

36:11

chemotherapies. They've progressed on all of those things. And so now they're,

36:16

they're kind of at the end of the road being, being treated with this, this, uh,

36:21

this relatively new agent. And so in that context,

36:25

I think a 40% objective response actually sounds, uh, really encouraging.

36:31

Uh, somewhere around, uh, oh, and I should mention, uh,

36:35

we've never found a difference, uh,

36:37

between LUTETIUM and PSMA 6 1 7 and lutetium and PSMA I N T in terms

36:42

of their efficacy, at least not a statistical difference between them. Uh,

36:46

a lot of our data transports LUTETIUM and P SMMA 6 1 7 being potentially

36:51

slightly more efficacious. Uh, but again, that that does not, uh,

36:55

that has not held up as a statistical difference between the two agents. So, uh,

37:00

whichever one i I could get ahold of,

37:02

and whichever one I have access to that I can use in clinic,

37:05

I would feel comfortable using either one. Currently,

37:07

lutetium PSMA 6 1 7 is the FDA-approved agent. And that's, uh,

37:11

and that's what I use in, in my own clinical practice

37:16

in terms of any P s A decrease, about 70% of patients will,

37:19

will experience a P S A decrease. Now, of course, that, uh,

37:23

that ultimately means that somewhere around 30% are going to have a P ss a

37:27

increase on therapy.

37:29

I think it's a little controversial as to exactly what that means right now.

37:33

And, uh, generally in in clinical practice, I,

37:36

we try not to check a P S A before we've had, uh, before we've given ther, uh,

37:41

a couple of doses of therapy. Now,

37:43

some of my oncology colleagues are a little antsy and, uh,

37:46

and are checking PSAs pretty often. But, uh,

37:49

we do believe that patients can have a, a short-term bump in P s a, uh,

37:53

after the initiation of therapy,

37:54

and that many of those patients will go on to have a good response to therapy.

37:58

So be hesitant to discontinue LUTETIUM PSM A on the basis of, uh, a,

38:03

a small bump in, in p ss a over the first couple of doses of therapy.

38:08

I think when you have a patient whose P S A is truly skyrocketing, very,

38:12

very short doubling times, many of those patients are,

38:16

are ultimately not going to benefit from Lutetia and psma. I would potentially,

38:20

again, give them, uh, you know,

38:21

give them at least two doses to see how they're doing. Uh,

38:24

but when you really have those rapid increases in, in P s A levels,

38:28

those patients really do need to, need to,

38:32

need to be encouraged to have additional chemotherapy if, if that's possible,

38:37

get chemotherapy if they haven't had it before. Uh, so, so we do,

38:41

we do wanna watch the P S A levels, but again, I,

38:44

I am sort of a believer in trying to give at least two doses to,

38:47

to every patient before we pull the plug, uh,

38:49

outside of relatively extenuating circumstances. But nonetheless, I, I,

38:54

I guess what I,

38:54

what I emphasize out of this data with patients when I'm talking to them, is,

38:58

again, that I, I'm a believer in this, this therapy. I believe it's effective.

39:01

And as we're gonna see over the next few slides,

39:03

I believe it's very well tolerated. But I also know that, know that,

39:07

at least based on our current understanding of what we should see on A P S M A

39:10

scan, where we should see high uptake, uh, uh, the,

39:15

we should see high uptake and relatively homogeneous uptake between tumors.

39:19

We don't wanna see a lot of heterogeneity between the uptake in different

39:22

tumors, but still, 30% of those patients are,

39:25

are going to be primarily refractory to this, this therapy. So,

39:30

uh, that's unfortunate. I think we'll get better over time based on nomograms,

39:34

based on machine learning,

39:35

that helps us better incorporate aspects of the patient chart along with their

39:39

imaging. Uh, we're eventually going to get better at selecting patients, and,

39:42

and this number will go down and our previous numbers will go up. Uh, but,

39:46

but at least right now,

39:47

about 30% of patients are gonna be primary refractory to, uh, to our therapy.

39:53

Uh, as I, uh, as I said, our, uh, um,

39:56

this is generally a fairly well tolerated, uh, fairly well tolerated, uh,

40:01

method of therapy. Uh,

40:02

somewhere around 20 to 30% of patients will have some kind of anemia.

40:06

This gets harder when you're dealing with patients who are anemic to begin with.

40:12

Uh, and so, uh, patients that have hemoglobins less than eight, uh,

40:16

the current guidelines would suggest we,

40:18

we probably need to either wait for that hemoglobin to recover, uh,

40:21

or that these patients just may not, may not be candidates for,

40:24

for this particular therapy, that that can be really hard. Obviously,

40:28

patients don't, distinctly don't want to hear that. Uh, but we don't,

40:32

we don't necessarily want to make patients transfusion dependent and,

40:35

and sort of not only not extend their life, but then sort of add on kind of a,

40:39

a big dinging to their quality of life by, by treating them with this. So, uh,

40:43

so I'll, I'll treat patients, uh, down to a hemoglobin of about eight,

40:48

although below 10, I, I really do start to get a little worried about them,

40:51

and I at least have a conversation with them that, uh, that, uh,

40:55

we have to keep a very close eye on their hemoglobin,

40:57

and that at some point they,

40:59

they may require transfusions to either continue on therapy, uh,

41:02

or they may not be able to continue on therapy, and they may still,

41:05

still need transfusions, uh, for,

41:09

for grade three or four anemia. This is essentially, uh, uh,

41:13

if we probably select our patients, this is very uncommon. Uh, but again,

41:17

if you,

41:17

if you are treating patients that are down in kind of that danger area with

41:20

hemoglobins of, of eight to 10, uh, you, you may push patients to,

41:25

to transfusion dependence and kind of, and unfortunately, uh, um,

41:29

sort of permanently shut off their, their bone marrows production of, of,

41:33

of red blood cells. So it is, uh, you,

41:36

you will potentially see grade three or four anemias. It, it is uncommon, but,

41:40

but not, uh, but not zero, uh,

41:45

don't see a lot of nephropathy in these patients. And, uh,

41:48

not that there isn't significant dose to the kidneys,

41:50

I just think the kidneys are, are relatively, uh,

41:53

relatively not all that susceptible to, uh, uh, to radiation. And so,

41:58

again, over the time course in which these patients will, will be alive,

42:01

which for many of them is, is a matter of months, I,

42:04

I don't think nephropathy is a, is a significant, uh, uh,

42:07

is a sign should significantly dissuade us from, uh,

42:11

from treating them or, or a,

42:14

a fear of nephropathy should dissuade us from treating them. Again, I,

42:17

I typically will not treat a patient with A G F R less than 30, uh, down to 30.

42:22

Uh, I'm keeping an eye on their renal function, but again,

42:26

I'm more worried about other things that may hit their renal function,

42:29

food poisoning, where they really become dehydrated and,

42:32

and they go into an a K i, things like that, that will then,

42:36

that will then sort of allow the lutetium P S M A to, uh,

42:40

run rampant and cause more toxicities. Those,

42:42

those are the things I worry about, um, more than, uh,

42:45

more than actually directly damaging their kidneys through use of, uh,

42:49

through use of this agent. Uh,

42:52

grade three or four nephropathy is distinctly rare. Uh, and again,

42:55

that that may be a function of these patients not having very prolonged life

43:00

courses after this. Uh, there's,

43:02

there's probably something to the fact that if all these patients live for 10 or

43:06

15 or 20 years, uh, we would start to see the, the impact on,

43:11

on kidney function more so than, than we do on the current, uh,

43:14

the current environment. Uh, xerostomia not,

43:19

not really a problem with the lutetium based agents. If you hear about, uh,

43:22

xerostomia with, with P S M A,

43:24

it's usually the context of ACTINIUM 2 25 P S M A, which, uh, uh,

43:29

which is, uh, is being used, uh, uh,

43:33

primarily in an investigative way in the us. Uh, it is, uh,

43:37

also being used clinically in, in parts of Europe for sure. Uh,

43:40

I think that toxicities associated with that are, are really quite severe.

43:44

And certainly any grade Xerostomia is gonna be quite a bit higher with, uh,

43:48

with, uh, with that agent, uh, as a, uh,

43:51

as an alpha emitter that also has daughters that emit alphas. Uh,

43:54

it is really quite a hopped up, uh, quite a hopped up agent.

43:57

We'll talk a little bit more about that. Uh, just a minute. Uh,

44:00

grade three or four Xerostomia, again, essentially unheard of with, uh, uh,

44:04

with LUTETIA and P S M A. I think my, my clinical experience, uh,

44:09

anecdotally is that, uh,

44:11

a fair number of patients will describe kind of a little bit of either jaw

44:15

soreness or noting that they have, uh, maybe, uh,

44:19

subjectively just a little bit of a dry mouth.

44:23

And so far, our approach has been to recommend that, uh, uh,

44:27

to eat a sour candy or something like that,

44:29

that's really gonna get their saliva going. And then many patients, uh,

44:32

seem to seem to do fine just with that. So, uh, so I, uh, again,

44:37

grade three or four Xerostomia would be unusual.

44:39

Grade one or two Xerostomia is maybe not that unusual, uh, but,

44:42

but pretty easily, pretty easily taken care of in, in my experience. Now,

44:47

there, there have been two pivotal clinical trials, both have used, uh,

44:50

lutetium and PSMA six 17. Uh, one of them was the therapy trial. Uh,

44:55

this initially, uh, this was a, uh, a two to one randomization against, uh,

45:00

cabazitaxel. And the initial findings, uh, from, uh,

45:05

uh, from the first paper on the therapy trial were that, uh, uh,

45:10

better tolerated than cabazitaxel. And a higher percentage of patients had,

45:15

uh, a, a bio,

45:16

a biochemical response by P ss a with LUTETIUM and PSMA 6 1 7, uh,

45:22

than cabazitaxel. So it was both more effective and better tolerated.

45:25

So it really looked like this was gonna be kind of a home run for, uh,

45:29

for Lutetium and PSMA 6 1 17, uh, as opposed to cabazitaxel. Uh,

45:33

however, uh, over the entire time course of that, that trial, uh,

45:37

there was not a difference in overall survival between, uh,

45:40

between patients treated with Cabazitaxel, most treated with Lutetium and psma.

45:46

Uh, I think that was disappointing for, for all of us on the,

45:49

on the side of Lutetium Pssm, a uh,

45:51

I think there's still something to the idea that even if these are equivalently

45:54

effective, that the quality of life with Lutetium PSMA is, uh, is better.

45:59

Uh, but, uh, but I will also admit that Lutetium P SSM A is very expensive.

46:04

And, uh,

46:05

employing an expensive agent in tens of thousands of men that is

46:10

not going to show an overall survival advantage, uh,

46:13

is a huge burden to the healthcare system. And something that we,

46:17

we clearly would need to, to figure out. Now,

46:20

perhaps a little bit more on the brighter side,

46:22

the other big clinical trial or pivotal clinical trial that was done, uh,

46:25

the vision trial, and I, I realize these,

46:27

these graphs probably predict kind of small, but the vision trial found, uh,

46:32

found that,

46:34

that LUTETIUM and PSMA 6 1 7 plus best standard of care

46:38

versus best standard of care alone.

46:41

So here you can see this maybe not quite as rigorous,

46:43

and that it's not a randomization to another agent like Cabazitaxel, uh,

46:47

but perhaps more reflective of kind of a real world clinical practice,

46:51

that there was a, uh,

46:53

an overall survival advantage predicated on a progression-free survival

46:57

advantage.

46:58

And there was also an advantage in terms of freedom from skeletal events such as

47:01

compression fractures or, or other, uh, uh,

47:04

other sort of painful events that a patient may undergo. So,

47:08

and it was the vision trial, uh, which was, uh, partly conducted in,

47:12

in the US that led to the US F D A approval of Lutetium P SMA 6 1 7, uh,

47:17

which again, uh, we, we now use as, as Pluto, uh, in,

47:21

in routine clinical practice. And, uh, I would say that our, uh, um,

47:26

that we e even at, even at our center here at U N C,

47:30

where I would consider us a relatively small center in,

47:33

in the sort of PSS m a therapeutics landscape, uh,

47:35

we're treating several patients a week. Uh, I think the, uh, uh, the,

47:39

the big new infusion center out at, at U C L A could do like 28 patients a day.

47:44

So maybe we're starting to kind of build that capacity out that as this,

47:49

uh, therapy, which again,

47:50

had showed an overall survival advantage in patients who are metastatic

47:54

castration resistant and post-chemotherapy.

47:57

As we move into the pre chemotherapy setting,

47:59

as we move into the metastatic hormone sensitive setting, uh, we,

48:03

we really are gonna have to work hard to kind of meet the capacity and get those

48:07

patients, um, in seen, seen by a, a,

48:10

a nuclear medicine physician or other physician, uh, and lined up and,

48:15

and getting them treated. It, it is going to be a herculean task, uh,

48:18

as we move forward over the next few years. And then the pool data from,

48:22

from therapy and vision, uh, certainly positive,

48:25

although that's kind of driven by, by the vision results, which, uh, um,

48:29

which vision was also a larger study.

48:31

So it's maybe weighted a little bit more in this, uh, in this polled analysis,

48:36

uh, I do wanna show a couple of example cases because there, there,

48:40

although the actual infusion process with, with, uh,

48:44

lutetium pa May 6 1 7 is relatively easy. Uh, you have to have a, you know,

48:49

a shielded setup. And, uh, it's still, uh, you still want to, uh,

48:52

very slowly infuse this in case, uh, in case you blow a vein or have an extra,

48:56

that would, it would potentially be a disaster. So, uh, so, but,

49:01

but that infusion is, is relatively straightforward.

49:04

It's everything that comes before the infusion that isn't straightforward.

49:07

And I, I know these are, these, the words here are small. So I, I don't, uh,

49:11

I don't intend anyone to read this, but this is just sort of our, uh,

49:14

our patient workflow for, for, for these folks,

49:17

and you really need the right personnel. So in addition to, uh,

49:21

someone familiar with, with therapeutics and, and with administering them, uh,

49:25

you need to, you need to have all the mechanisms in place, just like an onco,

49:29

like an oncologist would of, uh, a, uh,

49:33

somebody like a nurse or a very specialized technologist who can interface with

49:37

the patients kind of initially screen, uh, screen some of their information,

49:42

flag certain things for, for the physician that would be, that would be, uh,

49:47

supervising the infusion. Uh, make sure that the patients have their scans,

49:51

make sure that the patients, uh, are following up on their labs,

49:54

placing lab orders. You know, a lot of these things, uh,

49:57

now can be done in nuclear medicine or, or again,

50:00

other specialties that might do this, uh,

50:02

so long as you have the right personnel.

50:04

But hopefully we're moving past a point where we just expect our medical

50:08

oncology colleagues to do everything for us.

50:10

And all we are is kind of the infusion center.

50:12

We really want to actively co-manage these patients. And that, that again,

50:16

means, fortunately, it does mean investments on, on our side in,

50:20

in the proper infusion setups and infusion centers.

50:24

But then I think the thing that tends to get forgotten about, uh, are,

50:28

are having the right personnel on board. And again, that's not, uh,

50:31

that's by no means just the position there,

50:33

there are really other people that have to be involved to, to make this happen.

50:39

Uh, as I said, I do wanna show you a couple of example cases.

50:41

I think this would be, uh, uh, this would be one such case where, uh,

50:47

where this patient has, uh, widespread metastatic disease,

50:50

it's all very avid,

50:52

but it doesn't entirely take up all of their bone marrow space.

50:56

I think you could believe that this patient could be treated and that, uh,

51:00

and that although they,

51:01

they may have a hit to their bone marrow that you're not, uh,

51:04

you're not definitely condemning them to, uh, to sort of, uh,

51:08

transfusion dependence for the rest of their life. So, high volume disease,

51:12

but not overly high volume disease, very high uptake on P S M A pet.

51:17

This patient's gonna be a really good candidate for, uh, uh, for treatment with,

51:22

with Lutetium and psma. Uh, this is a patient that,

51:26

that maybe wasn't as, as good a, uh, as good a candidate. Um, he, uh,

51:32

he had a couple sites of very, very avid disease, so relatively low volume,

51:35

but a couple of sites of very avid disease, uh, on, on an initial P S M A pet,

51:39

we thought he was a great candidate. Uh, there was a, uh,

51:43

there was a supply shortage of, uh, of Pluto for,

51:47

for a couple of supply shortages, uh, of Pluto for a while.

51:51

And that interrupted his plan to get, to get treated with, with, uh,

51:55

lutetium and P Smma, uh, 6 1 7. So he went and got, uh, he got cabazitaxel,

52:00

and when he came back, his lesions weren't as p sm a a as they should be.

52:05

And what I mean by that is you can see that he has a couple of lesions on his

52:08

follow-up, P ss m a pat, a couple of which are new, uh, that, uh,

52:12

that are below, uh, below sort of a background liver uptake,

52:15

which is what a lot of us, uh, use as kind of a ballpark for,

52:18

for the degree of uptake that, that these lesions should have. Uh, he, uh,

52:23

uh, he had sort, if,

52:25

if you will been promised that as soon as this became available,

52:28

he would be back on the schedule. We had, I think,

52:31

some misgivings about treating him, but, uh,

52:34

also didn't know that he wouldn't benefit. Uh, however,

52:37

his P s A just kept right on rising. So, uh, so I think that, uh,

52:41

a a you can see patients who get something like cabazitaxel may not

52:46

have a lot of p s a expression in their lesions,

52:49

but then over time that p s a expression comes back and maybe, maybe the,

52:53

the thing to do in some of those patients is to wait for that sort of recovery

52:56

period. It's hard to wait though when a patient does have metastatic disease.

53:00

So again, unfortunately this did not, uh, um,

53:03

this patient wasn't a success story. Uh,

53:06

this patient also wasn't a success story. And ultimately, uh,

53:10

we treated him with one dose, but then, uh, but, uh, he, he had, uh,

53:14

uh, unfortunately his disease was just too widespread and too progressive. It's,

53:19

uh, if you look here, his, uh,

53:21

his bone marrow is diffusely infiltrated with disease,

53:25

and he did not really have any bone marrow reserve, very tenuous to begin with.

53:29

He also has lung metastases that aren't particularly avid. So again,

53:33

this patient wouldn't have, doesn't really strictly meet criteria,

53:37

but also didn't have any other options. And, uh, and so in a,

53:42

in a shared decision making between the patient and the oncologist, and,

53:45

and our group in nuclear medicine said, you know, let's give it a shot. Uh,

53:49

but again, his, uh,

53:51

his disease was so rapidly progressive and his bone marrow was already shot.

53:55

And so we, we were not able to, uh, get more than one dose in this patient.

54:01

And all of that brings us to, and I'll,

54:03

I'll wrap up in the next couple of minutes. 'cause I, I do, uh,

54:05

I do wanna be able to take any questions, gets us to what do we,

54:08

what do we do in those patients who aren't gonna respond to Lutetium m p Smma?

54:12

One option is, again, uh, treatment with alpha emitting, uh, radio tracers. Uh,

54:17

this has most, uh, commonly been actinium two five P S M A.

54:20

You can see here this patient who was, uh, quite honestly, almost on, uh,

54:25

quite honestly, my understanding was basically on death's door, uh,

54:29

winds up with an undetectable p s a after, after a few rounds of actinium.

54:33

But I think what you also notice is that all of the salivary gland uptake

54:37

disappears in this patient. So those salivary glands are being treated by the,

54:41

the therapeutic is just other tumors and it,

54:44

and it wipes out those other tumors, uh, if you will. So, uh, so there are,

54:49

this is where we start to hit real toxicities with these agents. Uh,

54:53

lots of things have been tried, uh, such as, uh, uh,

54:57

injecting various agents either directly into the salivary glands or into

55:01

salivary gland ducts, uh, cooling, uh, cooling pads on the face,

55:05

things like that. Uh, although, uh, although the,

55:09

those things may impact things like, uh, like scintigraphy, uh,

55:13

they don't seem to affect the, the patient's symptoms.

55:18

So there's maybe a few different ways to go and hopefully, uh, hopefully we can,

55:22

we can get these things into patients in the near future.

55:24

But different scaffolds, uh, different alpha emitters, uh, lead two 12,

55:29

astine two 11, those kinds of things are, are all in the pipeline. And,

55:33

and hopefully, uh, hopefully again, we start to see those in the near future.

55:37

I'll sort of skip this, it's a little arcane. Uh, and just, uh,

55:41

wrap up really quickly with the idea targeted radio tracers for the basis for

55:45

multiple theranostic agents, um, several of which are,

55:48

are now regulatory approved. Uh,

55:50

patients with these cancers can benefit either from prolonged survival or

55:54

abatement of symptoms. Uh, so it's not necessarily all about survival,

55:58

although that's a very important part of it.

56:00

And we do need new agents to either improve our efficacy or improve our toxicity

56:04

profiles. And, uh, with that, I, I thank you for your attention. I,

56:09

I guess I only left a couple of minutes here,

56:11

but I'm certainly happy to take any questions and I'm gonna, uh,

56:14

I'm gonna open up the, uh,

56:16

I'm gonna stop sharing my screen and open up the q and a and see if anything's

56:20

here. Alright. So, uh, our first question, uh, is it possible, uh,

56:25

we use diagnostic, uh,

56:27

pheochromocytoma with F 18 F DOPA and go on therapy with M I B G,

56:31

both tracers on the same mechanism of uptake and catecholamine metabolism? Uh,

56:36

I think that's a really interesting idea and I, I, I don't disagree that, uh,

56:40

that you can potentially con conform,

56:44

confirm a target expression with something that may be different than the actual

56:48

agent that you're treating with. Uh, and I think we,

56:50

we maybe even see that with, uh, with, say the,

56:53

the P ss A agents chemically something like F 18 D C F P Y L is,

56:58

uh, is distinctly different than, um, than,

57:03

uh, something like Lutetium Dotatate, uh, although they have, uh,

57:06

they have one sort of moty in common and that moty dri drives the binding of

57:10

both. So, uh, so yeah, I don't think we,

57:13

we necessarily have to feel kind of chemically constrained to have the exact

57:16

same molecule. My my concern would be more, uh, what,

57:19

what our source of I 1 31 M I B G is going to be, uh, uh, is going to be,

57:24

uh, going forward. Uh, so, so that may be the, uh, uh,

57:29

that may be kind of more of the problem than, uh, uh, than what we,

57:32

than what we select with. And then, uh, uh, second question. Uh,

57:36

in your experience, uh, best time for an F 18 P S M A scan, uh,

57:40

90 or 120 minutes, uh, we have issues with bladder and ureter uptake.

57:45

Yeah, so, so a couple of things to unpack there. So, uh, there,

57:47

there is some data that as you go to later and later time points post-injection,

57:51

uh, you can potentially find subtle things that may have missed it earlier time

57:55

points. I will say the label label in the US is,

58:00

I think anywhere from 45 up to 90 minutes.

58:03

I may not have those numbers exactly right. We do tend to scan at one hour at,

58:08

at my institution, uh,

58:09

only because it fits in very neatly with the F 18 F D G workflow, uh,

58:13

that sort of dominates our, our oncology practice. Uh, so,

58:17

so I think there are sort of practical advantages to one hour. Um,

58:20

I do think you may find some subtle things as you go out to those later time

58:24

points and, uh, uh, I wish I had the flexibility of my pet center to,

58:28

to potentially, uh, go to those later time points. Uh, and, uh,

58:33

in terms of, of bladder and ureter, yeah, absolutely, it can be,

58:36

it can be tough to read around those. Uh, so, um,

58:40

there are places that give Lasix. Uh, we, we don't,

58:43

and that's partly because particularly our patients who are post prostatectomy,

58:46

they're already having trouble holding their urine. You hit 'em,

58:49

wall 'em with a dose of Lasix,

58:51

and you're gonna wind up with a lot of radioactive urine on your,

58:54

on your pet scanner and all likelihood. So, uh, so we, we don't do that.

58:58

Although, although people do, and I I I don't think it's unreasonable. Uh,

59:02

there are, there have been studies done where patients are catheterized. Uh,

59:07

I can tell you, if you take most men with prostate cancer, they,

59:09

they're not gonna want you to put a catheter in them. Um, and, uh,

59:15

and in those, uh, and so, so we, we kind of just do our best.

59:18

We have the patient void right before they get on the table,

59:21

and then we start our acquisition from the bid thighs.

59:23

So hopefully we're only a couple of minutes, uh,

59:27

a couple of minutes post their last urination by the time we hit the,

59:31

the pelvis. And hopefully that minimizes, uh, uh,

59:34

hopefully that minimizes the amount of at least urine in the bladder that you

59:38

have to contend with, with, uh, with the ureters. It can be challenging. I,

59:42

I think it is very incumbent upon us in terms of anatomy to make sure we,

59:46

we've got the anatomy right. And then, um, and then the, uh,

59:51

you, you can potentially, if you're,

59:53

you're really stuck on ureter versus a lymph node, um,

59:56

if you have the flexibility,

59:57

you could also go and re reacquire the pelvis to kind of make sure that, uh,

60:01

kind of make sure that, uh, that if, if, if it moves, it must've been ureter,

60:05

and if it's still there, it, it's probably a lymph node. Um,

60:08

couple more questions and I'll, uh, uh, I'll, uh,

60:11

try to try to get through these, uh, uh, fairly quickly. So, uh,

60:14

as it might be g more sensitive than gallium dotatate neuroblastoma,

60:18

I don't believe so. I think gallium dotatate is what we're eventually, uh,

60:21

eventually going to all be doing, although, uh,

60:24

although that is not the guidelines recommendation in the US right now,

60:27

I think in Europe, a a lot of those, those patients are, are now image with,

60:30

with Dotatate. Uh, and then one last question. Uh, um, any thoughts on,

60:35

on FPI agents and their promise? Uh, y yes, I, uh,

60:39

I think FPI is a diagnostic tool, is definitely on the horizon. And, uh,

60:44

and I hope, I hope we have widespread, uh,

60:47

widespread a access to it in the very near future. I am, I,

60:51

I remain unsure what it's ultimate appli therapeutic applications might be.

60:56

Uh, I fear that when we go and we basically wipe out the cancer associated

61:00

fibroblasts, that at least, uh, um, that at least,

61:05

uh, some of those, uh, uh,

61:07

some of those cancer associated fibroblasts may be kind of holding the tumor at

61:10

bay.

61:10

And we don't necessarily understand enough about the biology to know if that's a

61:14

good thing or a bad thing. So those, uh, uh, those, uh,

61:18

all remains to be seen. But, but I agree, uh, uh, the fibroblast activating, uh,

61:22

protein, uh, both inhibitors and other things that bind to that I think,

61:26

I think are super promising. Uh, I do apologize. I think we're,

61:29

we're a minute or two over time. Uh, so I think I'll, uh, I'll probably have to,

61:33

uh, kind of stop answering questions, but, uh, but I really appreciate everyone,

61:37

uh, logging in. Uh, and it was, uh, really a pleasure to, uh,

61:41

to speak with you all today and hope to, uh, hope to see you back here in the,

61:45

uh, in the no too distant future. So thank, thank you all again. Uh,

61:48

really hope everyone has a great day.

61:50

Oh, thank you so much. Dr. Roe,

61:52

thank you again for sharing your lecture today and coming back and joining us at

61:56

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61:59

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