Latest / The Science of Skin / Treating Advanced Skin Cancer Without Surgery: Hedgehog & PD-1 Inhibitors with Dr. Todd Schlesinger

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Treating Advanced Skin Cancer Without Surgery: Hedgehog & PD-1 Inhibitors with Dr. Todd Schlesinger · The Science of Skin

• 0:08
  SPEAKER_00: Hello and welcome to the Science of Skin Podcast.
• 0:10
  SPEAKER_00: My name is Dr.
• 0:11
  SPEAKER_00: Ted Lane.
• 0:12
  SPEAKER_00: I am a board-certified dermatologist practicing in Austin, Texas.
• 0:15
  SPEAKER_00: And with me today is a really great friend of mine and a wonderful dermatologist, a leader in our field, a global dermatology expert, Dr.
• 0:24
  SPEAKER_00: Todd Schlesinger.
• 0:26
  SPEAKER_00: Dr.
• 0:26
  SPEAKER_00: Schlesinger is the medical director of the Clinical Research Center of the Carolinas.
• 0:32
  SPEAKER_00: He is a clinical assistant professor of dermatology at the George Washington University School of Medicine and Health Sciences.
• 0:39
  SPEAKER_00: He's also either an assistant professor or a clinical instructor at multiple other colleges of medicines, including University of Buffalo, Department of Dermatology, Medical University of South Carolina, and Edward Via College of Osteopathic Medicine.
• 0:54
  SPEAKER_00: Dr.
• 0:54
  SPEAKER_00: Schlesinger, I don't know how you have time to do all that, but it's so great to have you on the program.
• 1:00
  SPEAKER_00: Thanks for coming on.
• 1:02
  SPEAKER_01: Thanks, uh, Dr.
• 1:03
  SPEAKER_01: Waynes.
• 1:04
  SPEAKER_01: Happy to be here.
• 1:04
  SPEAKER_01: Uh speaking from the mouths of babes, uh talk about a world expert here at uh interpretology.
• 1:10
  SPEAKER_01: Uh so I'm very excited to be here with you.
• 1:12
  SPEAKER_01: And uh this is my first time being on uh the Science of Skin uh podcast.
• 1:16
  SPEAKER_01: So this is great.
• 1:17
  SPEAKER_00: Yes, we're we're super excited to have you.
• 1:20
  SPEAKER_00: And of course, Todd is also on the the uh board of advisors for the American Academy of Dermatology.
• 1:25
  SPEAKER_00: Uh so if you've heard his name, he was uh you you host of the dialogues of dermatology.
• 1:30
  SPEAKER_00: I mean, Todd has done so much in dermatology that if you haven't heard his name, uh you've probably had your head in a hole somewhere.
• 1:36
  SPEAKER_01: So Board of Directors is yeah, board of directors, the the Academy Board, yes.
• 1:40
  SPEAKER_01: Board of Directors.
• 1:41
  SPEAKER_01: That's okay.
• 1:41
  SPEAKER_01: No, that's that's uh yeah, so that would have better correct before I hear from the uh the powers that be.
• 1:47
  SPEAKER_00: I don't want that to happen.
• 1:49
  SPEAKER_00: All right, but one of the one of the topics that Dr.
• 1:51
  SPEAKER_00: Schlesinger speaks on internationally is uh treatment for non-melanoma skin cancer.
• 1:56
  SPEAKER_00: Of course, Todd, you're you're a Mo surgeon, um, which we rarely ever talk about, but you are a Moe surgeon trained at Cleveland Clinic, right?
• 2:04
  SPEAKER_01: Yes, yes.
• 2:05
  SPEAKER_01: And to be totally honest, I I did MOS for about 22 years, and actually I kind of gave that up by saying gave it up for Lent one year.
• 2:11
  SPEAKER_01: But uh during the COVID time, right before COVID, my hired another MOS surgeon in my practice, and I really turned over the visority of the practice to her after doing that for many, many years, uh, only because my travel schedule didn't support uh the clinic time it required.
• 2:25
  SPEAKER_01: So I wanted to make sure my patients were taken care of.
• 2:27
  SPEAKER_01: So I sort of put that aside in my practice, and it's gotten replaced with a lot of other things that I do.
• 2:32
  SPEAKER_01: So but again, the experience that I have doing mo surgery for uh 22 years is uh is invaluable and I continue to do a lot of work in skin cancer and surgery every day.
• 2:41
  SPEAKER_01: So absolutely.
• 2:44
  SPEAKER_00: Well, I thought we would focus on one of these areas of expertise that you have, which is the treatment of non-melanoma skin cancer using uh hedgehog inhibitors and PD1 inhibitors, PDL1 inhibitors as well.
• 2:56
  SPEAKER_00: And so maybe, Todd, if you don't mind, we could jump first into the hedgehog inhibitors, the vismodogib and sonetogib, and and we could just kind of talk about what hedgehog inhibitors do, like what they target and when they're indicated, because I think most of us don't see humongous basal cells every day.
• 3:15
  SPEAKER_00: But um, the more and more that we know about these drugs and and the safety comes out and the clinical use is um, you know, we have more clinical use, I think we're gonna feel more comfortable to pull the trigger on using them.
• 3:27
  SPEAKER_00: So you you have been a leader and innovator in this field for a long time.
• 3:31
  SPEAKER_00: So maybe you could just walk us through that.
• 3:34
  SPEAKER_01: Yeah, so a great question.
• 3:35
  SPEAKER_01: Yeah, so this these uh these uh molecules you mentioned, visbonojub, synodogib, work on an embryonic pathway that's normally quiescent in uh basal cell carcinoma.
• 3:45
  SPEAKER_01: Most basal cell carcinomas have mutations in some part of this pathway, not all.
• 3:50
  SPEAKER_01: Uh it's a basically a system of a transmembrane pathway called patched.
• 3:55
  SPEAKER_01: Uh there's also a uh a protein called smoothened, and through this pathway you get communication into the nucleus.
• 4:01
  SPEAKER_01: And so, again, normally it's quiescent, it's an embryonic pathway that normally stays quiet in the adult somatic uh situation.
• 4:08
  SPEAKER_01: And when mutations occur along this pathway, you get overactivation of gene transcription through what's called the GLI-1 pathway.
• 4:14
  SPEAKER_01: Uh and mutations can occur in different places along this pathway, typically in smoothing, sometimes it's patched, sometimes they can be suppressor mutations where uh you see a suppression uh of a gene that's supposed to be active, or it could be an activated mutation and a gene supposed to be suppressed uh in there.
• 4:30
  SPEAKER_01: So you could either have an overactivation of the GLE-1 pathway, which increases transcription in the nucleus.
• 4:36
  SPEAKER_01: And what happens there is if that pathway is uh active when it shouldn't be active, then you've got uh a cell that gets out of control.
• 4:43
  SPEAKER_01: It differentiates uh quickly, divides too quickly, uh becomes unable to sort of control itself.
• 4:50
  SPEAKER_01: As we know, basal cell carcinomas originate uh in the basal layer of the epidermis, probably in the interfoliar cells where they're coming from.
• 4:57
  SPEAKER_01: Uh and the basal cells, they really don't have those uh intercellular connections that keratinocytes do when they become keratinocytes.
• 5:05
  SPEAKER_01: So basal cells tend to be juicy, ulcerated, soft tumors that, as we know, uh you know, can can form what we classically know as the road noser.
• 5:15
  SPEAKER_01: When they get larger, uh they kind of have an eatenway appearance and then get can get very large.
• 5:19
  SPEAKER_01: And I think most people don't think about basal cell carcinoma as being that kind of dangerous tumor where it can get locally invasive and or metastatic even.
• 5:27
  SPEAKER_01: Uh that can happen.
• 5:28
  SPEAKER_01: So, you know, just think about that uh uh uh patched uh pathway.
• 5:32
  SPEAKER_01: We call it the hedgehog pathway, uh, which is what the whole sort of pathway these are hedgehog pathway inhibitors or uh hedgehog inhibitors or HHI is how they're commonly referred to.
• 5:41
  SPEAKER_01: And of course, we have got two of these that work very similarly uh on that pathway, but have important differences.
• 5:48
  SPEAKER_00: Yeah.
• 5:48
  SPEAKER_00: Okay, so let's let's dive into the differences uh between the two.
• 5:52
  SPEAKER_00: So Areveg and Odomzo, Areveg, of course, being Vismodojib, Odonzo being Sunidogib.
• 5:59
  SPEAKER_00: Um my understanding, Todd, correct me if I'm wrong, but so Odomzo is is the latest one for us to to to have available in our inventarium.
• 6:08
  SPEAKER_00: Areveg was the first, is that right?
• 6:09
  SPEAKER_01: That's true.
• 6:10
  SPEAKER_01: Yeah, Aroveg.
• 6:11
  SPEAKER_01: I can't remember the date it was uh first approved, but it's been a good while.
• 6:14
  SPEAKER_01: We've had that for over probably over 10 years, maybe longer now.
• 6:17
  SPEAKER_01: Okay.
• 6:17
  SPEAKER_01: And then Sundajeb was uh I can't remember when it was approved.
• 6:21
  SPEAKER_01: This is 2026.
• 6:22
  SPEAKER_01: I think it came around maybe the end of end of uh before the decade turned over around that time, if I can remember.
• 6:28
  SPEAKER_00: So they've been out for a while for sure.
• 6:30
  SPEAKER_00: For a while.
• 6:30
  SPEAKER_01: They both have been around for a while.
• 6:32
  SPEAKER_01: And I think the key differences are uh, you know, when I think clinically the number one people thing people are going to think about is efficacy and and safety, right?
• 6:41
  SPEAKER_01: Uh but but that's uh under underlined but a few things to think about about the two medications themselves.
• 6:47
  SPEAKER_01: So I think the most important difference, I think, with these two medications is what we call the volume distribution.
• 6:52
  SPEAKER_01: And the volume of distribution has a lot to do with how how the drug is distributed in the body.
• 6:58
  SPEAKER_01: So if you think about the volume of distribution of vismodygeb being between 16 and 18 liters, and the this the volume of distribution for sumidog being 9,000 liters, approximately just around 9,000 liters, uh, it's a much more lipophilic molecule.
• 7:12
  SPEAKER_01: So, you know, if you think about that, it it you know, from what we can you know understand just theoretically, it probably gets into far more areas of the body than uh a drug with a smaller volume of distribution.
• 7:24
  SPEAKER_01: And then the way I talk about that to compare the two is that the volume of distribution of human blood or plasma is around 15 to 18 liters.
• 7:32
  SPEAKER_01: So that's sort of you know what you're thinking about.
• 7:34
  SPEAKER_01: So if you think about something with an under 20 or under 40, it's probably staying mostly in the plasma, maybe a little bit outside, but a volume distribution of 9,000 is probably going everywhere in the body.
• 7:45
  SPEAKER_01: And of course, our uh skin is made up of lipids, as we know how much lipid there is.
• 7:49
  SPEAKER_01: So we're hoping that uh sanit uh as a medication, but that volume distribution is getting into those lipids.
• 7:56
  SPEAKER_01: But again, these are all theoretical uh differences that we see.
• 7:59
  SPEAKER_01: Uh and um so we talk about these a lot, but really, you know, we we know the difference is the volume distribution is there, but we don't really know how to directly connect that to the epicine safety of the medications.
• 8:09
  SPEAKER_01: We just think about it.
• 8:10
  SPEAKER_00: And and when you compare the two, Todd, I know there's no head-to-heads, but when you look at the the complete and partial clearance data between the two, I believe that Odomzo is it looks a little bit superior to uh Arab edge just from their separate trials.
• 8:24
  SPEAKER_01: Yeah, it's relatively similar.
• 8:26
  SPEAKER_01: And again, you're totally right.
• 8:27
  SPEAKER_01: You know, we don't have head-to-head studies to compare the two.
• 8:29
  SPEAKER_01: I would say in the clinical practice, they probably both work what I would call better than advertised.
• 8:34
  SPEAKER_01: You know, I've heard this term before.
• 8:35
  SPEAKER_01: Scott Deinhard loves to use that term as well, good friend of mine.
• 8:38
  SPEAKER_01: Uh basically better than advertised.
• 8:40
  SPEAKER_01: So when you put these drugs to practice in the clinic, you look at the numbers that you see in the labels and you, you know, they're kind of low, right?
• 8:47
  SPEAKER_01: You know, 6% complete complaints rate, you know, 20, 30%, you know, response, you know, complete response rate, which means complete absence of tumor on biopsy.
• 8:55
  SPEAKER_01: Um uh but they both they most of your patients probably will respond if you can keep on the drugs long enough.
• 9:01
  SPEAKER_01: The two trials were done very differently with different outcome measures.
• 9:04
  SPEAKER_01: Uh the the we could talk about that more detail, but there's significant differences in how the data was reported between the two medications, which can make it very hard for uh clinicians to compare the two drugs directly, even if you're in your mind would like to compare the outcome measures of the two, it's hard to because they were both measured differently.
• 9:23
  SPEAKER_00: Okay, we should definitely talk about that.
• 9:24
  SPEAKER_00: But Todd, I wanted to back up a little bit and talk about what these are indicated for.
• 9:28
  SPEAKER_00: So, so vismodogib, metastatic, or locally advanced basal cells, sonitogib, only locally advanced basal cell.
• 9:35
  SPEAKER_00: Of course, we know that metastatic basal cell is very, very rare.
• 9:38
  SPEAKER_00: But in your mind, Todd, what does locally advanced basal cell mean?
• 9:43
  SPEAKER_01: That is an existential question.
• 9:44
  SPEAKER_01: It the locally advanced term is a construct of pharma.
• 9:49
  SPEAKER_01: Basically, these drugs have been the the sun is not the original uh marketer of this uh medication, not the original developer of this medication.
• 9:55
  SPEAKER_01: So I think when it first kind of came around, people were looking for something to say to define what a you know sort of more advanced basal cell carcinoma is, and we still don't have a clear definition.
• 10:08
  SPEAKER_01: So when I think of locally advanced, I think of a tumor that is not amenable to surgery andor radiation, but mainly surgery in such that the procedure itself would carry a risk of morbidity to the patient that might not be acceptable, right?
• 10:25
  SPEAKER_01: So um, you know, you talk to a surgeon and it can cut, they'll cut anything off, right?
• 10:29
  SPEAKER_01: They'll cut our heads off if they if they have to, right?
• 10:31
  SPEAKER_01: Yeah.
• 10:31
  SPEAKER_01: But the bottom line is, is that what we really want?
• 10:34
  SPEAKER_01: The adverse of the you know, adverse effects of cutting your head off can be appropriate.
• 10:37
  SPEAKER_01: So um, so when you think of a tumor that is not something, you know, that you say, hey, maybe we shouldn't be cutting on this right away, that's when I think of locally advanced.
• 10:46
  SPEAKER_01: So you can define that further into a large tumor.
• 10:49
  SPEAKER_01: It can be defined as tumor with high risk factors, so uh such as perineural invasion, invasion deeper structures, bone, cartilage, muscle, things like that.
• 10:59
  SPEAKER_01: When basal cells get big, they can pretty much invade it.
• 11:01
  SPEAKER_01: Anything, it's just, you know, usually it's local.
• 11:04
  SPEAKER_01: Like you said, metastatic is rare, but locally advanced, it can base, you know, eat into any tissue it really wants to.
• 11:10
  SPEAKER_01: So that's what I think about there.
• 11:12
  SPEAKER_01: Uh, and I also think about one other category, and that's multiple tumors.
• 11:16
  SPEAKER_01: So you think about patients that walk in on a Monday morning, have got seven, eight, nine, twenty, thirty bisosol carcinomas of different sizes, or maybe they're clustered in an area that makes it.
• 11:27
  SPEAKER_01: I don't think we're gonna we're gonna spend the next five years cutting on this person, right?
• 11:31
  SPEAKER_01: It's another category to think of is multiple tumors.
• 11:35
  SPEAKER_00: Okay.
• 11:35
  SPEAKER_00: Okay, great.
• 11:36
  SPEAKER_00: Thank you.
• 11:36
  SPEAKER_00: And these are I I don't know that we've mentioned it, but these are both oral drugs, right?
• 11:40
  SPEAKER_00: These are pills that you take.
• 11:41
  SPEAKER_00: These aren't infusions much like the PD ones are infusions.
• 11:44
  SPEAKER_00: These are these are pills.
• 11:46
  SPEAKER_00: Uh, and they're they're supposed to be taken daily, but uh from what I understand, Todd, decreasing uh frequency of dosing and or taking breaks is pretty darn common because of the adverse events, which it means muscle cramping, it sounds like and lack of appetite or dyskeucia is are seem to be the top three.
• 12:06
  SPEAKER_01: Yeah, those are the most common things.
• 12:08
  SPEAKER_01: Muscle cramps, weight loss, dysgoosia, as you'd mentioned, loss of taste, uh fatigue is up there as well.
• 12:13
  SPEAKER_01: Those four of the main ones that patients will probably suffer from.
• 12:17
  SPEAKER_01: Uh and you mentioned a very important thing, which is alternate day dosing.
• 12:20
  SPEAKER_01: So the uh Vismodyib was studied on a study called the Mikey study, which we participated in.
• 12:26
  SPEAKER_01: It was a phase two study that was probably in the 15, 16, 17 time frame, maybe a little earlier uh in the in the early 2000s.
• 12:32
  SPEAKER_01: Uh and that study was designed to look at just at that because people were uh were doing all kinds of different things with dosing.
• 12:41
  SPEAKER_01: We still do, right?
• 12:42
  SPEAKER_01: The whole point is uh, you know, can we make the can we keep the patient on the medication?
• 12:47
  SPEAKER_01: Because we know these drugs take several months to work.
• 12:49
  SPEAKER_01: Fortunately, the beneficial effects, the efficacy usually precedes the development of adverse events.
• 12:55
  SPEAKER_01: So, you know, you know, if you could get people on the medication and keep them on long enough to start seeing a benefit for their tumor, maybe they'll tolerate the adverse event more than they would like if they weren't getting a response.
• 13:05
  SPEAKER_01: So out of that developed the Mikey study, which was looked at two different dosing regimens of motogem.
• 13:11
  SPEAKER_01: The whole point was to determine whether like an eight or a 12-week break uh between dosing would, and I can't remember the exact categories, but they had two arms and one had a shorter break, one had a longer break, and they they ended up coming out relatively similar.
• 13:24
  SPEAKER_01: The efficacy wasn't that much different if you gave the patients break.
• 13:28
  SPEAKER_01: So if they maybe went on for eight weeks and then took a four-week break, or they went on for 12 weeks and took a four-week break, they were pretty close.
• 13:34
  SPEAKER_01: Like I don't think even statistically significant, but the adverse events got worked better.
• 13:38
  SPEAKER_01: So that's one thing that they came out of that.
• 13:40
  SPEAKER_01: And there's another study called the the the Stevie study.
• 13:44
  SPEAKER_01: The Stevie study was a global large safety study for Vismota jub, and that was a kind of concurring or around the same time.
• 13:51
  SPEAKER_01: And the Stevie study was all about adverse events.
• 13:53
  SPEAKER_01: So what it told us is that if you've got um adverse events early on with these medications, if you were able to stay on it, they would fade.
• 14:00
  SPEAKER_01: So sometimes hair loss would get better over time.
• 14:03
  SPEAKER_01: So the those were important studies for us to understand what the short and long-term safety profiles are for these medications, so we can really the goal would be to keep our patients on long enough, either get that complete response or a good partial response, or that we could maybe turn the patient from a non-surgical into a surgical candidate.
• 14:23
  SPEAKER_00: I was doing a little bit of research for today's episode, and I there was a couple of papers that that sh were talking about strategies to to help prevent the adverse events, particularly particularly the muscle spasms.
• 14:34
  SPEAKER_00: And one was talking about taking calcium and coQ10.
• 14:38
  SPEAKER_00: Um, and I know Todd, you you have talked about um, you've told me about some other strategies as well to help limit that.
• 14:45
  SPEAKER_00: So I think we benefit from the the long time that these have been available for use and and many people kind of figuring out ways to help limit the muscle spasms in particular.
• 14:56
  SPEAKER_01: Yeah.
• 14:56
  SPEAKER_01: So if you look at it, basically what you're kind of doing with these drugs is the you think about this pathway.
• 15:03
  SPEAKER_01: That's I think a good way to think about clinically, is this pathway is present all over the body, right?
• 15:07
  SPEAKER_01: It's not just in basal cells, it's in the follicular stem cells of the hair follicles, it's in the GI system, it's in the tongue, it's in other parts of the body.
• 15:15
  SPEAKER_01: So when you attack this sort of this pathway and slow it down, you're also affecting other parts of the body.
• 15:20
  SPEAKER_01: So uh that's why you end up with those adverse events that affect the GI system and muscle cramp.
• 15:24
  SPEAKER_01: So you're kind of destabilizing mitochondria in the muscle, you know, with muscle cramps.
• 15:29
  SPEAKER_01: So that's really, really a you know, a mitochondrial destabilization.
• 15:33
  SPEAKER_01: And so one thing that came out of that is hey, what can we do nutritionally to support the muscle mitochondria so you don't get those cramps that you would normally get?
• 15:41
  SPEAKER_01: And this can also happen, like you know, we both work out, right?
• 15:44
  SPEAKER_01: So we know about anaerobic and aerobic uh, you know, musc muscle.
• 15:47
  SPEAKER_01: When do you get when do you get muscle cramps from lifting weights too much, right?
• 15:50
  SPEAKER_01: It's from anaerobic metabolism of the muscle.
• 15:52
  SPEAKER_01: So that's similar.
• 15:53
  SPEAKER_01: You start to turn from uh you know burning oxygen to burning uh anaerobically, and that's also it's a it's it can be give you bursts of speed, but it's also extremely inefficient as a mechan as a mechanism of burning energy.
• 16:05
  SPEAKER_01: So you end up with those cramps and the lactic acid build up and you get the muscle cramp.
• 16:09
  SPEAKER_01: So so the the out of that came alcarnitine, which was studied in small study, showed that it could help reduce the risk of adverse events for uh both drugs, really, and it's actually become quite popular when it's come into clinical practice.
• 16:23
  SPEAKER_01: So I routinely recommend patients take, if they can tolerate they don't have carbonidities, uh, to take L-carnitine.
• 16:29
  SPEAKER_01: I usually start them on in advance.
• 16:30
  SPEAKER_01: I think it's one thing we talked about.
• 16:32
  SPEAKER_01: Two to four weeks in advance, I'll recommend about 1,500 to 2,000 milligrams of liquid L-carnitine.
• 16:37
  SPEAKER_01: It's available on Amazon, so it's quite widely available, inexpensive supplement.
• 16:41
  SPEAKER_01: That's one thing I do, and I think that's really made a difference in the muscle cramp uh reduction for my patients and be able to keep them on medications.
• 16:48
  SPEAKER_01: It's almost one of the first things they start to get is muscle cramps after a couple months, usually they start to it starts to kick in.
• 16:55
  SPEAKER_01: So that's really helped a lot.
• 16:57
  SPEAKER_01: So, you know, one thing we can do is L-carnitine.
• 17:00
  SPEAKER_00: Okay, okay, great.
• 17:01
  SPEAKER_00: Well, if uh you know, thank you so much for that, Todd.
• 17:04
  SPEAKER_00: You're obviously such an expert.
• 17:05
  SPEAKER_00: You've got taken us through all the data, taken us through some tips on on how to to kind of combine the the both the air veg and and the DOMzo with supplements like L-carnitine to help reduce the adverse events.
• 17:18
  SPEAKER_00: Let's let's move on to the PD1 inhibitors and PDL1 inhibitors, which of course we're moving from the realm of basal cells to the realm of locally advanced and metastatic squamous cells.
• 17:28
  SPEAKER_00: Uh and and so PD1, program death one, it's a protein receptor on T cells.
• 17:35
  SPEAKER_00: And I think of that as like an immune checkpoint, right?
• 17:38
  SPEAKER_00: And if we if we affect it, if we turn it off, it essentially just allows cancer cells to evade the immune system because that that's that we need PD1 for the for the immune system to recognize cancer and others.
• 17:50
  SPEAKER_00: Is that how you think of it, Todd?
• 17:52
  SPEAKER_00: Am I am I too basic?
• 17:54
  SPEAKER_01: No, that's totally a great way to think about it.
• 17:56
  SPEAKER_01: You know, that my best analogy, and I I made this one up years ago, is the Starship Enterprise cloaking, right?
• 18:03
  SPEAKER_01: So um, you know, cancer cells are tricky, right?
• 18:05
  SPEAKER_01: They have figured out a way to hide themselves as basically being sense of self.
• 18:11
  SPEAKER_01: So they express uh cell surface ligands that make uh cancer cells that make T cells think they're fine.
• 18:19
  SPEAKER_01: So this all comes from the tolerance mechanism that our body has when we're developing.
• 18:23
  SPEAKER_01: There's a gland called the thymus gland that your T cells run through and that teaches them what's good and what's bad.
• 18:29
  SPEAKER_01: If the cells don't know what's good and what's bad, you have autoimmune disease like lupus, right?
• 18:33
  SPEAKER_01: Same thing with cancer.
• 18:34
  SPEAKER_01: Uh you know, cancer cells figured out a way biologically to trick the immune system into thinking they were okay.
• 18:41
  SPEAKER_01: Not always, right?
• 18:42
  SPEAKER_01: We have different mechanisms.
• 18:43
  SPEAKER_01: Sometimes they start to get inflammation, right?
• 18:44
  SPEAKER_01: But they're tricked themselves, so they're cloaked.
• 18:47
  SPEAKER_01: So when that mechanism is working, the enterprise is cloaked.
• 18:51
  SPEAKER_00: Yeah.
• 18:52
  SPEAKER_01: You block that checkpoint, you suddenly reveal the enterprise and it can be attacked by the Borg.
• 18:57
  SPEAKER_01: So that's kind of what I think of the CD8 cytotoxic, C D8 positive T cells or the Borg.
• 19:02
  SPEAKER_01: They go in there, they attack the enterprise.
• 19:03
  SPEAKER_01: So that's how it works.
• 19:04
  SPEAKER_01: So it's sense of self-protection, block the checkpoint.
• 19:08
  SPEAKER_01: So they're going, hey, um, I'm gonna keep going or I'm gonna stop here and I'm gonna attack.
• 19:12
  SPEAKER_01: And that's basically what what you're seeing.
• 19:13
  SPEAKER_01: And so these receptors are on the surface of your T cells, PD1, and they interact with PDL1 and PDL2 receptors that are actually in the surface of the cancer cells.
• 19:22
  SPEAKER_01: And that's the magnetism you're talking about.
• 19:24
  SPEAKER_00: Okay, right.
• 19:25
  SPEAKER_00: So PDL1, the ligand attaches to PD1 and that on T cells, and that decreases the proliferation of T cells, inhibits their killing ability, essentially switches off the immune response.
• 19:36
  SPEAKER_00: It's also it's interesting, PD1 also plays an important role in autoimmunity, right?
• 19:40
  SPEAKER_00: It prevents autoimmunity by suppressing overactive T cells.
• 19:43
  SPEAKER_00: So there's there's other opportunities for us to focus on PD1 aside from cancer, but we know that PD1 is upregulated in tumors and it's upregulated by UV exposure as well, right?
• 19:55
  SPEAKER_00: Through permitting.
• 19:57
  SPEAKER_01: It's all over the by T regs, this is extremely complicated.
• 20:00
  SPEAKER_00: Uh so I think we've gotten about as far as I'm able to go.
• 20:04
  SPEAKER_00: So let's move on to what these uh PD1 inhibitors are.
• 20:07
  SPEAKER_00: So we've got semiplomab or lipto, pembroligiumab, ketruda, and nevoliumab opdevo, and these are for uh uh squamous cell cancers.
• 20:18
  SPEAKER_00: Actually, semiplomab liptio is also for basal cells, right?
• 20:21
  SPEAKER_00: You can use those when those are are resistant to hedgehog inhibitors.
• 20:25
  SPEAKER_01: Yes, and it's approved, yeah, it's approved for both.
• 20:27
  SPEAKER_01: Uh locally advanced metastatic on both sides.
• 20:30
  SPEAKER_01: And it's still that same, it's it's a very similar sort of indication statement.
• 20:34
  SPEAKER_01: It's uh not amenable to cure surgery, curtier radiation.
• 20:38
  SPEAKER_01: So, and that leaves the judgment to the clinician of what that might be.
• 20:42
  SPEAKER_00: Yeah.
• 20:43
  SPEAKER_01: So they're basically designed for uh primary therapy when you know surgery's not an option or radiation's not an option.
• 20:49
  SPEAKER_00: I can understand derms prescribing the hedgehog inhibitors, oral drugs, we can deal with those AEs, but for these PD ones, Todd, are you prescribing these yourself or are you kind of doing this in partnership with an oncologist?
• 21:01
  SPEAKER_01: So the the I I when I did the studies, we infused.
• 21:05
  SPEAKER_01: So we did infuse in our clinic, and I have an infusion nurse and IV setup, and we did all of it ourselves, and we manage every side effect you can possibly think of with these medications, right?
• 21:13
  SPEAKER_01: So I think it's not something that derms can't do.
• 21:16
  SPEAKER_01: I think derms can, and some derms do do it.
• 21:19
  SPEAKER_01: I think the main barrier here is more logistics.
• 21:21
  SPEAKER_01: So, and of course, you you know, not every derm is going to be comfortable managing uh uh the adverse events that come from uh uh checkpoint inhibitors, right?
• 21:29
  SPEAKER_01: Uh immunoncology drugs.
• 21:32
  SPEAKER_01: And these are not medications you use in isolation.
• 21:34
  SPEAKER_01: They are there you do this as a team, a multidisciplinary team involving many different players.
• 21:40
  SPEAKER_01: So so but that doesn't mean the Durham can't be the captain of the care team in this case in monitoring this.
• 21:45
  SPEAKER_01: The thing is the infusion setup requires uh certain things to be in the office, you know, you need a setup, infusion hood, all these different things to do the infusion.
• 21:53
  SPEAKER_01: That's more of a logistical headache.
• 21:55
  SPEAKER_01: It's a buy and bill headache, and it could also be, you know, a volume.
• 21:59
  SPEAKER_01: Are you doing enough?
• 22:00
  SPEAKER_01: Infusions to make it worthwhile.
• 22:01
  SPEAKER_01: If Durham that's doing infusions probably should be doing multiple types of different things in their clinic and maybe be an infusion center, center of excellence.
• 22:08
  SPEAKER_01: Is every dorm going to do it?
• 22:09
  SPEAKER_01: Absolutely not.
• 22:10
  SPEAKER_01: Or most?
• 22:11
  SPEAKER_01: No.
• 22:11
  SPEAKER_01: Maybe a few.
• 22:13
  SPEAKER_00: Okay.
• 22:14
  SPEAKER_00: So most DRMs then we see a locally advanced scrama cell.
• 22:18
  SPEAKER_00: We think, oh boy, you know, worried about this one.
• 22:21
  SPEAKER_00: Looks like there might be metastasis.
• 22:22
  SPEAKER_00: And or it's so locally advanced, I don't think that the most surgeon would touch this, and they'll probably send for imaging and probably get the oncologist involved anyway.
• 22:30
  SPEAKER_00: Now we understand, you know, derms may not be prescribing these drugs, but certainly we need to be aware of these drugs.
• 22:36
  SPEAKER_00: And uh now hopefully everyone understands how these PD1 inhibitors work and what the target is.
• 22:42
  SPEAKER_00: Uh and again, PD1 is upregulated on tumors and by UV exposure, which makes a lot of sense.
• 22:48
  SPEAKER_00: Um, Todd, uh thank you so much for that.
• 22:51
  SPEAKER_00: Uh I I think that there's a couple of drugs that are interesting in development that you and I have have spoken about previously.
• 22:58
  SPEAKER_00: You know, we especially for basal cell cancers where now we're not talking about locally advanced basal cells, but just run-of-the-mill nodular superficial basal cells that we see a million times a day.
• 23:08
  SPEAKER_00: And we've got these startup companies that are focusing on intralesional therapies for especially nodular basal cells, which I think is, I think we both agree it's sorely needed, right?
• 23:17
  SPEAKER_00: We we surgirize these way too much, especially for red relatively indolent cancers.
• 23:22
  SPEAKER_00: And if there are a way for us to eradicate them without leaving a scar or making it easier on the patient, I'm I'm all for it.
• 23:29
  SPEAKER_00: Uh one of these is Verica.
• 23:31
  SPEAKER_00: Um they're they're moving into their phase three um with their intralesional therapy.
• 23:36
  SPEAKER_00: And I'm Todd, you did the phase two, right?
• 23:39
  SPEAKER_01: Uh, you know what?
• 23:39
  SPEAKER_01: I didn't do the phase two.
• 23:41
  SPEAKER_01: I looked at it very carefully.
• 23:42
  SPEAKER_01: I worked with Verica a lot, but I did do the phase two only because my site is um small and the requirements for that study were just more than I was excited about it.
• 23:51
  SPEAKER_01: But the the the you know, as you know, the that there was intensive monitoring requirements that were maybe not part of the phase three that were part of phase two, that my staff were like, okay, you know, we got to monitor the blood pressure, you know, every hour or whatever.
• 24:02
  SPEAKER_01: There's some things that we so we didn't do it, but I followed it very closely.
• 24:05
  SPEAKER_00: Yeah.
• 24:05
  SPEAKER_00: So so we were we were part of the phase two program and very interesting uh results.
• 24:11
  SPEAKER_00: I think our results showed what phase two showed.
• 24:13
  SPEAKER_00: I think we we mirrored it on my site what the overall results were, which were positive.
• 24:17
  SPEAKER_00: Certainly I'm excited and enthusiastic for the stroke to move into phase three and and looking forward to to seeing this at a greater patient population.
• 24:26
  SPEAKER_00: Um, but just super excited about the idea of using this on you know both the trunk and the face, not very close to the eyes or anything like that.
• 24:34
  SPEAKER_00: But um huge opportunity there.
• 24:36
  SPEAKER_00: And then there's another one highlight, right, which is uh probably earlier stage at this point, but also an intralional uh therapy for for basal cells.
• 24:46
  SPEAKER_00: And so there are lots of work going on uh now to to help us with these, as I mentioned, kind of indolent, annoying skin cancers that probably won't kill you, but we got to get rid of them, otherwise they can turn into that that rodent ulcer uh appearance and and and lead to some comorbidities.
• 25:04
  SPEAKER_00: But uh besides those two, I think Iviva might be another one, Todd.
• 25:07
  SPEAKER_00: Is that right?
• 25:08
  SPEAKER_01: Yeah, IVA is another one.
• 25:10
  SPEAKER_01: There's also um uh there's also a couple of well, first I want to mention the basal cell red light PDT study came out in the fall.
• 25:17
  SPEAKER_01: So that's a big one.
• 25:18
  SPEAKER_01: Just be aware of superficial basal cells, probably headed toward approval.
• 25:21
  SPEAKER_01: Um, and then you've got it's at the FDE now, uh, and then you've got uh the Feldan and FIO.
• 25:28
  SPEAKER_01: So PHIO and Feldan.
• 25:30
  SPEAKER_01: Those are other two companies.
• 25:31
  SPEAKER_01: One's uh a shuttle, basically just a way to shuttle proteins into the cells is one interesting thing.
• 25:37
  SPEAKER_01: And so um I think there's there's a ton of even things you haven't mentioned yet that are coming, uh, not only delivery systems, but new molecules.
• 25:46
  SPEAKER_01: So yeah, I think the America drug is very exciting on colidoprotein.
• 25:49
  SPEAKER_01: Hopefully, it's gonna be very specific to these tumors.
• 25:52
  SPEAKER_01: I think the big picture about all these new medications is gonna be where they're gonna fit.
• 25:56
  SPEAKER_01: So, are these gonna be neoadu therapies given before surgery?
• 26:00
  SPEAKER_01: Are they gonna be primary given instead of surgery?
• 26:03
  SPEAKER_01: Are they gonna be, you know, perioperative before and after, or adjuvant after?
• 26:06
  SPEAKER_01: So um, I think there's important things to do to talk about there.
• 26:09
  SPEAKER_01: And also in PD1, there's a PDL1 pathway, the other side of the world as well, when you're on the tumor cell.
• 26:14
  SPEAKER_01: So it's just I would say that I agree with you 100% that this field is exploding right now.
• 26:19
  SPEAKER_01: There's so much uh going on that's sometimes hard to keep up with.
• 26:22
  SPEAKER_00: Yeah.
• 26:23
  SPEAKER_00: Yeah.
• 26:23
  SPEAKER_00: I mean, you can imagine if we could do neo adjuvant to shrink the tumor enough to even be a minimal to like a punch removal or something like that, like make it so small to make it just super easy in the in the office.
• 26:34
  SPEAKER_00: I think that's where we will be in in the next, hopefully, certainly five years, and and by 10 years, we'll probably have multiple competitors out there.
• 26:43
  SPEAKER_01: The big clinical thing, Teddies, to think about is is how what the efficacy is.
• 26:47
  SPEAKER_01: So there's an efficacy range that you think about, I think, for neoadjuvant and an efficacy range you think about for primary therapy.
• 26:53
  SPEAKER_01: And I think those are very different.
• 26:55
  SPEAKER_01: So if a drug has a 30, 40, 50 percent efficacy complete response rate, that's probably neoadjuvant.
• 27:01
  SPEAKER_01: If you get higher, you know, when we look at PDT for AK and then PDT for basal, it's in the 60s and combined clinical response rate for path and uh and clinicals in the 60% range.
• 27:12
  SPEAKER_01: It's getting there, but really I think we need to be up in the 80s to 90, 95% to really be able to call these primary therapies.
• 27:20
  SPEAKER_01: Because remember, these patients don't want to come back in 10 years and have that basal cell coming back.
• 27:24
  SPEAKER_01: You know, we don't want to be in the E D and C range, we want to be higher.
• 27:28
  SPEAKER_01: So we got to have lofty goals, we got to aim high for this stuff.
• 27:31
  SPEAKER_00: No, you but Todd, thank you for bringing that up.
• 27:33
  SPEAKER_00: It's a great point in that, you know, we're we're definitely pushing the edge of science right now, but complete response rates in the 50 to 60 percent, you know, composite where we the clinical appearance as well as the histopathologic verification are the same.
• 27:47
  SPEAKER_00: Um, it's difficult, it's difficult in any trial.
• 27:50
  SPEAKER_00: Anytime you have a composite endpoint, no matter what you're talking about, it's the most difficult to do.
• 27:54
  SPEAKER_00: And we need that for a basal cell in particular.
• 27:57
  SPEAKER_00: Um, and and like you said, I think derms would probably only be comfortable with this as a primary therapeutic option if if we're looking at 80, 90 plus percent.
• 28:05
  SPEAKER_00: So thank you.
• 28:07
  SPEAKER_00: Great point.
• 28:07
  SPEAKER_00: Um, otherwise, neoadjuvant, though, is is worth it.
• 28:11
  SPEAKER_00: You know, it could be something that that especially for highly cosmetic areas, for example, um, this could play a huge role.
• 28:18
  SPEAKER_01: So not not to say, it's probably the way we're most of us are doing it.
• 28:23
  SPEAKER_01: So I want to get that point out there because you made basically that's a very important point you brought up on neoadjuvant.
• 28:28
  SPEAKER_01: It's probably the way most of these drugs are being prescribed now, and it's the current feature, which means it's the now before we have the data, because none of them are approved for neoadjuvant, although it's coming.
• 28:38
  SPEAKER_01: But you know, adjuvant therapy was approved for cemental mab.
• 28:41
  SPEAKER_01: We've got the label change and update that in the fall, right?
• 28:44
  SPEAKER_01: But neoadjuvant, I would argue most of my cases that I'm giving uh uh hedge hypothetical inhibitors and even uh PD PD1, PDL1s is going to be neo-adjuvant, unless it's to the point where you don't have any other options and then it's primary.
• 28:58
  SPEAKER_00: Okay.
• 28:58
  SPEAKER_00: So just to define some terms, neoadjuvant meaning you you give it before you do a surgery, adjuvant is is usually after a procedure, for example.
• 29:06
  SPEAKER_01: Yeah, and perioperative is both.
• 29:08
  SPEAKER_00: Yeah.
• 29:09
  SPEAKER_01: And there's data, great data showing in even a melanoma world, because you mentioned volume app, it's really more melanoma drug.
• 29:17
  SPEAKER_01: But in reality, you know, there's fake data showing, hey, you know, the key thing is do we want to activate the immune system before surgery or do you want to do it after?
• 29:24
  SPEAKER_01: And I would argue, and I think a lot of people would argue, you want to activate the immune system and start killing off the tumor, get those CD8 cytotoxic uh T cells active before you excise, and that can help to reduce the risk of recurrence later.
• 29:39
  SPEAKER_00: Brilliant.
• 29:39
  SPEAKER_01: So if you take the two, if you take that out, if you remove the tumor with all its associated tumor infiltrating lymphocytes surrounding it, and then you try to go and raise immunotherapy around that, what do you got left, right?
• 29:50
  SPEAKER_01: So you want to activate the cells that are there and get them going, get the tumor shrunk down to us, and then remove it, and then maybe hit it again after to get the best outcome.
• 29:59
  SPEAKER_00: For those who are listening to the podcast and are not watching on YouTube, you are missing a great show behind Dr.
• 30:05
  SPEAKER_00: Schlesinger.
• 30:06
  SPEAKER_00: His dog, Grady, is is having the best nap in the world.
• 30:10
  SPEAKER_00: Um, I I think we all wish we would have to do that.
• 30:13
  SPEAKER_01: Anytime I'm talking, he's usually doing that.
• 30:16
  SPEAKER_00: Most people.
• 30:18
  SPEAKER_00: Uh Todd, thank you so much, man.
• 30:19
  SPEAKER_00: This has flown by.
• 30:20
  SPEAKER_00: I learned every time we talk about this, I learned something from you.
• 30:23
  SPEAKER_00: You truly are an expert, and we really appreciate it because we need derms who are experts in this field.
• 30:28
  SPEAKER_00: It's rapidly changing.
• 30:30
  SPEAKER_00: And I think I would just urge everybody to make sure, especially for the hedgehog inhibitors, you are aware of them.
• 30:37
  SPEAKER_00: You understand that you can prescribe them.
• 30:39
  SPEAKER_00: And I and I think Todd has helped me tremendously.
• 30:42
  SPEAKER_00: I I called the red line and he picked up when I had a patient uh and he helped me through it.
• 30:48
  SPEAKER_00: And uh please uh can consider prescribing these on your own because I think it can be done.
• 30:53
  SPEAKER_00: And then just knowing about PD1 is important and and you know, utilizing the relationship with your local oncologist and then keeping an eye on the pipeline, as I mentioned.
• 31:02
  SPEAKER_00: Um Todd is is very much involved in that uh because I think it's going to change the way we treat specifically superficial and nodular basal cell, which again is I believe it's huge for patients.
• 31:12
  SPEAKER_00: So uh, Dr.
• 31:13
  SPEAKER_00: Schlesinger, uh, this was great.
• 31:15
  SPEAKER_00: Thank you again so much.
• 31:16
  SPEAKER_00: Appreciate it.
• 31:17
  SPEAKER_01: Thank you as well.
• 31:18
  SPEAKER_00: Yeah.
• 31:19
  SPEAKER_00: So this is another episode of Science of Skin Podcast.
• 31:22
  SPEAKER_00: Thank you so much for listening.
• 31:23
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• 31:25
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• 31:29
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• 31:32
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• 31:35
  SPEAKER_00: Schlesinger.
• 31:36
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