The Patient From Hell Podcast (00:00.834)

Hi everyone, this is Samira Daswani, the host of the podcast, The Patient From Hell. I have a very special guest with us today. I have Dr. Milana Dolezal from Stanford University who's joining us. Hi, Dr. Dolezal.

Milana V Dolezal (00:15.099)

Hi! Thanks for having me.

The Patient From Hell Podcast (00:17.174)

Before we get started, can you give us a bit about yourself and how you ended up in oncology?

Milana V Dolezal (00:23.545)

Sure, long story. I'll try and be quick. So I knew when I was age eight that I wanted to be a doctor. I spent a lot of time in the hospital. I was a pretty bad asthmatic. So I didn't get to trick or treat or do any of that stuff because I had such bad allergies. But I really loved just that hospital environment, being a healer. When I got better, I would go help the nurses do stuff like have patients make phone calls and

do other stuff, so that was a bit of a home for me. And then I was fortunate. I grew up in Bethesda, Maryland, so outside of DC, and I was right by the NIH and so the National Institutes of Health. And so I in high school and in college actually worked there in the summers. And then I was able to do a work study program and get credit to do

research at the National Cancer Institute, so bench science. So this is back when, you know, now you could fill an entire side of a house with all the different cancer signaling pathways. But back then, you know, it was like one little poster, there was like the four or five different cancer signaling pathways we knew about back then. So I started my career in cancer actually as a teenager.

And then it really hit home for me because my grandmother who helped raise me, my father unfortunately died when I was young in an accident. And so my Eastern European Czech grandmother lived with us. And then she unfortunately got breast cancer. And then when I was in college, she succumbed to stage four metastatic breast cancer. And so that...

really became my calling in terms of like, this is what I'm going to do. I had a little side track at one point where I also have family in not only in Eastern Europe, but also in South America. And I got pretty fascinated with different kinds of parasites and tropical medicine. And so I spent some time in Africa, in Zimbabwe. I had a Fodor fellowship there,

Milana V Dolezal (02:42.933)

did some work on HIV education and other stuff. And then I was in Ecuador studying a parasite called neurocystic psychosis. But that didn't last that long. I realized that most of the stuff that you do in the US is pneumonia inpatient, then maybe HIV management back in the early 2000s and stuff. But anyway, that's how my career was cast.

The Patient From Hell Podcast (03:11.626)

I love that. Okay, my first question for you has nothing, well, maybe something to do with oncology, we'll see. My first question for you is if you had to take one, maybe two learnings from what you saw in Zimbabwe or in your time at Ecuador, what would it be?

Milana V Dolezal (03:26.925)

Hmm.

Milana V Dolezal (03:31.189)

So I think Africa was tough then on multiple levels. I think that there is still a lot of misconception around HIV, for example. It was a white man's disease and it wasn't real. And I think the hard thing for me as a young, wide-eyed, similar to you, bushy-tailed, 20-something-year-old at the time,

was this idea like medicine men, and this is horrible to say, they would say that you would get rid of HIV by sleeping with a virgin. And so we had young girls who actually were assaulted. So that part was really, really hard in terms of understanding kind of the culture.

So I think what we did do that was amazing though was the WHO came in and gave AZT back in the day to prevent vertical transmission of HIV. So I think that was a big win. I think, you know, the culture piece is difficult. So I think, you know, flexibility, open-mindedness, maybe in some ways it helped me understand that I can't save the world or

You know, there's parts of it that aren't savable, but we do the best we can. I think from the time in Ecuador, well, my takeaway is I don't eat pork. I don't eat pig because you get neurocysticercosis from pig. Yeah, there's an interesting transmission there in terms of there's a whole New England Journal of Medicine article around.

The Patient From Hell Podcast (05:03.234)

Woof woof woof!

Milana V Dolezal (05:14.367)

seizures in young kids in very orthodox Jewish communities in New York. And it turns out it was from undocumented child care providers that weren't washing their hands. And they were actually passing the cysts to kids who then were getting seizures.

The Patient From Hell Podcast (05:36.494)

Wow.

Milana V Dolezal (05:37.631)

Right? An epidemiology thing because Jewish people do not eat pork. So how the heck are the kids getting this kind of thing that comes from pork? So, yeah, intense stuff. So I can say at the end of the day, all that stuff is intense, but I can sort of sit back and reflect on it now. But amazing experiences, just amazing experiences across the board. I guess it also taught me that set your aim high and

try, you know, if you don't try, you're gonna be in the same place. You know, you're gonna get no's along the way, you'll get some doors closed, but you never know unless you try. So have courage and do something every day that scares you. I think Eleanor Roosevelt said that.

The Patient From Hell Podcast (06:27.278)

I love that. Okay. All right. My second question. If you think about metastatic breast cancer from the time when you sadly had your grandmother go through it and today. So one of the things I heard you say was back then you could only fill up. You only had a four or five known signaling pathways. And today that's not true anymore. So if you have to look at the last couple of decades, what's transpired?

Milana V Dolezal (06:28.727)

Okay.

Milana V Dolezal (06:56.121)

So I really think like the last five plus years has been really the most exciting time in my career. I think we've seen the most approvals in breast cancer. I think if you look back, I believe in oncology in general, I looked at this recently for a different talk I did, 2023, there was something like 43 new approvals in oncology by the FDA,

The Patient From Hell Podcast (06:56.942)

Thank

Milana V Dolezal (07:26.105)

and 17 were new, what are called NMEs, new molecular entities. So this is not chemotherapy X, chemotherapy Y we're talking about. We're talking about novel ways to signal and figure out how cancer grows for targeted therapies, things called bispecific antibodies, which I call like a hydra. It's like a two-headed hydra that comes in there and just attacks and eats. So super novel stuff, right?

So I think that's what I'm so excited about when I was at fellowship at UCLA, one of my mentors was Dennis Lehman who worked with Genentech, which is another place that I worked before on all the HER2 agents. And, you know, one thing he used to say that I sort of modified was I hope that chemotherapy becomes obsolete by the time I retire or die,

hopefully the retirement parts first, but at any rate, I think this has just been so exciting. When my grandmother was diagnosed, she probably had maybe a HER2 positive aggressive type of breast cancer. And we didn't have monoclonal antibodies back then that have really transformed how we treat breast cancer and other types of cancers.

And now we're going to talk today about sort of the smarter version of that, of antibody drug conjugates. So we have those, we have the two-headed hydras, we've got targeted pills based on cancer mutations. So I think it's just so exciting. We're really using precision medicine now and personalizing that to an individual patient's care.

The Patient From Hell Podcast (09:18.958)

Okay, I love it. All right. Can we talk about the smarter version of the monoclonal antibody? What do you mean by that? What is a monoclonal antibody and then what is a smarter version of it?

Milana V Dolezal (09:26.028)

Yeah, yeah.

Sure, sure, sure. So when you think about a cancer cell, so if you're talking specifically about breast cancer, there's sort of three receptors that we pay attention to. And I like to think of them like little antennas kind of on the outside of a cancer cell, right? And they're just out there, they're getting food, they're getting information, that kind of stuff. And so one is estrogen, the other is progesterone,

and the third is HER2. So those are some of the main ones that we pay attention to in terms of targeted therapies. Now there are other types of receptors. So receptor, what is a receptor? So again, it's an antenna kind of on the outside of the cell, but it is a protein. So it's sort of a protein on the outside of the cell. Whereas when you go inside the cell, then you have DNA and RNA, okay? So proteins on the outside of the cell.

So when you think about chemotherapy, chemotherapy just basically kills things that are more fast dividing. That's why you lose your hair. So cancer cells are fast dividing. Non-specific sort of goes everywhere. So what we call tumor agnostic, meaning it's not specific for a particular tumor. When you talk about a monoclonal antibody, so let's use the third receptor HER2.

So HER2 is about 20% of breast cancers, does tend to be more aggressive, meaning higher grade, something called grade three, three of three, tends to divide under the microscope faster. So you see these cells dividing, making babies, stuff like that. So these cancer cells have a HER2 antenna and Genentech in particular,

Milana V Dolezal (11:24.119)

developed different antibodies and what an antibody is, it's a molecule that you get intravenous, it's not chemo, although we'll talk about the better versions, and it goes directly to those HER2 expressing cancer cells that have that protein on the outside of the cell. And there's two of them out there, there's more than that, but two main ones we use clinically these days.

So one is called Herceptin Trastuzumab that comes and binds to sort of the trunk of this antenna. And so then it sort of shuts that cancer cell down. It can't really signal grow. And the other one is called Pertuzumab or Projeta. And that binds actually to the top of this antenna and in a different spot. And then those cancer cells can't what I call kiss.

So they can actually kiss without a ligand, meaning there's nothing that needs to bind here. And then that's how they grow and make babies. So these monoclonal antibodies that you get intravenously, often used in combination with chemo, basically go to those cells, stop them from dividing and growing. So they have a lot of other proposed mechanisms of actions about maybe some immune boosting and other stuff, you know, but that's...

That's kind of generally what we're talking about in terms of monoclonal antibodies. And so Herceptin, Trastum, Tuzumab, same thing, Progeta, Pertuzumab, those are some examples in breast cancer. Then we've got other things in other types of cancers as well. And then we can talk about the newer and better version if you want to segue. Okay.

The Patient From Hell Podcast (13:17.592)

Yes, please. go. Mm-hmm. Okay.

Milana V Dolezal (13:20.747)

So then the other idea as well, I mentioned chemotherapy just is non-specific for the most part. So how can we do better? So now we have what are called antibody drug conjugates. So you take that Herceptin, Trastuzumab antibody backbone, and now you link it to chemotherapy bolts, okay?

Alright, so there's three components. So you've got sort of a upside down Y as you're monoclonally in a body. So trastuzumab backbone. Now you can have different chemos. So you can have, that's your poison. Alright, so now you've got anywhere between three balls. So that's TDM1, Kedsila. Okay, linked onto this

The Patient From Hell Podcast (14:13.614)

Yep.

Milana V Dolezal (14:17.401)

Perceptin backbone with a different chemo something called Maitansine or you have more recent ones like in HER2 trastuzumab Daruxican that is linked to eight chemo balls and so there's a linker there. So it's like a little rubber band. That's basically hanging on to that chemo ball. Okay so now this Y antibody

with the chemo, antibody drug conjugate, ADC, is injected through a port or whatever. And now that combination, either a smart bomb we call it, or I call it a Trojan horse is the other thing. Your Trojan horse is gonna actually come to those expressing cancer cells, and this could be

HER2 positive, this could be HER2 low, which is a whole other conversation, comes to those cancer cells, it's gonna bind, and now guess what happens? So it goes inside only that specific cancer cell. Okay, and now the rubber bands, which are holding the chemo, there are different linkers, they can either be pH-based,

The Patient From Hell Podcast (15:29.262)

See.

Milana V Dolezal (15:42.147)

based on the inside pH of the cell that's just different than maybe regular normal cells. But different kinds of linkers, whatever kind of linker it is, once it's inside, it's internalized into the cancer cell. Those little rubber bands are gonna break loose and they're gonna release the chemotherapy directly into those cancer cells. So now those little...

you know four balls eight balls of chemotherapy are going to go kind of indirectly to those cancer cells and thus they're going to kill that cancer cell. So it's a way to target the chemotherapy directly to the cancer cells so you're not getting all the hair loss You're not getting all of the diarrhea side effects. Now these things do have side effects. So I'm not going to say they're side effect free,

but they're a lot sort of less than the free drug going throughout the body. It's really Trojan horse, train, bringing the chemo to those cancer cells. And then there's other aspects depending on what kind of antibody drug conjugate you're talking about. Some of these are what are called membrane permeable. So they can kind of leak out and go to some of the neighboring cancer cells and kill them as well.

Now, why that's relevant is sometimes I think of different cancers, especially, for instance, pancreatic cancer, which I wish we've done more strides with. But what the cancer can do is if you have a particular tumor, for example, it's kind of like Wakanda. OK, so you know Wakanda? No? OK. You're not a Marvel person. All right, well, imagine

The Patient From Hell Podcast (17:22.658)

No, what's that? It's really bad with pop culture.

Milana V Dolezal (17:32.425)

Imagine there's a huge shell around the tumor, okay? And then you've got these different types of cancer cells in a big ball. Well, so if you got a ball, you you only have so many receptors on the outside of the ball, right? So your monoclonal antibody is going to be able to penetrate the outside, but it can't maybe get as much down low or in here, right? But now your chemotherapy, if it's the...

The Patient From Hell Podcast (17:35.352)

Okay.

Milana V Dolezal (18:00.761)

chemotherapy balls, if they're membrane-permeable, they can go kind of diffuse down lower, down sideways to really kill all the neighboring cells that might have some of this expression of HER2. And that's why within HER2, Trastuzumab, Diruxetocan in particular, that's why we're seeing this effect in this HER2 low. So it doesn't have to be the most

brownest expression like three plus it can be light brown so i'm referring to how the staining when the pathologist looks under the microscope how brown are those cancer cells if they're very brown they're HER2 three plus they're expressing lots of these extra cells everywhere but you can have some that are two plus with smaller amounts okay

The Patient From Hell Podcast (18:47.808)

Thanks.

The Patient From Hell Podcast (18:57.73)

I have so many questions for you. All right, first question. Are there ADCs for triple negative breast cancer as well? How does that work?

Milana V Dolezal (18:59.362)

Okay.

Milana V Dolezal (19:06.125)

There are, there are. So let's talk. Sure, sure. So one particular one is called sassatuzumab or sassy. So that actually uses a different type of receptor. So there's something called Trope 2. And this is a receptor that is expressed on a lot of different breast cancer cells,

but it seems to be higher expressed on triple negative breast cancer cells. And so that trope two is the antenna. All right. So now you've got a trope two antibody that's going to come to that trope two receptor and similarly internalize little rubber bands, release the chemotherapy.

So that's what sassatuzumab is. So that is a trope two receptor monoclonal antibody with the antibody drug conjugates, also an eight chemo ball to one antibody. And there's a lot of these that are in development that have different sorts of compositions. So there's always going to be three parts of these antibody drug conjugates. There's going to be the antibody.

There's going to be the linker, the rubber band, and then there's going to be the poison, which is which type of chemo. So you can kind of mix and match those, right? And you're seeing a lot of that now. There's something called Dato, DXT, you know, a HER-3, all sorts of combinations. So mix and match the antibodies and the chemo XYZ.

The Patient From Hell Podcast (20:49.966)

Hmm.

I see. Sorry, dumb question. I'm to go all the way back to... I have so many. You have no idea. So breast cancer cell, we were talking about the three receptors, estrogen receptor, progesterone receptor, and HER2. It sounds like TRP2 is also a receptor.

Milana V Dolezal (20:56.577)

There's never a dumb question.

Milana V Dolezal (21:02.029)

Bye.

Milana V Dolezal (21:07.993)

Mm-hmm.

Milana V Dolezal (21:15.893)

It is, it is. Now it's not, let's be clear. I think what you're asking is, well, do we need to have a three plus trope two for those antibodies to work? And that's actually been looked at to see if these kind of antibody drug conjugates are more effective. bottom line is it doesn't really matter. You don't need to have higher levels of trope expression for this to work. And this sassatuzumab also works

in this hormone receptor positive population as well that's endocrine refractory. Okay so it's not only for triple negative it's also approved.

The Patient From Hell Podcast (21:57.43)

I see, but not for HER2?

Milana V Dolezal (22:01.369)

It's not a HER2 target, but you can use sassatuzamab and HER2 positive patients as well. But generally we use it a little later on. There's a lot of options in the HER2 positive space, but right now the approval for sassatuzamab is in triple negative per what was called the ASCENT trial and also in hormone receptor positive. But that was more of a...

The Patient From Hell Podcast (22:08.238)

Hi.

Milana V Dolezal (22:28.451)

third line trial, those patients were heavily pretreated. So then you get into complicated discussions around sequencing. So if a patient has, for instance, a hormone receptor, estrogen progesterone receptor positive breast cancer that has some of this HER2 low, and they've gone through all these anti-estrogen hormonal therapies,

or endocrine therapies as they're called in the metastatic setting. So we're really talking more stage four. And now the cancer has figured out how to bypass the estrogen progesterone suppression. And so then, does that make sense? Okay. So you go through, you go through a lot of different types of endocrine blockers, right?

The Patient From Hell Podcast (23:14.028)

Almost. What does that mean?

Milana V Dolezal (23:22.681)

So these endocrine therapies are blocking, so that could be aromatase inhibitors, so that class of drugs, what do those do? So basically they work by blocking estrogen a different way. So even if a patient is postmenopausal, they can still make estrogen, ovaries are not the main source. And so what can happen is there's

like cholesterol is a building block of kind of all hormones there's an enzyme that comes in called aromatase, aroma means ring in latin, throws a ring on this molecule and that's how you get estrogen okay these pills aromatase inhibitors stop that from happening so what those do is get rid of the food okay

The Patient From Hell Podcast (24:16.206)

Hmm.

Milana V Dolezal (24:16.931)

So those estrogen positive little antenna cancer cells are looking for the food. So if there's no estrogen around, they can't eat. But guess what they can do? Well, they can put a mutation in this receptor, like an ESR1 mutation, and then they can just signal without food. So that's a mechanism of resistance. Or they can just say, you know what?

The Patient From Hell Podcast (24:30.168)

Hello.

The Patient From Hell Podcast (24:40.718)

Okay, yeah.

Milana V Dolezal (24:45.411)

kind of sick of being estrogen positive. I don't want to wear that yellow hat anymore. And I'm going to internalize that receptor. And now they're really more like estrogen negative, like almost a triple negative, et cetera. So that's when you go through, you know, and you're really talking later line, like, you know, stage four cancers that seen a lot of therapy, they get so sneaky. They internalize receptors, they ping these

mutations both outside the cell and inside the cell, for instance, like PA3 kinase mutations, it's about 40% of breast cancer. So over time, they'll figure out how to become resistant to different therapies. And then they become hormone refractory insensitive. And that's when you start bringing in some of these antibody drug conjugates. If there's

HER2 low, then you'd use the Trastuzumab dirux decan. know, if that doesn't, after some time it stops working, then you might use another antibody drug conjugate like this Trope 2 SASE1. You know, so the sequencing becomes sort of the question in terms of, you know, which one do you want to use first? Over time, what can happen is,

The Patient From Hell Podcast (25:47.758)

Yeah.

Milana V Dolezal (26:12.375)

with each subsequent line of therapy, you're going to get a little less time out of it in terms of the cancer's gotten more sneaky. So maybe the first line will work for two or three years. But then the second line will only work for two years. And then maybe the third line will only work for one year. So that's what we start to see is the cancer becomes more and more refractory

because it's figuring out different avenues. You have time for another analogy? Okay. So I have a sort of analogy around Mets, metastasis. I went to, I worked on an MD PhD in Philadelphia and I spent a lot of time in Manhattan. So I go to Manhattan almost every, every, every weekend. So if you think about how to get around Manhattan, so.

The Patient From Hell Podcast (26:49.738)

Always.

Milana V Dolezal (27:11.833)

Let's say you want to go from Grand Central to the Met, OK, the Metropolitan Museum of Art. There's a lot of ways you could go. So you could walk up Fifth Avenue, go by the park. That's nice. Walk up Park Avenue. That's also nice. You could bike. You could take an Uber. OK, so these are all sort of above ground ways that you can go to the Met. Well, what does cancer do? So let's figure out.

Okay, we figure out, right, well, you know, it's really using Park Avenue and Fifth Avenue. So why don't we just shut those two down? We'll bring an antibody in. We'll bring a HER2 antibody in. We'll bring something in above the ground, what we call above the cell, extracellular. So you stop these things. Okay, detour, detour. All right. Well, pretty soon it's like, you know, I don't even care about

underground and above ground, I'm just going to go underground. So then you got the Lexington line. I think it's green. You can take whatever you want, right? And so that's how the cancer figures out by using things like PI3 kinase, AKT, mTOR, all these inside of the cell underground mutations. And now it's using the subway to move, to grow, you know, little circulating tumor cells going around,

figure out where I'm going to go to set up shop next. If I want to go to the liver, that's at the Met stop. So I'm going to go hang out there for a while. I'm going to invite my friends. We'll make a little ball party. So anyway, that's kind of how sneaky cancer can be. It's constantly figuring out detours, mutations, above ground, below ground.

The Patient From Hell Podcast (29:01.326)

That is such a good analogy. And I think you know why I got very excited with that one. But that's for a different topic. I studied the subway map of New York almost religiously. And I'm adding in the subway map right now, just because it's also a decision-making process for patients. Navigating it from a patient perspective kind of feels in a similar fashion, where there's so many routes to go and how do you get from point A to point B. So anyway, I'm getting very excited with this. My question for you, is

Milana V Dolezal (29:13.612)

Okay.

Milana V Dolezal (29:19.659)

Absolutely. Yeah.

The Patient From Hell Podcast (29:32.002)

I've heard you say the word sneaky many, many times. Cancer runs like this.

Milana V Dolezal (29:34.615)

Yeah.

The Patient From Hell Podcast (29:39.078)

a very intelligent game partner. And there's this constant, like, a decision is made, cancer reacts, changes the strategy. A decision is made, cancer reacts, changes the strategy. So there seems to be this back and forth. And we've used this analogy before in the podcast, which is it feels like a three-dimensional game of chess. So my question for you is, if there is this of multi-dimensional chess game going on,

Milana V Dolezal (29:41.817)

Mm-hmm.

Milana V Dolezal (30:00.387)

Mm-hmm. Mm-hmm.

The Patient From Hell Podcast (30:08.814)

how do clinicians stay updated? Because information is coming all the time. In this conversation we've covered, and we're just talking about a static breast. We're not even talking about all of the other types of cancers. So how do you stay updated?

Milana V Dolezal (30:26.755)

So, you know, this is really why a lot of us have become subspecialists.

The Patient From Hell Podcast (30:32.204)

Hmm.

Milana V Dolezal (30:33.111)

Yeah. So for instance, you know, I am in a community practice with Stanford. Although I'm still associated with the university as associate professor there, but I work out in the East Bay and in the East Bay, you you kind of there's an expression, you see what walks in the door, you know, so it depends on what your referrals are. So I get a lot of referrals from my breast surgeons. So

you know, that's how I can keep my practice at least 50% breast, but you know, I'll see a colorectal cancer patient. I think, you know, multidisciplinary approaches and tumor boards are really, really helpful. So, you know, I sit on a Wednesday Sutter breast tumor board. I sit on a Friday Stanford breast tumor board. I also sit on a colorectal tumor board. So I think tumor boards are important.

And then we have a lot of meetings that we go to. Again, you know, this is all voluntary. You have to take your weekends or your after work stuff to kind of continue to educate yourself. But for instance, in Northern California, we have an organization called ANCO. It's the American Northern California Oncology Society. And we have different meetings. We have a nice meeting that

is tumor, you know, it's about three days and it's broken down. Each tumor type has about an hour and a half or so. And we actually go through cases and then we take the challenging cases and then we present the updated data, you know. So if there's something that's relevant that came out from our big oncology meeting in June or breast cancer December meeting,

you know, then we'll kind of educate the community on that. But it is very hard. And so I think a lot of us have gone to really trying to not be the jack of all trades and the master of none, but at least to sort of sub-specialize so we stay on top of what we're interested in. And so it's kind of what your passions are too. Like I'm wearing my little breast cancer, Betsy Johnson dress here, you know.

Milana V Dolezal (32:56.171)

So I'm passionate about breast cancer. So a lot of those patients will gravitate to me and I will stay up to date. But it really is a challenge. I think we live in a pretty metropolitan area, but I can't imagine if you were the only, you and your two partners were the only oncologists for 200 miles, I don't know, Montana or Wyoming.

you know, where are you going to find time to spend your weekends going to, you know, meetings and I think NCCN guidelines help a lot. And, you know, I think that's huge for any, you know, rarer tumor that I see. Even for patients, I print the NCCN guidelines out all the time and just say, look, there's a patient friendly version. This is the doctor version.

I circle, I take notes, I talked about chapters of therapy, and then I say, you can go sign up, it's free. And these are the websites that I recommend. I have a new patient binder that has the vetted websites that are not TikTok or other stuff like that.

The Patient From Hell Podcast (34:15.598)

Pat Delaney from NCCN Foundation, which is the group that puts together the patient friendly guidelines was the very first external guest on our podcast. I'm with you. That was my default place to start at least. At least as a place to like frame what's going on, at least as a patient. So very much, very much understand and agree. we roll back to ADCs?

Milana V Dolezal (34:25.143)

Mm-hmm. Yeah.

Milana V Dolezal (34:31.248)

Yeah.

Milana V Dolezal (34:36.857)

100%.

The Patient From Hell Podcast (34:45.886)

specifically focusing in on, said something earlier in the conversation, is because the drug is sort of, targeted and has this localized effect, because it's membrane permeable enough in several cases, there is a sort of like semi targeted, but, still, deeper, I put that in quotes, effect. The side effects are different.

than say generalized chemotherapy, which is going everywhere all the time and targeting anything that's fast growing. So if you were to help us understand what are the side effects for the class, acknowledging that there are God knows how many variations now. If you had to generalize just the class in terms of here are the types of side effects patients typically end up going through, what are they?

Samira daswani (00:00.078)

And what are the side effects for the plus acknowledging that there are God knows how many very simple. if you had to generalize just the plus in terms of here are the types of side effects patients typically end up going through. What are they? Yeah. So it's really going to be specific to the antibody drug conjugate. So let me just sort of frame it in terms of some examples.

So with TDXD, also known as ENHERTU in terms of what's a black box warning, okay, so what is the FDA putting this high bold prints on the top of a package insert? So it's something called ILD, intraciscial lung disease. What is that and why is it important? So in the original trials,

within HER2, which were in a very refractory breast cancer population. There were some grade five events. A grade five event is death, which is a big deal. So they did have, I don't remember how many, but I think it was probably about five grade five events. And there is something about this drug, and we don't know

which part of the three things could be contributing to this that increases the risk for interstitial lung disease. What that is, is basically an inflammation of the lung, kind of like a pneumonitis. Whenever you hear an itis, an itis is like an inflammation. And the good news is when a lot of these trials were being conducted, you know, was still during COVID.

And one of the number one symptoms of this is cough. So whenever you come into an infusion center during COVID times, and hopefully now, the first question our infusion nurses ask you, any respiratory symptoms, any coughs? So we had very stringent screening things before patients even walk in the door. Now, there is a...

Samira daswani (02:21.346)

How we add to that, so a lot of the early stage studies with these highly refractory patients in the stage four metastatic setting, the company that originally made ENHERTU, Daiichi Seiko, is out of Japan. The majority of those patients were of Asian descent, and we might think, because we see this with some oral...

um, pills as well, especially in lung cancer for patients who have a particular mutation that are never smokers, something called an EGFR1 mutation. Taking these EGFR1 pills, they can have a higher risk of this lung inflammation. And we don't know why, per se, why an Asian population would be at a higher risk for this ILD. So that's one thing.

As we have more experience with this particular drug, we are finding that having some kidney dysfunction, meaning a number called creatinine, which is lab test, if that is a little off, that might predispose patients. We worry about smokers, people who've had some underlying lung damage, but we're not exactly sure yet, like the who and the what.

You know, one thing I would say is, do I see as sort of a next generation of predictive medicine, not only predicting how you can get, you know, more targeted therapies to the cancer cells. How can we predict the side effects, right? If I could have a little chip that would tell me, you know, you're going to have a 50% chance of getting ILD, well, maybe I don't give you that drug.

Maybe I'll pick a different one that will cause that. So I wish we were that sophisticated. So that's definitely the huge concerning side effect. Now, the good news about that is through education, and hopefully it's through these weekend things that doctors are doing as well, we've worked with the cardiologists to kind of figure out in the lung doctors what is the best approach

Samira daswani (04:45.198)

approach to kind of monitor this. So now we've graded it. So in the clinical trials, because this came up, patients were getting CT scans of the chest every two months. And that could even pick up an asymptomatic mild. Now it's confusing too, because in the breast cancer community, lot of those patients have had radiation in the

early breast cancer setting, which can also cause some lung inflammation. You know, so it's complicated. think the side effect management, even though these drugs are transforming, you have a lot to learn about that aspect of, know, choosing wisely which patients you're going to use it in. And I think as oncologists, we're going to always default to the best drug. You know, and as a patient, you want the best drug.

You want the drug that's going to knock it out of the park. So there's that. So that's particularly for ENHERTU. And then with the SASSY drug I talked about, Sassatuzumab, one of the balls of chemo, the type is similar to a drug that we use in gastrointestinal cancers. A lot of these are what are called Trope 1 or Trope 2 inhibitors.

But in particular, that can cause diarrhea. And we see that sort of more with sassatuzumab in addition to blood count issues. And so that means these patients are needing more white blood cell growth factors. The dosing of that particular one is a day one and day eight, as opposed to an every three week.

So that makes it wonky. So you end up having to maybe give some growth factor day two and day three, and then maybe a long acting growth factor like the Ompro robot, new LASTA on day nine. wow. Yeah. So it really depends. can't just say as a last, some of these ADCs and maybe it's a linker thing can cause some eye stuff, some either dry eyes.

Samira daswani (07:10.146)

teary eyes, inflammation, even some light accommodation stuff, meaning that when you go walk outside, and we see these with some of the pills too, especially some of lung cancer pills, think called an ALK inhibitor. So I mean, can't be generic and say they all cause law. It really depends on the poison, the chemotherapy ball. It depends on the linker, the rubber band.

And it depends on the why, the antibody. You know, the antibody for the HER2 agents is still TRST-2 Zimab. And so we still do echocardiograms, for example, heart ultrasounds. So yeah, that's in a nutshell.

Samira daswani (08:00.324)

My feeling right now is one-up and terrified.

It's the reason I use that. I don't very often go into fear mode. The reason you see me go there is what struck me in this conversation is we're in exciting times where if you are a metastatic patient, you have optionality. And with each option, with each line, the time on that line seems to shrink, but you have an option, which may not have been true 10 years ago, 20 years ago.

But that option, despite it being the best option, is coming with a

Samira daswani (08:42.002)

There's a cost to it and that cost isn't, it doesn't feel like it's fully defined. So it's almost like a cost that may or may not happen. You may get ILD, you may not get ILD, you may get ILD that may kill you, but you may not get ILD that won't kill you. and by the way, you should come in every two months for a CT scan, which is going to be mortifying because... So it feels like a undefined cost.

which has at least just in hearing you talk about the like sassy drug and the I'm assuming you put your new last combination there off of the like white blood cell counts. And I remember just just getting back during new type of care for me and that alone was a whole thing for me and to never imagine. Yeah. And it causes yeah, it's like the bone pain is excruciating. And again, my experience not always true for everybody else, but it they

Day one, day eight, day nine. It's like, wow, okay, if I'm a patient going through this, you're driving to come see me from Chico? Exactly. Exactly. Well, let me reframe it a little bit. So maybe kind of that cost aspect can be put into perspective. So the one thing that is nice that we're seeing, and there's some really nice data that I think Hope Rogo presented

maybe at San Antonio or ASCO a couple years ago, specifically with salicytuzumab, but we've seen it for a lot of the other antibody-drug conjugates and it's quality of life data. And so that is a composite score. so quality of life, what are called PROs, patient reporter outcomes. So there's a lot of surveys in different aspects that are captured. So it could be the number one that's always in there is fatigue.

Fatigue, pain, neuropathy, ability to do activities of daily living, ECOB performance status. So that's what is a performance status. How much time in bed are you spending a day? Okay. You're spending more than 50% of, and we're not.

Samira daswani (00:00.078)

We're talking like bedtime, we're talking during the day. So these composite scores are put into quality of life. the one thing I think that is an important take home is that when you start treating the cancer effectively, patients feel better and they have a better quality of life.

So they might be willing to come in for that day two. And actually sometimes we can even just write a prescription, know, patients are giving themselves shots at home, but whatever it is. But the bottom line is when we start treating the cancer, you see pretty quickly within two or three cycles, so within four to six weeks, patients are spending less time in bed. They're less fatigued. So that's the seesaw balance of

toxicity versus efficacy. So if you have a drug that isn't working well in a patient, but that's just giving them toxicity, nobody wants to live an extra seven, eight months if the time is not quality and they're just going to be in bed the whole time suffering, right? So that's the seat of, wow, I feel better. And the other thing is I've been doing this for a while now. I in the,

The goal on stage four cancers, unfortunately, it's very rare to have a complete remission and we're probably not gonna cure this. So we go low and we go slow. And start with dose reductions, because I would hate to overdo it and then miss a couple cycles because we're recovering from side effects.

See what I'm saying? So I'll start at a lower dose with the idea of possibly dose escalating, especially in older patients who are on a lot of other medications and are kind of frail, right? So I'll start at a lower dose and then, because I know I'm not going to cure the patient and we're going to be on this therapy as long as it works, both from a cancer fighting standpoint and from a toxicity standpoint, right?

Samira daswani (02:19.064)

So I don't want to give them all the toxicity upfront. So just start low, know, have them ease into it. Wow. You know, our pain that I did a month and a half ago, you know, depending on where the cancer is, things can start melting. Maybe the breathing gets better. Maybe they get off oxygen. Maybe the liver enzymes get better. They don't get itchy. They have no right upper quadrant pain. Maybe they're able to take the dog for a walk now.

You know, so there's a lot of metrics that aren't necessarily tumor markers going down, which is something that we often use in stage four setting two. You know, there's a lot of quality of life stuff that you don't necessarily need a survey to figure out. So that's the balance. The balance is quality of life. I love that explanation much. I think my takeaway was go low and go slow. I think you've synthesized something that,

I think very beautifully delineates early stage disease from metastatic disease in kind of how we approach it as a community. And I think how patients feel on it as well. So I really appreciate that framing. I'm watching the clock talk and we are way over time, but I appreciate you taking the time. Can I ask you one wrap up question and we'll use that to close out? My wrap up question for you is we looked historically, we looked at today.

And we, heard a couple of inklings of in the future, I wish I hope if you had a magic wand, no constraints. And you cannot say cure cancer. That's not an answer. That's acceptable. Sorry. But in the world of outside of that answer, if you could wave that magic wand on anything, what does oncology look like five years from now?

I guess it might be a little bit of a short time, but... A little bit a stretch goal. You can have a stretch goal. You're right. So I think there's a lot of things that I'm excited about. I think all these things I mentioned are great, but they're kind of a little bit of incremental benefits. So, all right, we add another three months. We add another six months. So I think to buy for Kate,

Samira daswani (04:41.546)

One, I alluded to, boy, wouldn't it be nice if it could really not just personalize with precision management the cancer therapy, but the side effect management so we can maximize not just quantity of life, but that quality of life. So I think that's an area of supportive care, figuring out who might have which side effect up the front would be great.

Then the other aspect which I'm really excited about is gene technology. We haven't been able to have, you know, really that be successful until pretty recently. So CRISPR is an amazing technology where you just literally cut stuff out. Developed in my backyard here in Berkeley by Jennifer Dujia. And there's other people involved too.

But at any rate, mean, you now for sickle cell anemia, you know, we have a one-time infusion that we give back to patients that increases something called, I'm also a hematologist, so I have some bias there, that increases their, what's called hemoglobin F and their oxygenation. So then they don't go into these horrible, painful crises or have acute stress. I mean, it wouldn't be great. You know, the problem.

is that it's not, you know, I mentioned how sneaky cancer is. you know, it's usually not just one gene that's the problem. Similarly with sickle cell anemia, you know, we have, I mean, with hemophilia, we also have a gene therapy now. The FDA just approved something for cancer for synovial sarcoma, which is a kind of soft tissue bone type of cancer that we have gene therapy for.

And then there's some amazing data presented by Jeff Weber, who unfortunately we lost this summer to pancreatic cancer, who was really a hero in the oncology community. But he presented some data in melanoma on a COVID type of mRNA personalized cancer vaccine using that mRNA technology, in combination with immunotherapy. So that goes back to what...

Samira daswani (07:02.828)

what I started with, wouldn't it be great if chemotherapy was obsolete by the time, you know, a lot of us retire or pass on that the talent to somebody else. I love that. I feel very, very inspired and hopeful given the future you're talking about. So that blows out. am, if you're up for it, would love to do part two, maybe after one of the congresses where you may be able to help us synthesize.

what we've learned from the Congresses for patients. As if you're up for that, I'd love to slip that up. But I really appreciate you taking the time and for explaining, I think the complexities of the science in context that makes sense for the community. So thank you. Okay. Well, we'll see you again another time then. Done. Thank you. Okay. Take care. Goodbye.