The ABCs of ADCs: Ovarian Cancer and Antibody Drug Conjugates

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Unknown
Hello and welcome to today's webinar.The ABCs of ADCs: Ovarian Cancer and Antibody Drug Conjugates. I'm Maggie Nicholas-Alexander, the senior director of Gynecologic Cancer Patient Support and Education at SHARE. Before the presentation begins, I'd like to tell you a little bit about share. SHARE is a national nonprofit that supports, educates and empowers anyone diagnosed with breast or gynecologic cancer and provides outreach to the general public about signs and symptoms.

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Unknown
Because no one should have to face breast, ovarian, uterine, cervical or metastatic breast cancer alone. For more information about our upcoming webinars, support groups and helplines. Please visit our website at sharecancersupport.org

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Unknown
and that we're very excited to have Dr. Alldredge joining us today as our Speaker for this webinar.

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Unknown
So I'm going to hand it over to her now to introduce herself. Hi, I'm Jill Alldredge. I'm a gynecologic oncologist at the University of Colorado, where I have been for five years since finishing training out in California. I provide the full scope of gynecologic oncology care through the university, so that means doing all surgeries needed for gynecologic cancers as well as prescribing chemotherapy, maintenance therapies, surveillance care and genetic testing for those patients, really trying to provide comprehensive care across the board for individual patients.

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Unknown
And then I work to enroll patients in clinical trials, and I work through several national organizations on trying to move the needle ahead for gynecologic care nationwide through clinical trial work. So I am Maggie. I am going to try to share my slides here and we go. Thanks for your patience, everybody. Here we are. All right. Perfect. So today, I'm going to talk to you a little bit about antibody drug conjugates within ovarian cancer.

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Unknown
And I think that what we'll start with is just going over what is an antibody drug conjugate or ADC? What are some of the unique side effects for these and what are some of the potential ways that we can use ADCs within the field of ovarian cancer, including some current FDA drug approvals? And I'll tell you a little bit about what may be coming down the pipeline in the future.

00:02:51:23 - 00:03:18:22
Unknown
So just to get started, an antibody drug conjugate I think of as a Trojan horse. So basically what we're doing is we're linking an antibody that binds to the surface of the cells, and cells have little markers all over their surface. And this antibody links up with one of those surface markers, and that antibody is linked together with a little chemotherapy.

00:03:18:24 - 00:03:44:16
Unknown
And the idea is actually this really clever mechanism where this antibody attaches to the surface proteins on a cancer cell and then that cell eats it up. And I think this that bottom picture here shows it best that it basically starts to kind of go in and it swallows up those surface markers, including the antibody with the linked chemo.

00:03:44:18 - 00:04:09:05
Unknown
And then it creates this little bubble that gets delivered on to the inside of the cell where that chemo can then go have its action. So that's a really clever mechanism to try to decrease the toxicities of our traditional chemotherapy, whose job is really to go out into the system and kill all quickly dividing cells that it comes into contact with.

00:04:09:07 - 00:04:33:03
Unknown
So that works to kill cancer cells because they are quickly dividing, but it can also have side effects to other nearby tissues who happen to be quickly dividing things like our gut or our bone marrow and our blood counts. So that's where we get a lot of the side effects from chemo, is because chemo is killing cells that we don't really want it to.

00:04:33:05 - 00:05:09:20
Unknown
So this mechanism, this Trojan horse mechanism really allows for chemo to get delivered into the inside of hopefully just the cancer cells. So this is working by taking only the markers of surface markers that are highly expressed on the surface of cancers or tumor cells and are not expressed or very lowly expressed on normal tissues. And so we can't use this for all cancer types and we can't, you know, make all chemo's deliverable this way yet.

00:05:09:22 - 00:05:38:21
Unknown
But we're starting to find that, especially in ovarian cancer, there are a handful of surface markers on top of ovarian cancer cells that we can take advantage of. So some of those are things like the folate receptor alpha mesothelioma receptors trap two receptors, tissue fat and nappy to be. And I know those are just a lot of letters and numbers, and that hurts not terribly important.

00:05:38:23 - 00:06:07:15
Unknown
The idea is, is that we're finding more and more that there are unique markers on the surface of ovarian cancer cells that are not expressed on normal tissues, and we can take advantage of that for the moment. The chemotherapies that we leading up to this antibody are mostly like Taxol. And many women who have been through ovarian cancer treatment have seen Taxol as one of their early on chemotherapies.

00:06:07:17 - 00:06:35:00
Unknown
And this is a really similar mechanism to that. So these are little chemo's memory or dpp4 that are linked up with that antibody. So this has been an area where we have done many trials over the last few years trying to figure out which antigen or surface marker on the ovarian cancer cell we might be able to take advantage of.

00:06:35:02 - 00:06:59:00
Unknown
So as you can see here, many of these are highly expressed on the surfaces of ovarian cancer cells, and then they have a chemo link payload to them. And some of these have been not as promising as we wanted them to be. New phase one clinical trials are really early trials where we're trying things out, trying to find the right dose.

00:06:59:00 - 00:07:20:08
Unknown
Just get a basic sense of whether they're going to work or not. And you can see these are some low percentages here for some of these different agents. But for some we've had some really promising initial results. And we're going to talk about these in a little bit more detail. But the promising initial results have been led to further clinical trial development.

00:07:20:08 - 00:07:50:12
Unknown
And I know that this can look like a lot of jargon. So I just want to point out that the abbreviations here o RR means overall response. So that means people who had a complete resolution of all of their disease and people who had a partial resolution of their disease. So some shrinkage. So when we're looking at these percentages, these mean these women had some sort of response to these agents.

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Unknown
Pafs When we talk about progression, free, survival really means the time between recurrences. And our goal with ovarian cancer is to get as long as we possibly can in between recurrences, since often times. Complete cure can be difficult in these recurrence settings achievable, but we typically aim for the longest duration as we can between recurrences or PFS. So these potential targets have led us down the road of three drugs that I'll tell you a little bit more about.

00:08:29:08 - 00:09:02:06
Unknown
The first one, its brand name is Ella. Here we call it Merv Cetuximab or Merv. So you'll see us talk about each of those three names interchangeably. The antibody for Ella here is a fully receptor alpha antibody. And you can see here in this picture, this is a highly expressed folate receptor alpha. So all this brown is folate receptors on the surface of these tumor cells, and that's linked to a Taxol like chemotherapy.

00:09:02:08 - 00:09:29:18
Unknown
In the clinical trials that we've done in this space with more of a toxin. And those are not restricted to a certain subtype or histology of ovarian cancer, though they are for epithelial ovarian cancers. So not for sex, for stromal tumors, not for your germ cell tumors. These are epithelial cancers. So things like high grade, serous, endometrial, I'd clear cell carcinoma sarcomas.

00:09:29:20 - 00:09:54:16
Unknown
Those are the types included in the trials. And that in the original study that we did in this space, I'll show you in just a moment, we really found that this isn't helpful to give to all women with recurrent ovarian cancer. It's really helpful and limited in its benefit to those who have more than 75% of their cells.

00:09:54:16 - 00:10:26:03
Unknown
So if we took a slide like this, more than 75% of those cells are expressing that folate receptor one. So not for not for all recurrences. As of now, we don't have any data on giving these targeted folate receptor drugs in upfront ovarian cancer. So the standard of care remains a combination of surgery and carboplatin and Taxol or cytotoxic chemotherapy.

00:10:26:05 - 00:10:48:06
Unknown
And Ella here is not part of the upfront management yet. And I will say that perhaps that changes in the future. But we're not we're not there yet. So the places we'll talk about today are in platinum sensitive ovarian cancer and then in FDA approval and platinum resistant ovarian cancer. So just to touch base on what those terms mean.

00:10:48:08 - 00:11:13:18
Unknown
So using more of a text MAB in platinum sensitive recurrent disease means that from the time someone saw their last platinum drug, usually carboplatin, it's been more than six months. That means that we have a platinum sensitive type of tumor. And we did have a phase two trial done in just women with more than 75% folate receptor expression.

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Unknown
This was called the Piccolo trial and hot off the presses in June of this year with some really promising preliminary results out of that trial, saying more than 50% of patients had some sort of response, which when we compare that to just traditional chemotherapy in this space, is better as a really exciting result. Hot after the presses here.

00:11:40:12 - 00:12:03:11
Unknown
And at the average time, people stay in remission with that is about eight months, which again is about the same as what we get out of traditional chemo in this space. And so I do think that this will, with a little bit further data maturation, will end up being likely or our second or third line choice in this setting.

00:12:03:13 - 00:12:45:02
Unknown
There is also some data ongoing about adding the drug Avastin to Ella here, and those results are also really promising and exciting that maybe the combination of those two drugs could be better than Ella here all alone. And so that's underway as we speak. That's the glorious a trial that's enrolling across the U.S. and maybe a really wonderful trial to look into if it's opened at an institution near you as we continue to develop this, we've also studied more of a taxicab or Ella here in the space of platinum resistant or refractory disease.

00:12:45:04 - 00:13:19:21
Unknown
And that's when someone has a recurrence less than six months from their last carboplatin drug, or that they've had progression of their cancer while on a carboplatin drug. And so this was wherever taxicab first came online, we did a trial called the Forward Trial, where we found that really didn't seem any better than chemo. But when we looked under the hood and we looked a little bit closer, we found that we were looking at every one all amounts of folate receptor expression.

00:13:19:23 - 00:13:45:09
Unknown
And if we look all comers, you don't really have much benefit. But if we really look at those patients who have high expression, so more than 75% expression of folate, those women have a great response to this drug. So that led to another trial called Saraya, looking at just that group showing good promise and then a Phase three confirmatory trial.

00:13:45:11 - 00:14:15:14
Unknown
That means that compared here against the current standard of care chemotherapies, and it showed that it was better than the current chemotherapies that we use in this space and tended to have less side effects than traditional chemo in this space. So this really exciting data out of the Mirasol trial led to an FDA approval. So for right now, this is the only FDA approval of an antibody drug conjugate in ovarian cancer.

00:14:15:16 - 00:14:53:11
Unknown
But I do think that more likely to come, given all of this exciting information, more of a text. MAB is a unique drug in its side effects, so the linker that holds together the the linker that binds up the the immunoglobulin and the chemo has its own unique side effects so that linker can cause blurry vision or dry eyes in about 60% of patients usually takes about a month for that to take effect.

00:14:53:13 - 00:15:19:07
Unknown
And the vast majority of patients that will resolve either completely or almost completely. But that takes some special care. We have to give special eyedrops to try to prevent eye toxicities, and we have to have folks follow with an ophthalmologist throughout. In addition to that, really unique side effects that comes from the linker, we can also just see some traditional chemo like side effects.

00:15:19:07 - 00:15:56:04
Unknown
So some things just like Taxol and neuropathy. So numbness or tingling in the fingers or toes and maybe some hair thinning, some low blood counts and then rarely some lung inflammation. So some unique things that come with this Ali here drug. Overall, though, it tends to be easier to tolerate than chemotherapy is. I do want to briefly touch on a few other ADCs coming up in the ovarian cancer space, we have DSD is what we're calling it, Roadmap to Tag.

00:15:56:06 - 00:16:26:21
Unknown
It's a mouthful, but this is directed against CDK4 six and it's linked up with a top I chemotherapy. And we have several trials coming down the road in platinum resistant ovarian cancer with some promising early results just to give reference a response rate of almost 50% in platinum resistant cancers, a really good control rate. So really promising. We're looking forward to more work in this.

00:16:26:23 - 00:16:54:06
Unknown
The other we call it sassy, but sassy, too. Zainab is the formal name of this and this has been so promising and early trials that it's got a fast track designation. So the FDA really wants this to be studied as quickly as we can. And this also really promising results, the linker and this one maybe causes some mouth irritation or mouth sores, more so than eye side effects.

00:16:54:08 - 00:17:31:21
Unknown
So we have several really exciting antibody drug conjugates. So a chemo linked up with a Trojan horse mechanism that are in development in clinical trials across the country. And if you go to clinicaltrials.gov, you can search for clinical trials available in your area and many will include antibody drug conjugates or talk with your doctor about whether this is something that makes sense for your cancer or if there's a trial available for you at antibody drug.

00:17:31:21 - 00:18:04:06
Unknown
Conjugates are really exciting and are a developing area that I think of as personalized medicine, right? We're asking what your tumor expresses on its surface and then giving you Trojan horse chemo to link up with what your cancer cell expresses, which I think is as personalized as we can get. That being said, it does have some unique side effects and we have to be really cautious in people's care to make sure they're seeing eye specialists or taking special preventative measures to keep safe from those side effects.

00:18:04:08 - 00:18:30:24
Unknown
So I will turn it over to you all to share questions with me. Great. Thank you so much for that presentation. That was a really great introduction to a disease. So now let's start the Q&A. There were a lot of pre submitted questions and you can still submit questions in the Q&A section at the bottom of your screen.

00:18:31:01 - 00:19:06:22
Unknown
We will try to get through as many questions as we can in the remaining time. So side effects came up a lot in your presentation. And so one question is whether you think that the future ABC is are going to have a reduced side effect profile compared to Merv. When do I think what do you think? do I think I do think that antibody drug conjugates are relatively new in the world of oncology.

00:19:06:22 - 00:19:33:13
Unknown
They have really been up and coming in the past, I would say five years or so. And so certainly we have seen in lots of drugs that given time we can come up with small revisions, small changes to the structure maybe of these linkers that are causing the trouble and perhaps we could decrease that side effect risk in the future.

00:19:33:15 - 00:20:10:03
Unknown
I do think that just like with chemo, we have side effects on all quickly dividing tissue. When we're having side effects from the linker, it's usually that we have some expression of those things like tissue factor can be in the eyes. And so that's where we can see some of the side effects of tissue factor ADCs. And so there's going to be some expression of these different surface markers and other tissues that I'm not sure we're going to be able to get around, you know, as things develop.

00:20:10:03 - 00:20:43:07
Unknown
But certainly as these become more and more mainstream, I'm hopeful that the side effects can decrease. Great. Thank you. And I you know, obviously, Margaret Texoma has the the well is for those who have a folate receptor alpha expression. But there I think there's some confusion from our audience about some of the other targets. So could you maybe reiterate the the ones that are not looking at that folate receptor alpha expression?

00:20:43:09 - 00:21:06:00
Unknown
So a lot of those in the early trials are aiming for because a lot of those are phase one trial spaces still. We're still aiming for tumors that seem to highly express those markers. But for right now, in early phase, trials will often try them in in all comers, just like we did with Ali here early on in L.A.

00:21:06:01 - 00:21:34:23
Unknown
Here we looked at everybody and saw no good responses. And then when we narrowed the field to just people with a high expression, that's where the benefit was. So we're going through similar paradigms in some of these other antibody drug conjugates is looking at all comers, but also just having planned groups where we have high expression to, to make sure that we're not, I think for lack of a better phrase, we're not throwing the baby out with the bathwater.

00:21:34:23 - 00:22:01:03
Unknown
Right? We're not saying, well, this doesn't work for all comers, so it's garbage, because if we had done that, we never would have had it here. So I think we have to plan to have these high expression groups because that's where we expect to have the greatest benefit. Great. Thank you. And then someone's asking about, you know, they just started Merv.

00:22:01:03 - 00:22:41:18
Unknown
And, you know, one of the side effects is neuropathy. And what's a good way to prevent that? Yeah. So that neuropathy is coming from that chemo linked up with the antibody drug conjugate that taxol chemo in general for both L here with that Taxol and just for Taxol in general, there are lots of layers of options. So there can be things like vitamin B6 and B12 can sometimes be helpful using things like capsaicin, creams, acupuncture, CBD oils or creams, depending on where in the country you live and what's available.

00:22:41:20 - 00:23:03:16
Unknown
And then there are medication managements out there as well. So I think there are lots of layers of things to manage neuropathy, and I would encourage you to talk with your doctor about what they can offer or what a physical medicine and rehab specialist in chemo neuropathy might be able to offer because I think there are lots of choices to help with that side effect.

00:23:03:18 - 00:23:42:08
Unknown
Right. And then I know you mentioned that for Merv, Merv, that it's epithelial ovarian cancer that. So could this be appropriate for someone with low grade serious who had that expression for tricky receptor alpha? Yeah, I do think that low grade serious is a unique subtype of cancer. But I would say in those that have high folate receptor alpha expression, yes, I would still expect this to be an option.

00:23:42:10 - 00:24:11:15
Unknown
I think that that circumstance where a low grade serious is highly expressing, is a relatively rare beast. But I do think that I would think of this independent from the epithelial histology and think of it as a treatment for folate receptor, high tumors. And then we're getting a question about how is this different from PARP inhibitors, essentially? Woof.

00:24:11:17 - 00:24:37:22
Unknown
Yeah. So PARP inhibitors, how would be a whole lecture for you? But so PARP inhibitors are trying to take advantage of some of the broken DNA communication and repair mechanisms happening. So a faulty game of telephone dialog that we're shutting down to kill off cells that are not communicating well and aren't listening to the normal checks and balances.

00:24:37:24 - 00:25:07:23
Unknown
So kind of a different mechanism than this one, which is, you know, here's the cancer cell with a bunch of markers on it and let's deliver chemo only into those cells just to try to focus where chemo is being delivered. So mechanistically, kind of different beasts and should not be exclusionary to each other. Right? So if we've had a PARP inhibitor, it doesn't mean we can't have more.

00:25:08:00 - 00:25:36:01
Unknown
If we've had more, if doesn't mean we can't have a PARP inhibitor because they are separate. And then we have a question about how does someone know if they have that receptor alpha expression. Thank you so much for asking. I should have mentioned that. So more and more institutions when you have your initial surgery are actually adding this on to the pathology that comes out of that initial surgery.

00:25:36:04 - 00:26:09:22
Unknown
So when you have your initial surgery, you'll get a pathology report that says, you know, it's this stage and it's in these places and it expresses is estrogen or whatever else. And it expresses or does not express fully receptor and at what percentage so many institutions have that built into their normal pathology infrastructure now. Or your physician can ask for baked tissue, sort of tissue that your institutions held on from from a prior biopsy or surgery, and they can ask for that to be added on to existing tissue.

00:26:09:24 - 00:26:39:13
Unknown
The other option is through molecular testing groups things, and I won't list all the different brand names, but there are lots of molecular tumor profiling services that we use. And this is one of the markers that those will report back on. Thank you for that. And then how long can someone be on Merv, though? Is there a time limit?

00:26:39:15 - 00:27:12:15
Unknown
Yeah, great question. So both in the platinum sensitive and resistant spaces where Mir protects the MAB is currently has the most momentum. Those days are to be continued until progression or toxicity, so either until stops working or it's too toxic to tolerate. So that can really go on for months, years, however long it's doing its job in patients who have a complete response on l.

00:27:12:16 - 00:27:45:02
Unknown
Here I will often have a conversation about when makes sense for them to stop, but all of the clinical trials are built as progression or toxicity, not a set number of cycles. And at what point should someone consider maybe going off of the like in terms of the side of like how bad the side effects essentially have to be that you think it's warranted to consider going off of it.

00:27:45:04 - 00:28:23:08
Unknown
Yeah. So I do think that physicians prescribing this medication are keeping eyes out for things like bone marrow blood counts. They should be asking about neuropathy every visit they're keeping an eye out for things like lung toxicities. And so they're watching for those things to help guide when we should stop from an eye side effect standpoint, the ocular toxicities, we rely on our ophthalmologists to really help guide that they're doing special eye exams every time you go to see if the the external surface of your eye is really irritated or not.

00:28:23:10 - 00:28:52:17
Unknown
If you're having really bad dryness or eye pain, those are reasons to stop. And so if side effects are too much or if it's not working, we should stop using it. And what percentage of patients have had to have a complete response with nerve? So I would have to say it depends a little bit on whether they were platinum sensitive or platinum resistant and how many other drugs we've had.

00:28:52:19 - 00:29:24:22
Unknown
But just to show you, kind of generally in platinum resistant patients, about 40% of patients have a response that includes a partial and a complete response. And then platinum sensitive, about 50% have a response that includes partial and complete responses, so higher than traditional chemo. In both of these circumstances, which are typically somewhere in the range of 20% to 40%.

00:29:24:24 - 00:29:56:11
Unknown
Right. And that's as severe as they can get for. And great. Thank you so much. It looks like we're out of time, but thank you so much, Dr. Aldridge, for this informative program. And thank you to all of you for participating and submitting your great questions. Please check out shares upcoming. Educate national programs and support groups and follow us on social media.

00:29:56:11 - 00:30:04:12
Unknown
thank you again everyone. This concludes today's webinar.

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Unknown
I.