Welcome, good morning. I'd like to start off today's webinar entitled New Options in Platinum-resistant Ovarian Cancer, which is sponsored in part by an educational grant from Imogen. My name is Wendell Naumann. I'm a gynecologic oncologist at the Levine Cancer Institute to Atrium Health, Wake Forest University in Charlotte, North Carolina. And I'm honored to be one of the co-chairs of the 360 Education Platform for the IGPCS along with Flora Backus. We're beginning our second year of advances and updates. The program has been highly successful and these programs are recorded and will be put on the website for viewing later. This is being presented live and we will have an option for questions through the chat function today after the webinar. For today's discussion, I'm joined by Dr. David O'Malley. Dr. O'Malley is professor and director of the division of G1 Oncology. He's co-director of the G1 Oncology phase one program at the James Cancer Center at Ohio State University. He also leads the ovarian cancer portfolio for the GOG partners and was the PI on fall or two. Thanks for joining me, Dr. O'Malley. Great, thanks for having me. Great to see you this morning, Wendell. Yeah, so before I get started, just a few housekeeping items. Again, this will be recorded and put on the IGCS Education 360 portal within one business day. We encourage you to submit questions via the Q&A function at the bottom of your screen and we will do our best to address those questions as time allows. So that's all I have. Dave, if you wanna take over and just tell us a little bit about your approach to ovarian cancer, particularly platinum-resistant ovarian cancer. Yeah, actually, go ahead, next slide. You know, I think as we look here and we really have had a change in how we look at platinum-resistant ovarian cancer, maybe more so platinum-sensitive, which is continuing to go back to platinum unless people really progress on platinum or progress really immediately after completing platinum, thus they were progressing while on platinum. You know, we know from retrospective and ancillary data projects that the response rates go down with each line of platinum-resistant ovarian cancer in general in our progression-free survivals. So we're really kind of morphing this and the way I look at it, we're morphing this from, you know, in the past where we said, oh, they're, you know, platinum-resistant, which remember historically, I don't have to tell you this, we talk about this all the time, right? When, you know, it was defined as the first line in Markman's retrospective projects, the first line, but then we morphed it into the second and third line. If somebody has a, particularly if they have a complete response in the second or third line to a platinum doublet, and then they have four months disease-free, I am going back to that platinum again, that platinum doublet. So typically I will start with pathotoxin like we all do. I use a lot of Bev in the first line and if they recur beyond six months in that first line setting, again, I use a lot of Bev plus PARP in HRD-positive patients. If they recurred in their platinum sense, I would go back to it. If they then recur within six months, and I use a lot of platinum-Gemzar, then I will go back to platinum-Gemzar until they progressed on that. So I think that in my way, when we say platinum, you know, the historical versus the contemporary where platinum is no longer an option. Now hypersensitivity, and we publish extensively on desensitization, and I will use, you know, or we will use a lot of desensitizations to continue people on platinum, but there are some people that either, that are just too hypersensitive to continue, and those obviously are other reasons to discontinue platinum. Well, actually, if I can go to the next slide. Now really, it was to talk about platinum, as we look at this, one thing that we need to keep in mind, outside of weekly paclitaxel, which is about 30% overall response rate, unbelievably consistent across the contemporary landscape, about 30% platinum senses with weekly paclitaxel, and we saw that in Aurelia, we've seen that in multiple other trials. But when we look at the really, the contemporary forward one in those high fully receptor alphas, which we know is our poor prognostic sign, javelin 200, response rates is really about 5%, no higher than 12 or 13%. And really most single agent activity, and most is well less than 10%. You look at single agent gem, single agent topo, we're talking really low single digits at times with regards to that. So outside of weekly paclitaxel, which again, neuropathy, hair loss is not a favorite of our patients, our response rates are less than 10%. So, when I look at that clinical trial number one, next slide, Ashley, clinical trials number one in platinum resistant ovarian cancer, and then we look at the preferred regimens from the NCCN, we have the Aurelia regimens, and I'm not sure how they pick the other four regimens with cytotoxin, but I know, a couple of phase two trials, but doxotoxil, oralotoposide, and gemcitabine, I'm not sure why those are the preferred regimens, but those are in my mind, kind of our go-to. And then you have obviously the new approval of MIRV and folate receptor expressing tumors and BAB. So, I'll stop there. Wendell, you and I talk a ton about this is what we talk about on a regular basis. How about you? Am I off base on trying to get the platinum until they become refractory or? Well, I think that's a evolving trend. I know the NCCN guidelines were recently updated to say that platinum doublets are probably reasonable, particularly for patients who've had a good response to platinum, even if they recur within six months. I guess my question is how do you decide your regimen in the platinum resistant setting? And you mentioned who you use platinum to retreat patients who are technically both platinum resistant. I mean, obviously, if somebody's five months, just shy of six months, it certainly makes sense to go back to a platinum regimen or platinum alone. But how do you sequence your platinum resistance patients outside of a clinical trial? You mentioned weekly paplotaxel with or without BAB is a high response rate, but it doesn't tend to be our preferred regimen. Do you think sequencing matters there? I think sequencing somewhat matters in platinum resistant, but probably not as much. I tell my patients all the time, I have about three to five tricks, because remember one of those tricks gets spent, if not two of those tricks get spent on platinum sensitive. So I have three to five tricks, which are approved. And actually, if you go to the next slide, that was a great segue by Dr. Nauman. You know, I have three to five tricks. I have another series of other things that we can use, but they're all kind of, you know, taxanes. And then we talked about the platinum doublets to alert to the addition of platinum doublets to platinum resistant. And so I go with the platinum doublets. Once they become resistant, I look for clinical trials, because I tell my patients, I have three to five tricks. So if we can get a clinical trial, that gives me another trick. And even if you get only three to four months on that trial, which we're seeing home runs, and you look at the MIRV data and the MIRV-BAP data that we'll talk about today. And I have patients who have been on that combination for years, and there's no exaggeration. For years, obviously taking breaks and holidays. But, you know, when we look at this, we can hit home runs on the development of antibody drug conjugates, some of our new immune therapies. And if you get a home run on one of your clinical trials, you open up a whole new world of possibilities. So my sequencing really depends on what clinical trials I have open for patients. And then I fill in the gaps with the other agents. Doxil, excuse me, peglegliposomodoxorubicin, trade name's Doxil, I apologize for saying that. But, you know, if I have a patient who's asymptomatic, who doesn't need a WIN, right? Who doesn't need a WIN, who's doing all right, you're using the disease to control, excuse me, using the treatment to control the disease so she doesn't develop symptoms. PLD is great, PLD is great, okay? I said gemcitabine, I use that a lot in my platinum doublets. I prefer to use PLD as a single agent. And then, you know, that leaves our cytoxanabev, that leaves our weekly taxolanes. Weekly taxolanes when I need a WIN, that patient who is developing or has symptoms. And then obviously, as we always debate and, you know, the harshness, harsh decisions we make, when do we use BEV? In the U.S., we're allowed to reuse it, right? Across the world, that's not as easily done. But, you know, are we worried about the bowel perforation or do you really want to add to that progression-free survival and potentially the objective response? So if I need a WIN, that's when I go to my taxanes. So for me, patient shared decision-making, discussion with the patient and what her needs are, and then clinical trial. I'm going to try to get each one of those novel therapies in there to, again, extend out, hopefully by years, their survival by bringing new agents in. I've certainly seen that as well. Yeah, I think the data that has emerged with BEV, after BEV, is certainly compelling and I agree. I think that, particularly the patient who is symptomatic that might have ascites or pleural effusion and doesn't have bowel obstruction. Obviously, I worry about bowel obstruction in the patients with recurrence, but I think those are, you know, BEV is going to add about 20% response rate to your regimen, whatever you're using, so. Yeah, I think utilizing that and then, you know, I've been with BEV in the first line and BEV plus PARPS and LAPRs specifically in HRD, you know, they start to have some issues with proteinuria, hypertension, and from quality of life, if you're on three antihypertensives and you're spilling protein, you're seeing the nephrologist and, you know, at that point, that often will make decisions for me about when to stop utilizing BEV. So I wanted to put this slide together with the changes from this January and what's been added to the other recommended regimens and kind of highlighted those in pink with regards to the changes. And, you know, I think the exabethalone BEV kind of caught me by surprise. It's a phase two trial, some interesting results, obviously the platinum doublets all on the far left side, and then the MIRV-BEV, which I'm pretty proud of. One of my passions throughout is obviously antibody drug conjugates. I participated in the first in human trial on MIRV, and then we opened forward to it. Next slide, please. Which is actually, you know, the first antibody drug conjugates I worked with. In remembering that we've learned a lot over the last 10 years, so we just had a 10 year anniversary of opening up the first in human phase one trial with MIRV. Antibody drug conjugate, they need to express folate receptor alpha. You, you know, and then internalize your warhead. In this case, it's DM4, an anti-microtubulin, and a pretty convenient dosage. Once every three weeks, it's just based on adjusted ideal body weight, and actually have now in the U.S. have accelerated approval, which is not full approval. We're waiting for Mirasol. Next slide. So the accelerated approval is based on a single arm trial, and Ursula Manolonis and Rob Coleman presented this. Ursula will actually be talking about in the future, so I won't dive in too much here, but really we're looking about 32% response rate with a duration response of seven months. Again, one to three priors. They needed to have Bev. We know that prior Bev does impact subsequent therapies, but really well tolerated, as you see here from the, whatever I'm trying to say. I'm sorry. Our side effect profile here on the right, our table. Sorry about that. Had a little seizure, and we do see some neuropathy. Very little to no alopecia. You'll see some hair thinning, and very minimal hematologic. Obviously, we've really talked about the eye toxicity across time, and well, actually, I saw that you had planned one of these for just the eye toxicity, so it's very manageable. It happens very consistently, cycle two, day 10 to 14, and I partner a lot with my ophthalmologist. Next slide. Dave, just a quick question. So, you know, obviously, the accelerated approval is for folate receptor alpha two plus, greater than 75% of the cells. What percentage of patients in your practice do you see that in? And you mentioned that this is a poor prognostic factor. Do you think it's, do you need to re-biopsy people when they're progressing, or is that helpful in terms of looking at the folate receptor? In other words, does it express more as the cancer progresses? Yeah, it's an interesting question. So, we did this, part of forward two actually was a biopsy cohort, and we saw that the concordance was actually pretty high, greater than 70%. It's not 100%. And the other is, you know, do you need to re-biopsy? I do not. I re-biopsy very few patients outside of clinical trial. Is it unreasonable to re-biopsy the check? It's not unreasonable at all, but, you know, I think you see pretty good concordance from the primary. Now, what's interesting is we need to start looking at, should you send the primary tumor or the metastatic tumor? And I'm probably going to start sending both, because obviously the metastatic tumor at the time of diagnosis is probably more telling than the behavior. But, you know, it's a good drug, and we'll talk a little bit about even at those non-high folate receptor alpha expressions. So, you know, I think as we look at this, I don't re-biopsy. The overall occurrence in Sereo was about 35%, 36% of high folate receptor alpha. If you look at across really the continuum of when we've tested, it's about 40% plus or minus a few percent. So, you know, in clinical practice, I don't know what it is. It seems to be maybe a little bit higher than that for the high folate receptor alpha, but really I count on more of the objective and prospective, which is going to be about that 35% plus or minus, excuse me, 40% plus or minus 5%. So, you know, if you look at all tumors about who express any folate, it's going to be greater than 80%, 90%. And you have the medium expressors, which are 50% to 75%, which will be about another third, okay? So those medium will be just over half the patients. Then you have low. Then you have very few with none. So, you know, you see that across kind of the continuum as you test more here. Actually, why don't we go to the next slide? So, you know, in the U.S., November 14th, we saw 10 years of work lead to FDA accelerated approval. And in platen-resistant ovarian cancer, the biggest challenge for us from November until January was getting the tissue tested. And that was because a lot of people over a long time knew the activity of this agent and was very excited for a new option for platen-resistant ovarian cancer. It's really the first one in nearly 10 years. And we had a lot of patients who desired. So we now test everybody. It's available on commercial vendors. And I really have started testing it when I send my tissue for next-generation sequencing. Next slide, please. So this is really about Forward II. And Forward II, again, just to remind the audience, was actually a multiple cohort trial that we tested different combinations. Obviously, the big combination here that's developed was the MIR-BEV data. And we just published this in GYN-Oncology this year with regards to the totality of our MIR-BEV experience. The platen-resistant was about 94 patients. There's another 40 that we put in an agnostic group. And we'll talk about that in the safety. But we got about 94 patients. About half of them, to your earlier question, were high folate receptor expression. Now, that's taking up all the ones that were low or high, so eliminating those that were less than 25%. So this is what I was just alluding to, that medium expressors. And then you're going to lose about another 10 up to 20% that had less than 25%. Heavily pretreated, half the patients had three or more lines of therapy. And more than half had BEV. Next slide. So objective response rate in this entire 94 patients was 44% with a medium duration of almost 10 months, really almost unheard of. Again, this is using the MIR-BEV. With 5% having complete responses, again, almost unheard of and platen-resistant. Next slide. And really, when we look across the upper right, you have expression in not only high, but medium and lows. Now, lows are only 11 patients. Because over time, we wouldn't allow those to be included in the trial. You do see some differentiation. Again, low numbers, confidence intervals overlap with regards to BEV-naive versus BEV-pretreated. Next slide. So this is the entire population of patients, to include 126 patients, that also utilized in the platinum-sensitive. And you see the entire population with about 44% response rate, with response rates slowly going trending down. I'm not going to say trending down from high to low expressors. And then when we look at prior BEV exposure, this is just schematically showing what I just said, but also including the platinum-sensitive. So about 58% versus 32%. Interestingly, we're not seeing much differentiation between platinum-resistant, classic platinum-resistant versus platinum-sensitive, 48% versus 44%. And then a slight downward trend in the more heavily pretreated, which you would expect. But from that first slide that I put up there, we really expect less than 10% response rate in these heavily pretreated. We're seeing 35% response rate. Next slide. And then when we start looking at the duration response, overall population, 12 months, 12 to 10 BEV-pretreat exposure, platinum-free intervals, 13 versus 9.7. Number of prior lines, interestingly, we see inverse correlation, probably, again, by the very small numbers in the heavily pretreated. This is only 10 patients. But if you hit a win, this is what I alluded to earlier. If you hit a win on these patients, your duration response is sometimes miraculous. 14% response rate in, excuse me, 14 months duration response in patients at four or more prior therapies. OK, again, small numbers. Next slide. Wendell's rolling his eyes at me right now. Wendell always beats me up on statistics. So I got to be careful what I say here. No, I agree. I think we've certainly seen this. I've actually been in folate targeting for a long time. And the patients that express this can have long responses to these drugs. And that's a very interesting phenomenon, because we don't see that in the traditional chemotherapy regimens. Right, if you get six months, you're excited, right? And you get out to nine, you're like, holy mackerel. I've seen 12 months in four plus. So I think as we look at this, the total safety population, this was MIR-BEV, slightly increased risk of diarrhea, kind of interestingly. We don't know why. But we have a little bit more than our single agent when we add it with the BEV. Hypertension, which you expect BEV. Obviously, with that, you also will see some headaches. The eye toxicity, peripheral neuropathy, fatigue, not really much difference. But I think it's very interesting that it's consistent with the single agent. When we looked at, it was really interesting. A lot of people have asked me about this. We had a 30% discontinuation rate of MIRV, which is quite high. But when we looked at the average number of cycles, the median mean number of cycles, it was 12. So the discontinuation rate of these patients, a lot of them are like, dude, I'm done. I need a break. And that was the reason for the discontinuation. And it's really interesting, in clinical practice, building in some holidays here. Give the patients a little break from the neuropathy, from the fatigue, even from the GI. And you see that, again, median number of cycles was six. We did have one patient, unfortunately, in the grade five. And that was a perforation, most likely related to BEV, as we all know. Next slide. So I'm very, very excited that MIRV-BEV made it to the NCCN guidelines as a 2B recommendation. It's interesting wording with regards to the expression of folate receptor alpha. And you see a little bit, probably, why the NCCN guidelines. I sat on the guidelines for 10 years. I have been off of it now for a couple of years. I was not privy to any of these conversations. This is conjecture. But I suspect that the NCCN guidelines but I suspect that data on our paper that they did review, obviously, that shows kind of activity across all levels of low, medium, and high is maybe one reason that the wording was the way it was. Well, we kind of talked about we're coming up to the bottom of the hour here. And there's so many exciting things going. When I talk about clinical trials here, man, there's a lot going on. And how do I sequence this? I sequence this. First thing I ask is, are they or do I need weekly tax zanes? So if I need weekly tax zanes, that's the trial. Do I need that when? Second, do they have a biomarker? Because I test everybody for biomarkers because in those, if we have that biomarker, especially if it's only a 35%, 40% prevalence or incidence, that I want to make sure I capture those patients. So sutro drug year, very well aware of with regards to that is currently ongoing and is going to be a trial that's open forever, not forever, excuse me, in the future. Now I misspoke, in the future. So we have IO therapies. We're starting to see some really exciting results, particularly for next generation. We have next generation IL-2 and next generation CTLA-4. We have CAR-T. I mean, really exciting stuff. It's the next generation here. And obviously, targeting the DDR pathway with regards to our WE-1 inhibitors, PIK3 kinase inhibitors, and CHEK1-2 inhibitors is also very exciting. Next slide, please. And we're waiting for a lot of trials to read out. INOV-8-3, which is a trial I led in the US, which tumor treating fields and apparatus accelerated a GAS-X6 activity, again, with a weekly paclitaxel. These have all completed enrollment. We're obviously on the edge of our seats with regards to Mirasol. UPRI, which is an API-2b ADC, has completed enrollment, platen-resistant. And a shameless plug, there's actually two ongoing phase 3 trials in antibody drug conjugates and maintenance. UPNEXT, which is the UPRI agent, and GLORIOSA, which is MIRV-BEV. So both of those are enrolled in the platinum-sensitive maintenance. So please consider screening for both of those trials and enrolling. And then we're also waiting to hear about some IOs, mostly on the NRG side. We're curious to see if that's going to move the science forward and our patient care forward with regards to IO therapy. And we have some disappointment in two negative trials, 3018, which was the OVIL trial, and then Moonstone, which was norepirib distylomab. So lots of exciting things going. Clinical trials, number one. Clinical trials, clinical trials. And then we have some really new agents. I'm starting to screen everybody for folate receptor alpha and in clinical trials, NAPI-2b and folate receptor alpha to try to look for opportunities there to get patients on trial. It's an impressive portfolio through the GoG Partners mechanism and some very exciting work. And in terms of targeting these hard-to-treat cancers in other ways, and I love the resensitization, whether it's the alkalytic virus, the WE1 inhibitors, very exciting there, new targets with ADCs, new therapies that the IL-2, without the traditional IL-2 toxicity, very interesting work there. So I think the GoG Partners group has done a great job bringing these trials forward. And I'll put a plug in for the GoG. I mean, if you're not a GoG site, you should consider this to boost your clinical trial portfolio. So how's that, David? That's wonderful. I appreciate that. And again, we're there. We're looking for good sites. And really, it's the culture. You have to have the culture locally to say, I'm about to change therapy. What clinical trial are they eligible for? What is an option? Obviously, but you're seeing the activity. We don't develop agents for the most part in platelet-resistant ovarian cancer unless the response rate is 25%. Just told you, the expected contemporary response rate, 10% plus minus. So we're not really looking forward to develop it as a 25%. So we have a couple of questions in the last minute here. If patient develops hypertension in treatment, should we discontinue treatment? I do not. I treat. I work with my nurse practitioner. We don't count on our primary care physicians. We treat. There's wonderful algorithms. I put it in my computer, smart phrases, and I just drop that in. It tells me exactly what I should do. And so I could continue to treat with hypertension. They start getting the three agents. They start having significant proteinuria. That becomes different. And then I start partnering with them. I'm going to add to that. I think it's very important, as a gynecologist, that you learn to treat hypertension. If you're going to keep people on a BEV regimen, if you try to do this to another physician, I find that it's a little bit cumbersome. And it leads to higher discontinuation rates because the response time to get them treated can be slower. And so I think it's not really that difficult to treat with one or two agents. And I would encourage everybody to do that. I think as we look here and also get to know your nephrologist, more so than cardiologists, the nephrologists are wizards at this. And I don't send everybody nephrology. I send that when they start getting over a couple of grams of protein, about a gram and a half, actually. And then if I start getting up to three agents. But if you wait for the primary care, they'll see a 150 over 90, and they think it's fine. And then they show up to the infusion suite and we can't infuse them. So really important point of that. The other question that came in, Wendell, it just popped in is, you know, where's the future MIRV? And an option in first line, is it going to be an option in first line? And, you know, I think platinum sensitive, platinum sensitive right now is absolutely the next line. Becca Aaron has a investigator initiated trial, multi-center that we're participating in, in the neoadjuvant setting, with a lot of correlatives, kind of looking at what happened to the folate receptor alpha expression, things like that. So yeah, I think we're going to see it moving earlier lines. I hope so. I've got access to our patients. And it is unbelievably exciting to have earlier lines again, I'm checking folate receptor alpha as soon as I check the next generation sequencing. So I'm going to have that information. We talked briefly- The ocular toxicity, is it reversible? That was one of the questions here, so. Yeah, so it's in our experience, it's been a hundred percent you know, the FDA, and you look at the wording on that because there was some people with persistent grade one, they weren't able to say that it's a hundred percent, but I can tell you in our experience, it's been a hundred percent reversible. And- And I think, like the sterolins, eye toxicity is not quite as bad as the vedotins, which I use an R-statin, but it's dependent on a lot of different things. And it has to do with the linker and the dose and the, so, but yeah, I mean, I think this is something that we're going to have to get used to managing, just like the hypertension with Bev. I'm with you. And, you know, I think they've done, we've done a nice job. They have some, you know, kind of sheets. We actually have formatted the information we need from our optometrists and ophthalmologists. We hand it to the patient and we say, just have them fill this out. And we get that information. You know, in clinical trial, it's very regimented. You know, you know what the ophthalmologists are seeing. They get appointments in clinical care. It takes a little bit of new process flows, but nothing over that we can't overcome. And again, we see it with TB and we just need to start partnering with our ophthalmologists as well as potentially get comfortable. But when it comes to the eyes, I get freaked out. I'll manage blood pressure. I'm going to have to manage eyes. We have the next slide. I want to put in a plug. We've got an upcoming deadline. The deadline for the abstracts, for the 2023 meeting in Seoul, Korea, is coming up on, I believe it's May 9th or May 8th. I stand corrected. So this is going to be a great meeting. If you would like to attend, I believe registration is open or will be open shortly. So that's really all the time we have. And I want to thank Dr. O'Malley for joining us and giving us his insights with particularly with his direction of the Forward II trial. And we look forward to the results of the Mirosol trial and really this is great. This recording will be available on the IGCS 360 if you want to watch this in the future. And we look forward to our other programs coming out. So stay tuned. Thank you very much. Thanks for having me.

platinum-resistant ovarian cancer

treatment options

bevacizumab

mirvetuximab soravtansine

clinical trials

objective response rate

International Gynecologic Cancer Society