Welcome everyone, and welcome to today's webinar, Treatment Options for Platinum-Resistant Ovarian Cancer, which is supported in part by Immunogen. My name is Dr. Kathleen Moore, people call me Katie, and I'm gonna be your moderator today. I'm so excited to be here. I am a gynecological oncologist and I'm the Associate Director of Clinical Research and Director of Phase I Clinical Trials at the Stevenson Cancer Center in Oklahoma City. IGCS is committed to providing meaningful opportunities to our industry colleagues to gain exposure to our gynecologic oncology community through a unique year-long education engagement program. This platform provides the level of strategic engagement and exposure needed to educate and inform gynecologic oncology professionals on current and future medicines to optimize patient care, both locally and globally. Before we get started, I want to mention a few housekeeping items. Please note that a recording of this webinar will be available on the IGCS Education 360 Learning Portal within a week. We encourage you to submit questions via the Q&A feature at the bottom of your screen, and we will do our best to address as many questions as possible at the conclusion of today's presentation. Now, it's my honor to introduce today's speaker, who is not only a world-renowned medical oncologist, but also my good friend. Joining us is Dr. Ursula Matulonis, Chief of the Division of Gynecologic Oncology at the Dana-Farber Cancer Institute and Professor of Medicine at Harvard Medical School. So without further ado, to kick off today's webinar, I invite Dr. Matulonis to begin. And Dr. Matulonis, please share your screen. Thank you. All right. Katie, thank you so much for that lovely introduction. It's great to see you, and it's great to be here. So I think I've got my screen shared. So I'm gonna talk about treatment of platinum-resistant ovarian cancer today in the next 28 minutes or so, and then really focus on a medication-antibiotic conjugate that was recently FDA-approved through the accelerated approval process just a couple of weeks ago, ribotexamab, serapinazine. So I think everyone on this call knows that platinum-resistant ovarian cancer is a problem for our patients and has been limited by new treatment options. So we've really just until two weeks ago have really been able to use single-agent chemotherapy, and the majority of our patients will have received prior bevacizumab. But we've also used combined chemotherapy plus Bev through the Aurelia study, which also has some good response rates. But single-agent chemotherapy has had limited activity from single digits up to around 13% and considerable toxicity, peripheral neuropathy, drop in blood counts, hair loss. Dr. Moore has been instrumental in a great review in allopathic oncology a few years ago, reconsidering the use of platinum, even in our platinum-resistant patients, those patients who are not platinum refractory, but have shown responsiveness to it, their cancers have shown responsiveness to it, and there's been an appropriate amount of time that they haven't received platinum, certainly can reuse platinum, but platinum has allergies. And we all know this every day when we get called by our nurses because a patient is having a carboplatinum reaction. The table here is really from the Aurelia study, the second JCO publication on it, breaking down the benefits of chemotherapy with or without bevacizumab, so weekly paclitaxel, with or without bevacizumab, which really carried the results of the Aurelia study to an FDA approval back in 2014. You can see that single-agent to pegalabel liposomal doxorubicin has a response rate of around 8%. Topo-Tecan has a response rate of 0%. So when you add bev to Topo-Tecan, that is the response rate of bevacizumab. I'm going to talk about mirvotuximab, seraptoncine in the SREA study. So folate receptor alpha, which is also known as folate receptor 1 or fol-R1, does have limited expression on normal tissues, but it's elevated in most ovarian cancers, making this target FR-alpha attractive for the development of novel therapies. Mirvotuximab, seraptincine is an antibiotic drug conjugate or an ADC against folate receptor alpha that is linked by a cleavable linker to the main tanzanoid DM4, which is a cytotoxic tubulin inhibitor. Single-agent MTD of mirvotuximab through the phase one and expansion cohort led by Dr. Moore is six milligrams per kilogram calculated by the adjusted ideal body weight. And SREA is a global single-arm pivotal study that evaluated mirvotuximab for the treatment of patients with platinum-resistant ovarian cancer who have high FR-alpha expression and who have received up to three prior therapies, including the mandatory eligibility requirement of receipt of prior bevacizumab. And as I mentioned, mirvotuximab, seraptincine received accelerated USFD approval on November 14th, 2022, which is just two weeks ago for the treatment of platinum-resistant ovarian cancer, again, for this specific indication when SREA, FR-alpha high-expressing ovarian cancer and patients who have received up to three prior lines of treatment. So the SREA study, which has been accepted into Journal of Clinical Oncology just recently, the primary endpoint was confirmed overall response rate by the investigator. Again, this is a single-arm study. There was also a big or so blinded independent central review for sensitivity analysis. The key secondary endpoint was the duration of response and the patient population, as I mentioned, platinum-resistant ovarian cancer treated with at least one up to three prior lines. Patients with primary platinum-refractory cancer were excluded. Patients had high-grade serocystology, all had received prior BEV. Patients could have received prior PARP inhibitor. And importantly, the tumor had to, and this could be archival tissue, patients were not required to have an on-treatment biopsy. So archival tumor was tested for FR-alpha and had IHC done by the PS2-plus scoring system and had to have 75% or higher of the cells, of the cancer cells, staining positive with at least two-plus staining intensity. The treatment schedule, as I mentioned before, MERT was given six milligrams per kilo once every three weeks. Sample size was 105 patients. And we were looking for the 90% power to detect a difference in overall response rate of at least 24% versus 12%, which would be considered analogous with single-agent chemotherapy overall response rate. This is the investigator-assessed objective response rate. These are confirmed responses. This is 32.4% and obviously surpassed what the aim was, was 24%. There are five complete responses. So definitely an active agent. There are two predefined subset analyses, the number of prior lines of therapy, one to two or three lines, as well as if patients received a prior PARP inhibitor and the response rates held up regardless of patients receiving one to two or three lines of therapy. And also if patients had received a prior PARP inhibitor, yes or no. This is the median duration of response, which was 6.9 months. Again, quite extensive. And this combined with the overall response rate and the tolerability of the drug is what the FDA allowed this drug to be granted accelerated approval. Also looking at the median duration of response compared to the number of prior lines, one to two versus three. And whether or not patients had received a prior PARP inhibitor, no changes, no significant differences in these two subgroup analyses. This is the Swarmer plot looking at the patients who had achieved a CR or PR. And you can see those black dots are when the patient first has a response. So two thirds of the patients get a response, achieve a response, either PR or CR. Within first six weeks of the first treatment assessment, another about a third of patients at the second assessment and there are a few stragglers who achieve a response a little bit later on. This is a slide that looks at the treatment related adverse events. On the left is from the treatment present or the SREA presentations I've made over the past year. Most common side effect is blurred vision that occurs in 41% of the patients, mostly low grade keratopathy. And that term keratopathy is defined at the bottom. It's really what the eye specialist sees and reports out to us and to our patients, whether that's a corneal cyst, a corneal microcyst, keratitis, et cetera. Again, most of that is low grade, 8% grade three, 1% grade four. None of these patients had permanent eye toxicities, all reversible. The most common GI toxicity was nausea, happened in 29% of patients. All of this was grade one or two. And you can see from the other side effects, most of them are grade one or grade two. The most significant hematologic toxicity was neutropenia, happened in 13% of patients, 2% had grade three, the rest were grade one or two. So as I mentioned, the adverse events were primarily low grade, reversible ocular and GI events. Serious grade three or higher treatment related adverse events occurred in 9% of patients. And these led to dose delays in 33% of patients and dose reductions in 20% of patients. 9% of patients discontinued treatment due to a treatment related adverse event. One patient discontinued due to an ocular adverse event, which eventually resolved once the drug was stopped. This is taken directly from the package insert. And obviously the package insert is readily available now. And it is a black box warning for the ocular toxicities that it can, that Elaher or Mirtuximab can cause ocular toxicities. And that an ophthalmic exam should be, and is really mandated to be done before a patient starts on Mirtuximab. And then every other cycle through eight cycles, once a patient reaches eight cycles, it can be done on an as needed basis. And patients have to have prophylactic artificial tears and topical steroid skin, given Elaher or Mirtuximab for ocular toxicity should be held until improvement and resumed at the same or reduced dose. And then a patient has grade four ocular toxicities, the drug should be permanently discontinued. We know that the ocular toxicities, whoops, sorry, happen because of off-target effects on the corneas. This is not an on-target effect. The cornea does not have expression of fully receptor alpha. So what happens is that the corneal stem cells on the periphery of the cornea uptake the DM4 and that corneal damage begins peripherally. And then those cells then move in centripetally and then cause the cysts, the microcysts and the blurred vision. Corneal cells are replenished within seven to 10 days. So you can see why the eye toxicities really resolve and improve pretty quickly after holding or dropping the dose of Mirtuximab. This is taken directly in a nicer font and it has nicer look to it. But it's taken directly from the package insert. This is proactive management of ocular events and it's key to work with an eye care provider, either an ophthalmologist or an optometrist to manage the ocular events. We talked about the importance of patients receiving a baseline ophthalmic exam, including visual acuity and a slit lamp exam prior to treatment starting and then every other cycle, three cycles. Patients should avoid the use of contact lenses. The use of ophthalmic topical steroids is recommended and the initial prescription should be made only after examination with a slit lamp exam and patients should administer one drop of topical steroids in each eye six times daily, starting the day before each infusion of Mirtuximab until day four and then patients administer one drop in each eye four times daily on days five to eight of each cycle. Lubricating eye drops should also be administered at least four times daily and as needed during treatment with Mirtuximab and we really have to make sure our nurses and all of us are making sure patients are taking care of their eye care, doing the eye care. This is important also taken directly from the package insert of prophylactic medications that are given prior to the infusion to help reduce the incidence and severity of infusion related reactions. There are 9% rate of infusion related reactions. Most of them are low grade, but still they can occur and also reducing the incidence and severity of emesis. So pre-medications, corticosteroids, IV, dexamethasone 10 milligrams and antihistamines or diphenhydramine, Benadryl given 24, 25 milligrams to 50 milligrams oral RIV and antipyretics, so Tylenol and then 5-HT3 serotonin receptor antagonist or something appropriate also before each dose. And again, this is written into the package insert. How do you gain access to the drug? Obviously this just started two weeks ago and when the accelerated approval occurred, this is a list of specialty distributors where we can gain access to the drug. So important for our pharmacy to have access to this so they can order the drug. And this is again available on the LAHR.com website. Once we order the test, so this happens to be through NeoGenomics. So this is a companion diagnostic looking for levels of expression of FR-alpha. Our group is doing it through LabCorp. So our nurses have been essentially instructed how to get the piece of paper, the ordering paper and sending it to LabCorp or here in this case NeoGenomics with the tissue. This happens to be a positive result. So this is what's gonna look like when the test comes back and it will give you a sort of the positive or negative but also the levels of expression as well which is important to know. And then this is a negative test. So the patient's FR-alpha expression was around, looks like 20%. So that would be considered negative. You need to have 75% or higher. So in conclusions, Mirtuximab demonstrated clinically meaningful anti-tumor activity in psoria and patients with FR-alpha high platinum-resistant ovarian cancer. Overall response rate was 32.4% with a median duration of 6.9 months. consistent anti-cancer activity regardless of the number of prior therapies or use of prior PARP inhibitor, the safety and tolerability of mirvoteximab and psoriasis was consistent with other trials of mirvoteximab, low-grade reversible ocular and GI events managed with supportive care, but remember the eye toxicities and the management and mitigation strategies for the eye toxicity and then what patients should receive prior to receiving mirvoteximab to also help mitigate infusion reactions as well as GI toxicities. 9% of patients treated or discontinued treatment due to treatment-related adverse events, only one patient in the trial discontinued because of an ocular event. So we talked about the accelerated approval on November 14th and obviously this accelerated approval is dependent upon the mirosol study results which Dr. Moore is the overall principal investigator of. This is a trial in the same population except patients do not have to, they're not mandated to receive prior bevacizumab but that high fr-alpha expression of either mirvoteximabs rather than seen as single-agent versus MD choice chemotherapy, single-agent chemotherapy for platinum-resistant ovarian cancer. That trial is completed and in the package insert and in the press release, it is public information that the FDA did look at some of the mirosol data as a requirement for the accelerated approval, really showing, giving us some, I think some encouragement that mirosol will be positive. And then there are other trials ongoing of this drug looking at upfront use of carboplatin, mirvoteximab, the piclo studies testing mirvoteximab in the platinum-sensitive setting, a recurrent setting. The Gloriosa study which is a GEOG partner study is mirv plus bevacizumab post-platinum for platinum-sensitive recurrence. And then Godfrey-Konechi study which we're participating in is mirv plus carbo in cancers that have different levels of fr-alpha expression, not just high but also in lower to medium high. And that's my end of slides and I'm happy to answer any questions along with Dr. Moore who's also a total expert on this on this agent. We both know a lot about this agent. It's been a long journey getting it here. So a long journey, absolutely. One more big hurdle to overcome hopefully next year. So thank you for that. That was excellent. And hopefully we have a lot of people on. So hopefully that was very helpful. We do have, I think one of the big questions that people have now that this is launched and let's just be honest the companion diagnostic was not quite ready to roll yet. So we're having to get it rolling in these other ways. And so we have a question from the group. I won't call out names although hi to this person. So they want to know if we can send archival tissue for folate receptor alpha status or do you need to read biopsy? Does it change over time? You know what's your practice and what's that based on? Yeah so great question. A really important one. It you know from previous studies that were done of myrbatexamab the levels of FR alpha expression do not appreciably change between initial diagnosis. So from patient's initial surgery to recurrence. So there is not a need to to do a fresh biopsy and we can definitely use formalin fixed archival tissue to send for folate receptor alpha testing now. So our pathologist will be able to to pull the pull the slides pull the blocks from patient's initial surgery and send that out for FR alpha testing. And then you mentioned yeah you mentioned in your talk your group's using LabCorp. We're using I don't know why we're using LabCorp but we are. That was decided with our nurses and they're like they're like totally on it. They they I just tell them I what I do is I just say I send them an email to our nurse navigators and say look I need FR alpha testing on patient you know XZ. And then I'll tell them which pathology specimen which date and then I'll give them a case through the Brigham and just put that into the email. They fill out the form get the form sent out and then arrange for the pathology you know to be pulled from the Brigham. Yeah so so just for the group to know there will be a companion diagnostic through Roche Diagnostics available soon. But until then and even when that's available LabCorp is doing this testing as well as Neogenomics. And those are the two that I've been informed are not billing the patient at this time. So so we're using Neogenomics just because my MSL sent me the form and so that's what we're using not because it's a better test. But and it takes about five days so it's a pretty quick turnaround. The other notification I just received in my email during your talk in fact was that this fully receptor alpha has been added to KRAS's panel now. So if you're ordering KRAS otherwise it's included. I don't know if you can add it to something that's already been run in the past. So so I think I would go with the other two that aren't billing just so we don't end up with patients getting bills. That's just I don't know if you feel any differently but I just try to minimize financial risk. Absolutely you know yeah KRAS has also informed me that they're that's that's already on the panel. Yeah that's that's great and that could be great you know when patient's diagnosed that can be part of the initial panel you know that that FR alpha testing is is sort of a true a true reflection of the cancer that that's not going to change in recurrence and that that can be used to determine hopefully the patient won't recur but unfortunately she might but we can use in the recurrence setting too. Exactly and so that bridges so someone else has to ask the question what percent so it's going to be on this panel it's probably going to be on all the panels really so we're not um trying to give a commercial for any of these assays please don't mistake this um all the assays will likely add this relatively quickly but what percentage of patients will be positive by the definition that we are seeing full receptor alpha high yeah for full receptor alpha. Yeah so so it's it's around 35 percent um so one in three uh for that for that you know at least 75 percent of cells standing two plus or higher um so you know again it's a it's a targeted test and I think um benefits patients that you're not going to be giving them a drug um that has you know not a good chance of working so makes sense to only use this as per the FDA guidelines in patients whose tumors are FR alpha positive. Right um and it's kind of exciting you know to see these we've just been a little bit bereft in new targeted therapies after PARP inhibitors and ovarian cancer this is really our first one but there's many other antibody drug conjugates sort of in clinical trial development all targeting different targets and some of them have different payloads so what do you think you know are these all going to be overlapping targets Dr. Manchelonis do you think they're going to separate kind of how do you see um mirvoteximab open the door for us I feel um for targeted therapy here yeah so I think I think you know just because of the way that the that the accelerated approval has occurred has occurred and hopefully you know mirosol is going to be um fingers crossed uh positive right but again as I said the data's already been somewhat interrogated by the by the FDA um so yeah I think so when trials of other drugs are being are being or drugs are being tested um I think that eventually they're going to have to take into account FR alpha positivity because mirvoteximab is the first antibiotic conjugate to be to be approved or given at least accelerated approval in this setting um you know 35 percent is not 100 percent so there are going to be other opportunities for other antibiotic drug conjugates and I think it's really going to be um dependent on us as investigators to to to figure out the landscape of these different antibiotic conjugates based upon um the target and then based upon the payload uh and based upon the patient's previous toxicities what she's responded to what she hasn't responded to um and those toxicities that she is left with um and what the toxicities of those agents are so um to kind of to kind of move through this field it's really exciting um you know as we've seen harp inhibitor approvals being being rescinded um now we've got you know kind of a new class of agents really offering lots of opportunities for our patients absolutely and I think that it just emphasizes a lot of what we're seeing in drug development you and I work on a lot of projects together this is 35 percent some things that I'm working on are less than that um you know these sort of niche targets um HER2 and ovary I'm sending HER2 IHC and all my recurrent ovaries right now because I've trialed them and they freaking work um and so like what percentage are HER2 1 plus 2 plus fish negative like we have no idea but it's probably less than 25 percent but I want to know who they are and I want to know who my NAPI 2b are and I want to know who my folate are yeah so we're really going to get into this you know individualized you know um target and then the payloads you know can you use dm4 again with a different target do you need to roll a roll over to a camphylothesin or topoisomerase right so many different targets it's going to get very nuanced but so many good opportunities for our patients to like right drug right time for right patient I think we're actually starting to see that promise it's very exciting but it's going to be a different world than taxylocobo for everybody you know it's like absolutely and it really because we don't have you know just lots of of sort of mutations within lots of copy number changes that are that are just hard to target in high-grade serosevere and cancer um this really opens up that field through just you know levels of expression of different targets so I totally agree with you Katie yeah it's exciting yeah so we have another really good um question this may be our last one uh if a patient's baseline eye exam is abnormal for example a cataract or long-standing complications of diabetes would they not be a candidate for mirabituximab um were these patients excluded from sorya mirasol forward etc yeah so good question um really again think you have to think about the about the the cornea that that's that's the that's the part of the eye that's um uh affected here um if a patient has a cataract that cataract I don't think I don't think that would exclude the patient I mean it may have excluded on the trial but certainly I don't think would exclude exclude the patient from receiving it but you just have to be careful the steroid eye drops um could make that cataract a little bit worse and that patient may need cataract surgery sooner rather than later that's the key point and you know the studies actually didn't exclude anything other than baseline corneal abnormality which are really rare like corneal transplant they couldn't come on study um and then now I'm forgetting but there's a baseline corneal abnormality that's really uncommon so there were very few patients who were excluded from the trial based on their baseline eye exam but you know we've all become sort of anecdotal ophthalmologists I'm not really but I know a lot more about the eye than I did um eight years ago and you're absolutely right the and we are working with some new protocols to hopefully maybe we can decrease the steroid eye drops someday but initially we need to do both and this drug works since they have patients on it sometimes a long time and they can have I feel like we do see escalation of of cataracts and other visual changes maybe because we're more attuned to it and we're asking the questions and so our patients are telling us or maybe it's really is more common it's just hard to know but um but I think having a really good relationship with an optometrist or ophthalmologist um because you really can see development of cataracts over time that need to be addressed so the patient continues to have great quality of life and that's something we'll have to address moving forward um and it's not negligible but but it's their mitigation strategies and we just have to continue to learn and grow and mature as we learn how to use this drug over time exactly right and then assessing you know not only with the with the optometrist or ophthalmologist tells us through the through the exam but also what the patient tells us like how how troublesome are the eye toxicities you know can can you can you read those sort of things I mean most of the time it's low grade but it's just important to for that patient to tell us just like it is for neuropathy or you know other side effects that we can't only they can tell us it's not like a white blood cell can or a platelet can that they that they need to communicate with us yeah it's really different so like I was joked I'm like maybe I should learn how to do a slit lamp but I'm not going to I'm not going to it's just going to be patient has to tell me or not tell me um you know what's what's going on then we have to act on that um appropriately but things are you know that so it's I feel like our patients have so much grace and they tolerate so many toxicities from the medicines that we use and collateral damage to their hair and their nerves and their skin yeah which is all very important eye toxicity is sort of a different um egg and so it's very the mitigation strategies work it's low grade this drug works I'm very passionate about it yeah very reversible like no one's going blind on this I'll just say that I've treated a lot of patients that's a view but we take it really seriously so I guess I don't want people to think we're just like blase about it it's a great one we take it seriously we send them to the ophthalmologist but these are good mitigation strategies and reversible uh so patients can have really good quality of life yeah so yeah I think that um with that I don't see any other open questions um and so I'll just turn it over to you for any last thoughts Dr. Machelonis congratulations on Soria thank you so much for getting this available for our patients finally hallelujah well it's it's really a team effort um you know led by you uh Katie honestly you've done so many so many studies and with myrtuximab so it's really a team effort and totally appreciate all of your work and dedication um and it's uh it's an honor to work with you it's great to see you um this is really important for our patients and I think opens up the door to yet another realm of new therapies for patients with ovarian cancer which is super important and much needed amen can't say anything more than that okay well um thank you again uh to our guest speaker Dr. Machelonis thank you for taking some time out of your busy day to give us this wonderful update this is all the time that we have for today I want to thank everyone for attending I'd like to very much thank immunogen for supporting this webinar as I said earlier the recording of today's session will be available uh in the IGCS education 360 learning portal within a couple days upcoming IGCS education may be found on the IGCS website and we wish you all continued health and safety stay well until we meet again bye-bye bye-bye take care

Treatment Options

Platinum-Resistant Ovarian Cancer

Webinar

Mirvotuximab Soravtansine

Folate Receptor Alpha

Ocular Toxicities

Antibody Drug Conjugates