and I am the current president of the IGCS. I'd like to welcome you to today's webinar called SEREA. This is the SEREA trial that is going to be presented by my good friend and colleague, Dr. Ursula Matalones, who I'll introduce here in just a second. This webinar is being supported in part by Immunogen. IGCS is committed to providing meaningful opportunities to our industry colleagues to gain exposure to our gynecologic oncology community through a unique year-long educational engagement program. We thought this came up through a series of conversations we had internally with council and our disease site experts to figure out a way that we could reach the educational mission, not only of the society, but also of our sponsors who are bringing and spending the time to develop new assets. This platform provides a level of strategic engagement exposure needed to educate and inform gynecologic oncology professionals on current and future therapies and to optimize patient care both locally and globally. So before we get started, I want to mention a few housekeeping items as you can't do a webinar, and I'm sure you've never been on one in the last two and a half years. But before we get started, I wanted to mention a few housekeeping items. Please know that a recording of this webinar will be available on the IGCS educational platform or educational portal within a week or so. So this will give you the opportunity to take a look at this again. If you missed something or for those of you who didn't get an opportunity to see the whole program, you can go and watch it there. We encourage you also to submit questions via the Q&A function at the bottom of your screen. Hopefully you know where that is. So again, I feel like I repeat this like so many times a week. But go ahead and send your questions through there, and I'll also be following the chat. So if you get, and hopefully you can do it through the Q&A function, because it's easier for me to organize those. But I will monitor those during the presentation, and then we'll have some time at the end to go through this presentation and to speak with our colleague and expert, Dr. Ursula Matalonis, who I'd love to introduce right now. So of course, it's my honor to introduce Dr. Matalonis. She's the Chief of Division of Gynecological Oncology at Dana-Farber Cancer Institute, and she's a professor of medicine at Harvard Medical School. Great friend and collaborator for many, I hate to say it, decades. Although we're both so young looking, aren't we, Ursula? So, but without further ado, and she also has worked with me on this particular project, so we're really excited to have her present this. And we're lucky to have the time that we didn't really get to do at the SGO to be able to go through the data carefully and hopefully allow for opportunities for you to develop questions. So without further ado, Dr. Matalonis, please take the screen and take it away. All right. Thank you. Thank you, Rob, for that really kind introduction. And if you, yeah, perfect. I'm gonna share my screen. There we go. It's bigger. And here we go. Excellent. So it's great. I can't see everybody, but it's nice to know that people are out there. And Dr. Coleman, thank you so much for that great introduction. And it really has been a great partnership over decades and look forward to continuing to work together. And in fact, we did work together on this. Rob is a co-PI, I'm a co-PI in this trial. And we presented this data at the Society of Gynecologic Oncology in March of 2022, presenting the results of the efficacy and safety of mervatexamab, seraptoncine in patients with platinum-resistant ovarian cancer with high folate receptor alpha expression. And these are the results from the SEREA study. And this is truly a global effort. It was an international trial. So really want to thank all of the collaborators, all of the sites and investigators who participated in this trial, which really accrued during the pandemic. These are my financial disclosures and they've been updated. And then this is also something that we had to mention in SGO that mervatexamab, seraptincine is not yet approved for outside use besides clinical trial use. So as many of you know, probably all of you know, the treatment options for platinum-resistant ovarian cancer are quite limited and they consist predominantly of single-agent chemotherapy since many of our patients will have received prior bevacizumab. And we know that single-agent chemotherapy has quite limited activity. Drugs like topotekin, gemcitabine, oral citoxin, et cetera, have overall response rates of up to about 13%. And certainly all of these agents have considerable toxicity. To date, there's no biomarker-directed therapy that's been developed. Bevacizumab does not have a biomarker. PARP inhibitors certainly do, but they are now being used more upfront in our newly diagnosed patients. And there's actually the clinical biomarker of platinum-sensitivity and resistance, but certainly no biomarker-directed therapy for platinum-resistant disease. We know that ovarian cancer overexpresses folate receptor alpha, and folate receptor alpha, or FR alpha, is associated with poor clinical outcomes. Mervatexamab, seraptincine is a first-in-class antibody drug conjugate that's comprised of an FR alpha binding antibody, a cleavable linker, and the matanzanoid DM4, which is a potent tubulin targeting agent. And this study was really based upon pooled analysis from previous studies from Mervatexamab that identified 70 patients that fit into the eligibility criteria for this trial. So they had FR alpha high, platinum-resistant ovarian cancer, up to three prior lines of treatment. All patients had received prior BEV, and the response rate was 31.4%, median duration of response of 7.8 months, and the median PFS was 4.4 months. So this is what we were really aiming for. So SRAE is a global single-arm, even though it's called phase three, it's a single-arm trial evaluating Mervatexamab in adult patients with FR alpha high, platinum-resistant high-grade serous epithelial ovarian cancer, primary peritoneal, or fallopian tube cancer. This is a study design in patients. So the objective is to evaluate the efficacy and safety of Mervatexamab in patients with FR alpha high, platinum-resistant ovarian cancer. And the primary endpoint was confirmed overall response rate by the investigator. There was also overall response rate by blinded and depend on central review for sensitivity analyses. Key secondary endpoint is the duration of response. And these are the sort of basic eligibility criteria. You have to have platinum-resistant ovarian cancer. So recurrence within the traditional definition within six months of after last platinum dose treated with up to three prior regimens. Patients with primary platinum refractory cancer were excluded. Patients had to have high-grade serous histology. All patients enrolled had received prior Bevacizumab and the use of prior PARP inhibitors was allowed. And this is important in terms of how the staining was scored. It's something called a PS2, which is the sum of staining of 2-plus and 3-plus staining. So tumor demonstrated FR alpha high membrane staining with IHC 2-plus scoring. So 75% or more of the cells stained positive with at least 2-plus or higher staining intensity. The treatment schedule as follows. Patients received Mervituximab six milligrams per kilo through adjusted ideal body weight IV once every three weeks and kind of coming to this dose took many years. And I always tell the story that we started working on this drug back in 2013, 2014. And again, took several years to get to this dose and using adjusted ideal body weight. The sample size calculation was 105 patients. So 110 patients were planned to enroll to get approximately 105 efficacy valuable patients. The stats were designed to achieve 90% power to detect a difference in overall response rate of 24 versus 12% using a one-sided binomial test and a one-sided alpha level of 0.025. 12% was chosen as the overall response rate to rule out based upon the overall response rate for single agent chemotherapy in patients with more heavily pre-treated platen-resistant ovarian cancer. These are the baseline demographics of the patients. Median age was 62. A considerable number of patients had stage four disease. And we really think that that's because of the high level FR-alpha expression, more aggressive cancer, higher stage. 20% of patients had an underlying BRC mutation. About 50% of patients had three prior lines. So a heavily pre-treated patient population. All patients had received Bevacizumab and about half the patients had received a prior PARP inhibitor. The primary platinum free interval was three to 12 months in about 60% of patients and more than 12 months in 40%. The platinum free interval when coming into the trial was zero to three months in about 37% of patients and three to six in 60% of patients. This is the overall primary endpoint of the study, which is investigator assessed objective response rate, 32.4%. There were 34 responders out of the 105 patients, five complete responses and 29 partial responses. And in terms of the pre-specified subgroups, so on the left is the 32.4% that I mentioned. The two subgroups that were predefined were the number of prior lines of therapy, one to two versus three, and then whether or not the patients had received a PARP inhibitor previously. And you can see that for one to two lines, response rates 35.3%. And for patients with three lines of therapy, response rate was 30.2%. And these are all confirmed responses. Prior PARP inhibitor exposure did not impact response rate 30% for prior PARP inhibitor exposed patients versus those who had not, and that was 27.5%. This is the investigator assessed duration of response. The median duration of response is 6.9 months. And at the time of the data cutoff, which was March 3rd of this year, there was still seven responders ongoing. This is the swimmers plot looking at the duration of responses. Complete responses are in pink, and then the partial responses are in blue. The black dots represent the first response. So two thirds of the responses occur at the time of the second cycle, and over 90% of the first responses have occurred by the time of the fifth cycle of therapy. So really, as I mentioned at SGO, these responses are rapid, and they're also quite durable considering the median duration of response is 6.9 months. And the green arrows represent patients who are still on therapy as of the data cutoff. So looking at the predefined subgroups with respect to the duration of response. So here's the median duration of response, 6.9 months. The duration of response did not considerably change regardless of how many number of prior lines the patient had received. One to two lines, 5.9 months, and then three lines of therapy. So obviously more heavily pretreated patient, seven months. The same is true with prior exposure to PARP inhibitor that did not alter significantly at all the median duration of response. And these are the efficacy endpoints as assessed by the investigator on the left, and then the blinded independent central review, 32.4% versus 31.6, so nearly identical. Also in terms of the complete responses, both the investigator assessed and Bicker assessed CR is lined up. The median duration of response, 6.9 months versus a little bit longer in the Bicker assessed of 11.7, and median progression-free survival, 4.3 months, which is what we were aiming for based upon that initial subset of patients in previous Mervitux-MAP trials, slightly longer in the Bicker assessed population or Bicker assessed stats or results. These are the treatment-related adverse events. So most adverse events were low-grade, reversible, ocular and gastrointestinal events, and these were managed with supportive measures. There was a low incidence of peripheral neuropathy, no alopecia, and limited hematologic events. And in serious grade through higher treatment-related adverse events were reported in 8% of patients. And these adverse events led to dose delay at 32% and dose reduction in 19%. Only 7% of patients had to discontinue treatment due to treatment-related adverse events, so quite low. One death was recorded as possibly related to the study drug from respiratory failure, but at autopsy, that patient had no evidence of a drug reaction, and she had extensive lung metastases. So overall, really a very well-tolerated medication. So ocular events we know are common with antibody-drip conjugates, but we also know that ADCs are not all the same. The ocular events observed with mirvoteximab were reversible and primarily included low-grade blurred vision and keratopathy. And these were managed by predefined protocol, dose reductions, dose modifications. All patients were instructed to use prophylactic lubricating eyedrops and tears, and also used corticosteroid eyedrops. All patients had a baseline ocular exam and then if at any time the patient developed some kind of an eye symptom, then that patient underwent every two cycle ocular exams by an ophthalmologist until she came off the trial, and actually until the eye toxicities resolved. The eye toxicities are predictable. The median time to onset is around cycle two, so around 1.5 months into treatment. As I mentioned, these are manageable with dose modifications if necessary. 22% of patients had a dose delay and or a dose reduction. And at the data cutoff, vast majority of patients with grade two to three events had resolved to zero to one. And there was really just one patient who came off trial because of eye toxicities. And that patient actually had resolution of her eye toxicities within 15 days after stopping therapy. So in conclusion, Robotuximab demonstrated clinically meaningful anti-tumor activity in patients with F or alpha high platinum resistant ovarian cancer. The overall response rate was 32.4%, and this was investigator assessed, including five complete responses. The median duration of response, 6.9 months, and there was consistent anti-cancer activity regardless of the number of prior therapies that the patient had received or the use of prior PARP inhibitor use. The safety and tolerability profile of Robotuximab in Serea was consistent with that observed in previous studies. We saw low grade reversible ocular and gastrointestinal events, which were managed with supportive care. There was no appreciable bone marrow suppression and very limited low grade neuropathy. As I mentioned before, no alopecia. 7% of patients discontinued due to treatment related adverse events. Only one patient discontinued due to an ocular event and her eye symptoms, as I mentioned, resolved 15 days later after she stopped and came off treatment. So these results position Robotuximab to become a practice changing biomarker driven standard of care treatment for patients with F or alpha positive platinum resistant ovarian cancer and are certainly looking forward to and hoping that this will be the first drug since really 2014 that's been approved for platinum resistant ovarian cancer. So I'm happy to, oh, actually I wanna mention, how can I? This presentation is dedicated to all the patients, obviously, and their families who participate in the Serea study and wanna thank all of the clinical investigators and the research teams. And these are everybody and it's really an outstanding group of investigators. And it's really been a pleasure to participate in the study and work with Rob Coleman on this effort. Awesome, thanks so much, Ursula. It's very nice. It's so nice to be able to have the opportunity to go through the data carefully so that people can absorb it. And there's been a few questions that have come in that I'll get to, but first of all, just congratulations and thanks for taking the time out of your busy day to attend to that. Oh, my pleasure. So one of the questions that comes up frequently just is about the patient population and you mentioned some very key elements there. So, and one of the things I think that strikes most people's eye is that it was kind of the restriction on, or not the requirement for prior Bev and then the allowance for prior PARP. Why was that important to do in setting up the trial? Yeah, so it really, Rob, revolved around regulatory requirements and input from the U.S. FDA that given the activity of weekly paclitaxel and bevacismab that either you'd really want to see efficacy similar to that or go after that. So this was really a trial positioned post-Bev and really an unmet need. PARP inhibitor use is really now ubiquitous around the world. So I think to either mandate it or to exclude it would be a problem. And instead of the study, opted to use it as a pre-specified subgroup whether or not patients had received PARP inhibition or not. The ongoing Mirasol study in relationship to the Bev question doesn't necessarily mandate prior Bev, but SREA did. Excellent. Yeah. Thank you so much. Now, a question just popped in and it has to also do with eligibility and that's the requirement for a foot receptor alpha staining. I think this physician was from Spain was I think lamenting over the issue of lots of screening, not so many positives. I think we've all experienced that. Yeah. So what was the importance of that expression? Yeah. So as many of you know, Rob's really knows he was investigator in the forward one trial that Katie Moore led. And this really loosened the criteria for the folate receptor alpha levels of expression. Not only enrolling patients with FR alpha high but also medium. And in that trial, ribotexamab really did not have that deep and durable responses in the more medium levels of expressors. So hence why Mirasol randomized phase three study ongoing and this trial SREA focused on patients with FR alpha high. So really having that 70, more than 75% of cells seating two plus or higher. Yeah. So it sounds, we knew that we were going to have a limited population but we really wanted to show proof of mechanism and efficacy by selecting the patient's tumors that had the best likelihood that the drug would work. Obviously as a targeted drug smart bomb, if you will, to the tumor. A couple of questions came in about, maybe some nuts and bolts just about clinical trials. The one thing was, what was a BICR or what does that stand for? I know we always talk about that. And the other was a question that came in about how do you, what's the definition between, or what's the difference between a complete and partial response and how is that determined? So BICR stands for blinded independent central review. And it is a, it's something that in a lot of trials that are going for potential approval, regulatory approval. There is a basically a way to make sure that we as investigators are doing what somebody else would be doing in an independent setting. So when we see patients, maybe we want the patient to come off the trial, stay on the trial. So we have some judgment impacted in our decisions around responsiveness and then taking patients off study. So a blinded independent central review, basically a bunch of radiologists and some clinicians as well will look at CAT scans blinded, not knowing the patient, not knowing who they are and how they're even doing on the trial. But really saying, okay, is this a complete response? Is this a partial response? Do they have progression? Do they have new lesions, et cetera? So that really gives corroboration to the data. And sometimes if there's a difference, there can be a difference that the investigators say, oh yeah, this response rate is 50%. And then the blinded independent review says, oh no, it's more like 20%. So there's a discrepancy. But in SEREA, we saw essentially equivalent results. And in terms of responses, the responses are dictated by something called resist criteria, which are criteria that investigators and radiologists use to measure baseline, sort of identified baseline areas on a CAT scan or an MRI scan that are followed for growth, followed for regression, and also looking for new areas as well of cancer. Yeah, so it's kind of a set of, it's like an instruction sheet on how to monitor tumors as time goes on. Thank you, that's awesome. You know, I think lots of people were struck and I think you mentioned, you emphasized this point, and that's that two thirds of the patients had their response, the ones that responded had that response documented by essentially their first CAT scan. And that was obviously very exciting. Why is that important for this patient population? Yeah, that's a good question. I think, you know, as, and we know that single agent, I mentioned the single agent chemotherapy and platinum resistant ovarian cancer, you know, single agent response rates. So you can have stable disease in a lot of patients' progression, but not many responses where you get sort of meaningful tumor regression. And as our patients become more heavily pretreated, that level of response lessens. So it's important because our patients become symptomatic, they may have disease that's, you know, about impending obstruction, impending ureteral obstruction, bowel obstruction, and having a response can be, you know, again, transformative. And we had a few patients on Soraya, one of my colleagues who, again, had a, some patient who was, you know, getting symptomatic and had this great complete response and really, you know, was kind of resurrected and taken out of her symptom state and brought into, you know, ECOG performance status more like zero. So the responses are important because they'll just take somebody out from a potential dangerous situation in terms of symptoms or organ dysfunction. Right, excellent. Well, talking about toxicity in the last couple of minutes that we have here, I thought, you know, obviously there's a lot of attention paid to the ocular toxicity. I think you did a great, really nice job of walking us through that toxicity. I think one of the things that you mentioned, which is spot on, is that all of these ADCs are different. You know, so those of who maybe had experience with Dasodamab know that there's a different type of toxicity seen with that. But one of the toxicities that kind of struck my mind in seeing these patients was, you know, this blurred vision, but what we see is reduction in ocular or in visual acuity. Like all of a sudden they realize that their glasses have got to be changed. And we see this with chemotherapy patients, obviously, as well. But what was your experience with that? You probably have the, I think probably the global experience of the most patients treated with this over the number of years. How do you, what was your experience with the patient who, you know, complained of those eye changes? Yeah, it's interesting. I think it, I mean, the patient population is obviously advanced recurrent, platinum-resistant ovarian cancer, and they know they're going to, you know, eventually, unfortunately pass away from this cancer, but still they were able to really articulate the symptoms, because I think sometimes patients will maybe underrepresent symptoms because they want to stay on something, especially if it's working. But I think this is such an overt symptom, you know, blurred vision. So what happens is, you know, they were, people would bring newspapers in, they were maybe needed a different set of reading glasses, they needed larger print, you know, they couldn't read their phone very well, but it was all acceptable. You know, I didn't have any patients tell me this is unacceptable because they knew that, you know, the drug had really potential efficacy for them. So again, minor toxicities. And by the time, you know, as I mentioned, two-thirds of those patients, by the time they hit the next cycle, the time just corrected things. For the minority patients where they still had persistent symptoms that were significant by the next cycle, they had a dose reduction from six down to five. Yeah, that's great. While we're at time, I'm sorry to say, but I'm so excited that we've had this opportunity. Let me go to this final closeout slide here. This has been great. Thank you for those of you who sent in the questions as well. I was able to get to basically almost all of them. So that's really exciting. But I'd like to just close by, first of all, thanking Dr. Madalonis for her fantastic presentation. Lots of comments about your fantastic presentation to her slide, just in case you were concerned. There you go. You guys are very kind. So, just a reminder, I also want to thank the Immunogen for supporting this webinar. As mentioned earlier, the recording will be made available in the educational portal at the IGCS website. And as will be kind of the calendar of upcoming educational forum that we'll do as part of this continuing educational opportunity during the year. Also would be remiss if I didn't highlight and mentioned that the IGCS annual global meeting will be from September 29th to October 1st in New York City. We're so excited to be there. The abstract submissions are open until Monday, May 9th, and there will be an in-person, and this will be an in-person and virtual opportunity for those of you who are interested in attending this meeting. So please visit the IGCS2022.com website to get more information about the meeting. We wish you all a healthy rest of the year and happy summer for those of you in this part of the hemisphere, and winter for those of you on the South. And I really appreciate all of you joining us today and I hope you have a great rest of the day. Take care.

SEREA trial

Mervectuximab

platinum-resistant ovarian cancer

Dr. Ursula Matalonos

folate receptor alpha

overall response rate

complete responses