Welcome, everyone, to IGCS Education 360 Advances and Updates Journal Club. Hey, this is the inaugural one, the first ever, and we are super excited about doing this today. We hope that there will be many more of these so that we can bring these latest advances to you in a podcast format and discuss this with the authors of this study. Today, we'll be discussing the recently released publication, The Efficacy and Safety of Mervituximab, or if tansy, an FR-alpha-positive third-line and later recurrent platinum-sensitive ovarian cancer, the single-arm phase II piccolo trial. That's a pretty long name title there, Angeles. Great job, though. The publication is available online now at the Annals of Oncology. In this journal club, we'll provide an in-depth discussion of the paper, including the background of the study, the aims of the research, methods used, results, and, of course, conclusions. We'll also discuss the strengths, weaknesses, and statistical analysis of the trial. Our main goal from today's journal club is to take you through the study itself, its key findings, and how these results could be applied clinically to day-to-day patient care, and what further research is needed to continue to advance the care of our patients in this setting, recurrent platinum-sensitive ovarian cancer. I'm honored to be joined today by Dr. Angeles Alvarez-Sakor, my good friend, who is the lead author of this publication and who will share the key data and insights into this trial publication. Then we'll get into some discussion. Angeles, thank you so much for doing this. Please go ahead and introduce yourself. Rob, thank you so much for inviting me. What an honor to be part of the first inaugural journal club for IGCS. I also just want to acknowledge that this was a huge team effort, amazing sponsorship from Immunogen, and also incredible, incredible impact and participation from individuals around the world. So on behalf of all my colleagues who participate in the trial, and then our patients, which I think are so pivotal to everything that we do. They're truly in the center and provide us purpose for our work and these trials moving forward to make progress for all of our patients, right? And I just want to acknowledge that this study was launched by Immunogen, which is now wholly owned by AbbVie. And we're just really thankful for our sponsors. So going toward the study, are you ready, Rob? I'm not ready with all the IT stuff. Baring the screen is really challenging for me, so let's see how I do. And I cleaned up my desktop for you all today. So the big important thing is hopefully I have this right and I have the right version. So we'll see as we go through this. Looking good so far. Super excited to be part of this study because there is an urgent unmet need. As you know, we're in clinic, many of us like every day of the week taking care of our patients. And we recognize that we need novel and effective therapies to treat patients with all the gynecologic cancers. All the gynecologic cancers, but this was really focused on patients with recurrent ovarian cancer and a specific type, which is platinum sensitive recurrent ovarian cancer. And that need has gotten greater as we know that induction of platinum therapy and patients who progress after receiving a part inhibitor therapy may not have as strong as efficacy. So a critical, important need for our patients. And mirvotexamab sorantansine is an ideal drug to evaluate in the setting. It is the first in class antibody drug conjugate, and it was approved by the U.S. FDA based on a study that I believe you were part of, Rob. Mm-hmm. Yeah, exactly. Just read it out. Yep. Great. And then received full approval based on the mirosol trial. And this drug is highly active. The approval was for patients with platinum resistant ovarian cancer that had high expression of folate receptor alpha. And so I just want to declare my interest here and then also really focus on this trial design and what our primary objective was. So the primary objective of this study was to evaluate investigator assessed objective response rate in individuals with heavily pretreated platinum sensitive ovarian cancer. The key secondary endpoint was duration of response. And there was multiple other secondary endpoints, including safety and tolerability, SA-125 response, progression-free survival, overall survival. And we also conducted a sensitivity analysis regarding exploratory parameters that I'm super excited to share with you today. In terms of the key eligibility, as I mentioned, patients had to have folate receptor high expression based on immunohistochemistry using a PS2 plus intensity and greater than or equal to 75% of the viable tumor cells. They had to have at least two prior platinum regimens. There was a case where, you know, patients had a platinum allergy. They could go on this trial after receiving one platinum regimen. If they had a BRCA mutation, they had to receive a PARP inhibitor. And Bevacizumab was not required. Actually, it was allowed, which I think is really important. And this study had very specific parameters for the statistical analysis that I hope that we can have time to dive into deeper when you ask me more about the paper. Okay, so the study actually enrolled 302 patients. 44% of these individuals had high FR-alpha expression, which we can also explore further. And I think it's really important to note that 82% of the patients identified as white. So we still have a lot of work to do there in terms of diversity. This was a very heavily pretreated group. Almost 40% had at least three prior regimens and 97.5% had received a taxane. And actually, 25% had received taxane multiple times. Prior Bev exposure was incredibly high, 81%. And about 75% of patients had received a PARP inhibitor and actually progressed on that PARP inhibitor. And prior Bev exposure was 64.6%. And over 50% of patients had a platinum-free interval of less than or equal to 12. All right, going on to the exciting part, this waterfall plot. I know, so cool, right? So this waterfall plot shows that almost every patient derived clinical benefit. There was only two patients that progressed. And the investigator-assessed objective response rate was 51.9%. Six patients had a complete response for 7.6%. It's really exciting to see the duration of response was over eight months. And important to note that the median time to response was 1.6 months, which I think is a really important consideration to take into account when patients need a rapid response, especially for those who are having clinical symptoms. The median progression-free survival was approximately seven months. So going on to my favorite slide in this slide deck is the sensitivity analysis that we talked about, looking at the efficacy in these different subgroups. And I do want to point out that there's two groups that have response rates of over 70%. And that's in this gray bar to the left, showing that patients with the BRCA mutation had a response rate of 73%. And for those who are PARP inhibitor-naive, the response rate was 75%. And that's in that middle teal box there to the left. Efficacy was noted across all of these different subgroups. And there's a varying degree of response rate based on some of the subgroups. And I also want to just point out here in that dark purple, patients who are BEV-naive had a response rate of 57%. If they had been previously treated with BEV, it was a little bit lower at 49%. You know, we do have to be cautious about how we interpret some of this data, because there are relatively small numbers in some of these subgroups. There is a lot to unpack here. We could probably spend 20 minutes on this slide. I mean, I know, Rob, I'm just going to throw it out there right now that we did not conduct a formal statistical analysis around these. So this is not going to be something that we can assess in an analytical method. But I do want to highlight this really important signal. So let's dive in and really put this PARP inhibitor-exposed group under the microscope. So if patients had received a PARP inhibitor and progressed on a PARP inhibitor, the response rate dropped to 46%. It was patients who had prior PARP inhibitor that did not progress on that PARP inhibitor. So they received it. Who knows how long that period of time was before then they were on the progressed. And that response rate was 60%. But again, incredibly small numbers in this group. There's only five patients. So it's a signal that I think warrants further exploration. In terms of median duration of response across all these different subgroups, it ranged from seven to eight months. All right. So a lot to unpack there. In terms of treatment emergent adverse events, for the most part, this agent is very well tolerated. We have a lot of data around Mervituximab right now. And really, it's mild GI and neurologic side effects and reversible ocular events. So I think it confirms the safety profile that we previously had seen with Mervituximab and other studies. There were treatment-related serious adverse events in 9% of patients. And 16% of patients discontinued therapy due to a treatment emergent adverse event. So in conclusion, the PICLO study demonstrated that there was notable efficacy in a platinum sensitive ovarian cancer population that had really, for the most part, been heavily pretreated. And among those may have had high levels of PARP inhibitor resistance. Say approximately 75% of patients fit into this category. The investigator assessed objective response rate was 51.9%, including six complete responses and a median duration of response that was over eight months. And in those with progression on PARP, there was still a durable response rate of 45.8%, with a median duration of response of 7.3 months. The median time to response at 1.6 months was really exciting if you want to get fast disease control. Mervituximab continues to demonstrate a differentiated safety profile consisting mostly of low-grade neurosensory, GI, and resolvable ocular side effects. And the data position Merv to become a novel treatment option for select patients in the third line or beyond platinum sensitive ovarian cancer setting in those who have high FR alpha expression. Merv is also being evaluated in a lot of earlier lines of therapy. And I'm really excited, not just for what this study does to build on the experience with Mervituximab, but in terms of the entire arena for clinical trial development and giving us really important benchmarks. And I'm hopeful, Rob, that you're going to ask me more about that soon. So that's my summary of the study. And I'm happy to answer any questions and have further discussion. Thank you. Thanks so much, Angeles. Yeah. I mean, obviously, these are really exciting data to dive into. But I want to go back to the kind of at the very beginning, and that's to talk about what was the motivation to move a drug like this, a non-platinum into a platinum sensitive space? You know, in the manuscript, it's really nicely outlined that, you know, that there was, you know, patients that, you know, for which platinum retreatment for the, say, the third time, you know, wouldn't be a great option because of concerns about potential toxicities. Obviously, you mentioned one, hypersensitivity. And certainly, there's higher risk of hypersensitivity with more exposure, like with any other antigen. But again, I think that I think people that are listening would want to know, like, well, why would we do this? And I know you mentioned something about options. But can you just give us a little bit, take a step back and say, OK, when I was sitting down thinking about this trial, why did I want to do this? Well, I have to be really frank. I commend the sponsors for bravely entering into this space and conducting this trial. I tried to anticipate some of the questions that you would have for me. So I put together a few slides. I wanted to share this information. I think this is really, the driver for this is really a patient need, right? So with the subsequent line of therapy, and this was really driving in patients who have platinum sensitive disease, but had been previously treated with at least two prior lines, right? So when you look at this graph, and this is a really interesting paper, and you look to the third line from the left, and you see line three, three lines of therapy, we're talking about response rates of about 42%. And the other really important thing that has happened during this time period was the use of PARP inhibitors, which I think we recognize has really changed the landscape of care. And there's concern about diminishment of response to subsequent lines of therapy, not just platinum. So you take into account, we know from a historical perspective that with each line of therapy, your response rates decrease. And then we also know with reinduction of platinum in this PARP inhibitor era, that reinduction of platinum specifically, you're going to have lower response rates. So we need novel therapies. You talked about hypersensitivity reactions. So hypersensitivity reactions do happen, and they happen more frequently the more number of cycles your patients receive. Hypersensitivity reactions range anywhere from 8% to 16% in patients with gynecologic cancers, but they tend to occur with more exposure. So carboplatinum hypersensitivity reactions are very different than paclitaxel. Probably, you know, it's paclitaxel patients, if they're patients receiving paclitaxel, if they respond, it's more likely to be in the beginning. But with carboplatinum, it's after repeated exposure. So that risk goes from 1% between cycles one to six, all the way up to 27% if we're talking to greater than seven cycles. So that's your patients who got, you know, neoadjuvant or primary upfront therapy. You're already talking, they've received, right? And then if you get to third line therapy, so greater than equal cycle 15, that risk of hypersensitivity reactions are 46%. Now you can combat that with desensitization, which is a really good strategy, but I have had some patients who've had such severe reactions that they're really cautious to even do that. And I don't know if you're aware of this, Rob, but in North Carolina, we kind of live in this belt where there seems to be a higher rate of hypersensitivity reactions. So maybe I'm a little bit more sensitive to this. It could be, you know, it's interesting when we look back at the mechanisms for hypersensitivity, this is one of the reasons why I mentioned about antigens that, you know, people that mine platinum actually develop hypersensitivity to the platinum metal itself, the dust. So this is not uncommon, not unexpected for us to see this in our patient population and this relationship. So, okay, so that's good. Now I see the why. You know, we focused on this patient population who had, you know, you said heavily pretreated third line. Walk us through what a typical patient would be. That would have three lines of prior treatment. So most of our patients get, right? Most of our patients get platinum sensitive, you know, they get frontline treatment with a platinum and most of those patients end up with a PFI that's more than six months. And then most of those patients who progress will get platinum again and they'll get it either with or without that in this situation. In current days, you know, we don't have many options for parping in that platinum sensitive. Okay, so then those patients are now, now they've had their second platinum. So now there's third line. But with respect to the eligibility of the trial, so how did those patients, how did those patients come into study? Did they progress on that platinum and then had a waiting period of time? Did they go on to a non-platinum regimen and then come back? Did they, you know, so walk us through what a typical, you know, third and fourth line patient would be. No, these patients had to be sensitive to platinum based on they didn't have a recurrence before six months, that six month time period. So it wasn't like these patients had persistent disease or resistant disease and they got a subsequent line of therapy. And then this, they had platinum sensitive ovarian cancer. Most of them went on, actually a pretty significant number had three or prior lines of therapy. And then most of them were at like the two lines of therapy. I can go back and look exactly where we have this. Well, this is just saying, if you think about like when you saw a patient in clinic who had had platinum once, platinum twice, had responded and then had, let's say had a recurrence three months after or yeah, three months after. So they had responded, let's say they had a partial response and then they were observed and then three months later they progressed and then were treated with a non-platinum agent. And then now their platinum free interval is more than six months. And so therefore they would be potentially eligible, right? So are you trying to figure out like what's that typical patient look like? Yeah, I don't think that's a typical patient here, but I can do a deeper dive and answer that for you later, Rob, like in 2025. But anyway, just want to go back to eligibility. It was defined as radiographic progression after six months of therapy. So I don't, the patient that you're describing, I don't think was a candidate for this. And then of this group here, the 49 that had one to two priors, only one of them had that one prior and it was a patient that had a hypersensitivity reaction. So you can see here that a lot of these patients had two prior lines of therapy and then the 40% had greater than equal to three. And that's gonna be a variety of different patients, but they all had platinum sensitive disease. I wanna go, I hope I addressed that question. I think, I think, I think the point is, yeah, cause I want to go back to this. I think this is really important. The point is that in 2019, the world changed, right? I know you were in the audience. I was in the audience. We were all excited because several pivotal studies were presented that really launched a PARP inhibitor maintenance strategy into frontline treatment. At Duke, my partners and I tend to use biomarkers direct therapy. So patients who have HRD positive disease, especially those with BRCA1 or 2 mutations, we're going to recommend PARP inhibitor maintenance. Now I don't typically do that as an all comer approach. I think there's differences in magnitude of benefit, but it has changed the landscape of care. And I think that the use of Bevacizumab remains controversial. Some providers give Bevacizumab to patients who have advanced disease. Some make it more selective, whether it's a stage four disease or they have ascites or pleural effusions, or they have sub-ultimate bulk stage three. But the bottom line is, I think there's a lot more use of maintenance therapy in that setting. So we're not seeing patients in clinic. It seems as if there's more patients with platinum sensitive disease after first line treatment and even second line treatment and beyond what there was in the past. I mean, ultimately a lot of patients still develop platinum resistant disease, but I feel like the patients of today are different than the patients being with platinum sensitive disease years ago. Yeah. So part of the motivation to ask the question about the typical patient is that it gets to really your statistical design. So in manuscript, it's nicely outlaid that you estimated what the go and no-go kind of boundaries would be in your assignment two-stage design for a success versus non-success. And so you wanted to exclude this 20% lower boundary, which was where you thought the average response rate would be in this population. So I asked this about the patient population because essentially these are patients that would otherwise be eligible for a platinum treatment again. And so in that patient population, now you're looking at, okay, I've got a choice between a platinum and a non-platinum. And so I need to show that I'm gonna be better than this platinum essentially kind of background rate. And you use this data here to kind of show where that number is. And I think that's what you were trying to ultimately achieve based on the statistical modeling of the trial. But one question that we'd look at this years ago, but the question was that all of these patients who in the study were full at receptor alpha positive by the PS2 of 75%, is that an adverse or favorable prognostic factor? So actually there's data to support that it's an adverse prognostic factor that patients who have high FR alpha expression are not going to do as well compared to those that don't. I don't necessarily know if that's been evaluated in a robust fashion, but based on the literature review that, or the data that I reviewed. Can I add to that one thing? I think it's really important. These patients, and maybe I failed to really make this point more strongly, these patients were not considered to be in some cases eligible for more platinum, or I guess it was patients that you wouldn't necessarily want to treat with more platinum because they may have been at higher risk for accumulative toxicity or they had sensitivity reactions. So if that can kind of clear that up, this maybe wasn't your run-of-the-mill patient that had tolerated platinum well, had no hypersensitivity reactions, were like, oh no, just treat me platinum again. It's a little different that way. But I think it's a really important signal for how this drug, the efficacy of this drug in this setting. Can I go to my next slides here? Because I think that may also go to what you're talking about. When we did the statistical analysis, and you're absolutely right, it was a Simon Tate stage two design with that lower conf boundary of 28%. And that was one of the really hard things about designing the study is, you know, we, and when I say we, I'm talking about the entire team, did not know what to choose as the landmark- A historical comparison. A number for that statistical analysis, right? Like what is the objective response rate in this group? What is the medium PFS? And so you're kind of in a vacuum of trying to figure this out. And so the top three studies there, one is, I think you were involved heavily in several of these studies, 213 was your study. I know that was like your seventh child, or? I think it had to be grandchildren before it was published. But all of those studies were done in earlier line of disease. So these patients obviously one per line. Then the next series of studies really heavily weighted toward patients who had one per line of therapy, but they did have some patients who had a second or third line therapy. And then the other consideration here was that not all of these patients had received prior PARP inhibitors. In fact, the top four rows, nobody had received a prior PARP inhibitor. And then there were some BEV uses, but it wasn't really high in several of these studies until you get to the bottom two, where it's over 50%. And so when you're trying to choose what your objective response rate should be, we don't have the correct setting, we don't have patient population from a historical point of view. So you're really aiming in the dark, right? And you can see the objective response rate for those last three studies, they range anywhere from 43 to 71%. And the PFS is pretty similar across all of these studies, if you take into account the entire table ranging anywhere from 8.4 to 13.8%. So I cannot even hone into that strong enough of how challenging this was. And then when you get to this next slide, I wanna show you is a little bit further stratification based on GY004. If you remember, this was the negative trial, which really has some interesting signals that was conducted evaluating a platinum-based doublet to olaparib, siderinib, and olaparib. And this was in patients with platinum-sensitive disease. So here, I just wanted to dive into the fact that you have patients with platinum-sensitive disease that have BRCA mutations and those that don't, and their response rate with a platinum doublet is about 70%. And then I went to just, I don't know if I can zip back to my other slide here. I don't, I'm sorry if I'm giving you whiplash. But look at this. HARP-naive patients, 75%. Again, a small number, but this is with single-agent mirvotexamab in a more heavily pretreated group of patients with pretty strong signal there. And then I just wanna make one last point, okay? Bear with me. Okay, there's been several series now, whether it's post-hoc analysis from phase three trials or real-world analyses of PARP inhibitor exposure and subsequent response to therapy. And so the post-hoc data from SOLO2 and POLO1 is, I think, really important to dig into that a little bit more in terms of response rates and progression-free survival may not be as high in patients who received a PARP inhibitor compared to those that did not. I'm gonna show you the POLO1 slide in a second. And then the other thing from the real-world analyses is the response rates post-PARP inhibitor are much lower. They range anywhere from 14 to 20 or to 43%. And the median PFS ranges from 3.5 to 8.9 months. So it is all over the place. But there is a strong signal that prior PARP inhibitor therapy, especially for patients who progressed on PARP, their response to subsequent platinum or any therapy is going to be lower. And we've talked about this for years, right? I mean, it's been for a while. And then lastly, this slide, and I know you have some data from ARIEL3 as well, but this was a post-hoc analysis of POLO1. And what you can see here is patients who received a LapRib and progressed in blue have a median PFS of 6.1 months compared to around 11 months for patients who had a LapRib and then progressed after their treatment and the control group that did not receive a LapRib. And so I think this goes back to the question you asked me about why the need is there's a strong need for novel therapies in this space, but also to provide a review of the literature that we had and how hard it was to identify what is the benchmark that we should be looking for in terms of whether a new drug in the future hits that mark for further evaluation. Right, so just to kind of summarize, because that was a lot of information, but I think that, you know, so there are things that modulate our expectations for response to not just platinum, but all chemotherapy in a recurrent space. So one of those obviously is whether or not they're actually fall into a platinum sensitive kind of situation. Second is when the line of therapy that they're had, that they're being considered for there, and then also, of course, the previous treatment. And then whether or not they had a response or progressed on that previous treatment at all. And then what that treatment was. And so all those were essentially assessed in the study through the design, which was to, you know, allow Bevacizumab, yes or no, also to require PARP for BRCA positive tumors. And of course, evaluate this in multiple lines of therapy. So all those are important to help us understand how to modulate the background efficacy rate. I would say without a control arm, it always makes it very difficult to know exactly what that is. But I think that, as you said, the signal here was very strong and very consistent, and that's nice to see. One, because then we're kind of a little run on time, but I wanted to just ask a couple, about the safety signals. There's obviously, in the recurrent setting, we do want to be mindful of what potential toxicities might be seen here. And I think, as you mentioned, did you feel that the safety profile of this line of setting was similar, different to what we saw in Soraya and Mirosol in the platinum-resistant cohort? I thought it was very similar. I do think what was a little bit different is maybe there's more discontinuation from therapy than I would have expected, but perhaps that's because, even though part of the reason to do this study is to expand the options, there's limited options because it's platinum-based therapies that the options people go to. But still, there's a lot more options compared to if somebody is platinum-resistant or wearing cancer, right? So there's a lot of things that they can still receive. But I'm hoping, Rob, that you'll ask me about some more about the weaknesses of the paper. I just got to get there. But one thing, before we leave that, though, I want to say that, overall, the toxicity-related discontinuations rates were still relatively low in the setting, which is good to see. But two-thirds of the patients require some form of dose modification or dose delay. So do we have the right dose? Kind of an ambiguous question, but do we have the right dose here if two-thirds of the patients require some form of modification? Oh, I'm not too concerned about the starting dose with this agent. I mean, I think it's safe. And I do think, quite frankly, in the clinical arena, it's the art of practicing medicine. If you need to do a dose reduction because somebody's having toxicity, but you're able to mitigate that with a dose reduction or delay, that's really just not too concerning with me. I mean, think about, we started everybody at Doxil back in the day at 50 milligrams per meter squared, and quickly recognized that we didn't have the right dose. But even at 40, sometimes you have to do dose delays or decrease the dose. And you especially see that in carboplatinum, too. So I honestly, I understand what you're saying. I understand why you bring that point up, but I honestly, from a clinical perspective, I'm not concerned. I do think what we need to understand further is who is at risk as we continue to use more and more Vorteximab. Like who are the patients who may develop pneumonitis, for instance? Absolutely. Okay, now, what are the weaknesses? All right, weakness. You mentioned one already. We don't have a comparator arm. And it would be really, really hard to go head-to-head against a platinum doublet, but I hope that, I hope it can be done, you know? So that's a huge weakness. Another weakness, which is near and dear to my heart, and I know many of you as well, is the lack of diversity. We have got to do better to enroll more diverse patients into our clinical trials so that we can ensure these results are generalizable for everybody, because that's a key thing that we don't really know. So I think those are probably, to me, the lack of diversity with regard to race and ethnicity continues to be an issue. And we- Totally agree. You know, the exploratory data that I shared, the signals are really exciting, but we do have to be very wary about how strongly we interpret those findings. Awesome. I really appreciate that. And it's good, obviously, to do a good critique. Last thing I want to mention before we close out is something you brought up in that waterfall plot, which is that only two patients have had progression as their best response. I think that's a really important concept for people who are listening in to understand, in that in the clinic, while in a clinical research trial, we're actually looking for objective measures of efficacy, such as response, duration response, progression-free survival. But in the clinic, we basically treat with a combination of, is this working and is it safe? And is this working, can be stable disease. So patients who are tolerating treatment but don't have objective tumor shrinkage is not a reason to panic. Many of these patients in the tolerable regimen can go on therapy with stable disease for extended periods of time and really gain benefit without having met what you considered as the primary endpoint of the trial, which was objective response. So I'm glad you brought that up in your discussion. I think that's an important concept there. I'm so glad you mentioned that too, because 11 patients were still on treatment at the date of cutoff for the analysis. And so stay tuned. I'm sure we'll be able to give updated- There you go, updated. I love it. So, all right. Well, thanks so much, Angela, for taking the time to discuss this publication in more depth and providing your insight into the publication. We brought up a number of topics that actually are touched on in the paper, but this was much more colorful. And I think people will really gain a lot of insight from your comments. And I obviously wish you continued success with the trial. And thank you all for listening in. We hope today's Journal Club was enjoyable, insightful, and we look forward to future Journal Clubs from IGCS. Thank you so much for having me, Rob. Absolutely. Happy holidays.

Mervituximab Soravtansine

ovarian cancer

phase II trial

folate receptor alpha

treatment response

clinical trial diversity

toxicities