Hello, my name is Wendell Nauman. I'm the co-director of IGCS 360 and associate director of clinical trials at Levine Cancer Atrium Health at Wake Forest University in Charlotte, North Carolina. Today, I have Angeles Alvarez-Sicord joining us. She is a professor at Duke University and she is the PI of the PICOLO trial, which was recently presented at ESMO and involves a new option for patients with platinum-sensitive ovarian cancer. Welcome, Angeles, and thanks for being here. We're excited to see your data that was recently presented at ESMO. Yes, thank you so much for inviting me. It's a pleasure to be here and I'm so thrilled to be able to share this data. I am happy to go through the slides and if you can pull those up, that would be awesome. So, this study, the PICOLO trial, was an evaluation of myrbatexamab soratansine, which is MYRB for short, in patients specifically with recurrent platinum-sensitive ovarian cancer and high folate receptor alpha expression. So, can we move on to the next slide? I think we can go to the slide after that as well. This study was funded by Immunogen, now AbbVie, and I think many of you are familiar with the mechanism of action of MYRB. This was the first ADC to be approved in platinum-resistant ovarian cancer since 2014. I love these drugs. I call them high intellectual capacity heat-seeking missiles. Essentially, these drugs are targeting the protein on the tumor cell. They have an FR alpha binding antibody, this cleavable linker, and then the payload is a metansinoid DM4, which is a potent tubulin targeting agent. So, as it gets embedded or incorporated into the cell through internalization, it releases that payload. It's really exciting in terms of the drug that is already in clinical practice for patients with platinum-resistant disease, and we know that the platinum-sensitive disease is a very important space. Wendell, you and I have talked about this. How has platinum-sensitive disease changed in this new era? One of the things that we know is that over time, the number of chemotherapy regimens someone has, their likelihood of responding to subsequent platinum decreases, and also there's cumulative toxicity from platinum, specifically the risk of hypersensitivity reactions. The other thing we talked about was that individuals who receive a PARP inhibitor may have diminished response to subsequent treatments, especially platinum. So, the space has changed, and we're always looking for novel new therapies to enhance efficacy of our patients and improve their overall survival. So, let's go to the next slide, because this really shows the study design. So, this was a single-arm open-label phase II trial of MIRV in patients that were essentially heavily treated. So, this was third line and beyond, and we're going to dive into the eligibility criteria shortly. Patients were treated with MIRV-Tex-MUB at 6 milligrams per kilogram based on adjusted ideal body weight dosing, and they received therapy every three weeks. And the primary endpoint was objective response rate by investigator assessment, and the key secondary endpoint was duration of response by investigator assessment. So, I want to dive a little bit into the key eligibility criteria, because this specifically was for platinum-sensitive disease defined as radiographic progression greater than six months from the last dose of most recent platinum therapy. And patients had to have the presence of the biomarker defined as immunohistochemistry based on the Ventana-Fuller-R1 companion diagnostic with PS2 plus intensity in at least 75 percent of viable tumor cells. And they had to have at least two prior platinum-containing regimens unless they had a hypersensitivity reaction. If they had a hypersensitivity reaction and one prior regimen, they couldn't rule. Prior PARP inhibitor was required if they had a mutation in BRCA, and prior BEV was allowed. Patients could have received BEV or not received BEV to go on this study. And they had to be felt to be appropriate for single-agent therapy. So, I know we talked about this a little bit the other day, Wendell, and just wanted to get your thoughts on that eligibility criteria. Yeah, so, you know, the definition of platinum sensitivity has defined the way we treat ovarian cancer, particularly in the recurrent setting, the first recurrent setting. I think that definition in the second recurrent setting is probably less well-defined, and I think we don't know what to do with those patients. And as you mentioned, there is cumulative toxicity of platinum, particularly in our BRCA patients. And I do worry about some of the reports that have shown increased risk of MDS with additional lines of platinum, and I've had several patients now with BRCA mutations who have actually died from MDS. So, it is interesting and exciting to have an agent that works in a different way. Yeah, absolutely agree. So, let's go to the next slide. I think this is a really important slide to highlight the demographics and characteristics of these patients. The median age of these patients was 66, and you can see that the age range is anywhere from 41 to 84. So, love the fact that there were some individuals who were more up-seasoned on this study because a lot of our patients do tend to be older, and I think it's really important to have options for these patients as well. Sixty-two percent of these patients had one to two prior lines, and actually it was just one patient that had one prior line of therapy. And then 38% had three or more prior lines of therapy, so again, heavily pretreated group. The exposure to taxanes was very high, 97.5%, and 25% had multiple exposures to prior taxane regimens. And then prior PARP exposure is something that's very important here. Eighty-one percent had previously been treated with a PARP inhibitor, and 75% had actually progressed on that PARP inhibitor. And this is what we're seeing in our practice, too, as we incorporate PARP inhibitors in the front-line setting. And then 15%, only 15%, had not previously been seen a PARP inhibitor. Prior exposure… So, Angus, do you think the people who progressed on a PARP inhibitor would have been much more likely to be platinum-resistant, since the mechanism of action is similar, if this had not been a phase two trial? There's so many different mechanisms of PARP inhibitor resistance, right? I mean, they're just… you could… we could have a whole conference on that alone, but I do think there are elements that are overlapping cross-resistant mechanisms to chemotherapy, not just platinum-based only therapy, but chemotherapy as well as PARP inhibitors. So, elucidating that furthers is really important as we continue to try to develop novel targets. But I do think this is a really key group of patients who progress on a PARP inhibitor are harder to treat, and, you know, for the last few years, we're all looking at all these different options to try to overcome PARP inhibitor resistance. And it's a really small group. You know, the group that didn't progress on a prior PARP who received the PARP, it's only 6%. So, it's a small group, but we can get some ideas of a signal from this patient population. I want to point out one other thing, Wendell, that I think is going back to what you alluded before in terms of, in this new world, platinum-sensitive isn't the same of what it was in the past. And just point out that 54% of these patients had a prior experience with had a platinum-free interval of less than or equal to 12 months. Were you surprised that the folic receptor alpha high group was 44% of the population as opposed to slightly lower in some of the other trials? Great. I really wasn't too surprised because I think by this time, a lot of us were utilizing the companion diagnostic clinically. And so, I think there was some pre-screening of the pre-screening for patients to go and study, right? So, if patients were FR alpha high, you'd be more likely to say, let's screen you for this study. Do you have any thoughts about that? That was my thought. I think that probably makes sense. There is some data that suggests that as patients progress, there is a higher rate of folate alpha expression, and that might be actually a marker of more aggressive phenotype in ovarian cancer. But I don't think we have enough data to really pin that down. I'm just interested that this comprised a larger percentage of patients than I would have anticipated. But you're probably right. It's about a screening mechanism. I will say, Wendell, I'm so glad you brought up the thing about the aggressive phenotype. There are studies that show that FR alpha high expression is associated with worse survival outcomes. And so, I think we have to take this into account. We always make the joke of you can't compare apples to oranges with these clinical trials. But it's even more important in this day and age because these patients may have a more aggressive phenotype. They may have worse outcomes. So, we can't compare them to an all-comer platinum-sensitive trial. All right. Can we go to the next slide, please? All right. I love this slide. I have two favorite slides that I'm going to show you today, and this is one of them. So, this demonstrates the investigator-assessed efficacy measures. And what you can see from this waterfall plot is there is a broad depth and breadth of response. Almost every single patient who participated in the study had evidence of clinical benefit. You can see that there are some deep responses here on the right. And the objective response rate in the overall treatment population was 51.9%. The 95% confidence interval there ranged from 40 to 63%. And 7.6% of patients had a complete response. 44.3% had a partial response. 36.7% had stable disease. Progressive disease was noted in 9% of patients. And only two patients, or 2.5%, were not evaluable. The median time to response was 1.58 months. And so, what that tells me is that patients are likely to benefit from this therapy between cycle one or shortly after cycle two. And so, this is really important for patients who are symptomatic with their disease, that hopefully if they respond, they're going to respond quickly and have some benefit early. And the median number of treatment cycles was nine, with a range all the way up to 27. So, I think that's interesting, too. Not only was the response rate high at over 50%, but it looks like from your waterfall plot, almost 90% of patients had some benefit with either slight shrinkage with stable disease or a response. Were you expecting a response like that in a pre-treated population like this? Not with single-agent therapy. I have to say, I kind of had to check my own bias at the door of, because my historical knee-jerk treatment plan would be a platinum-based regimen. And so, to receive responses this high, I was really excited in this heavily pre-treated group. And also, a group of patients that may not be candidates for retreatment with platinum therapy, while we can do desensitization, sometimes patients are somewhat traumatized by having a hypersensitivity reaction, or you're requiring such high doses of the steroids that they're symptomatic from your pre-treatment. So, if you have somebody who's had two prior platinums, do you automatically go back to platinum combination? Because I find that at that point, patients are a little bit sometimes fragile, as you pointed out. And I sometimes will use single-agent platinum in that patient population as opposed to combination. So, Wendell, I have definitely done that. It will still be something that I'll consider to do in the future as well. But I think what this does is it provides us more options. And so, I'm hopeful that we can get this option into the clinic to provide our patients these two different treatment choices, and then review the risks and benefits with them. And I do agree with the platinum concerns that you expressed. I have challenges sometimes with single-agent platinum and the thrombocytopenia. So, I find that even a little bit of the taxing can help with the platelet-sparing effect. But often, you do have to mitigate. You have to start at lower doses, or plan on some dose delays, or even go to a four-week dosing rather than three-week. But again, the excitement here is that I think this is a really active agent in a heavily pre-treated platinum-sensitive population that we can bring into the clinical arena. That's great. All right, you ready for my next favorite slide? Is this subgroup slide. So, we talked about how my text-to-med works with a 51.9% response rate in the overall population. And now, look at the responses across all of these subgroups. And now, you know, we can dive into the subgroups of subgroups, which is always fun to evaluate this efficacy signals. But what we can see in that the number of prior lines of therapy, that even in patients who have had four or more therapies, the response rate is 33%. If patients had a BRCA mutation, the responses are really high, 72.7% compared to 43.9%. They don't have the mutation, or it's unknown. I want to take a look. Look at that block in blue. We're going to come back to that group very soon, because that's the previously PARP inhibitor-exposed patients. And I want to spend some more time on that. In terms of BEV exposure, if they had prior BEV, the response rate was 49% compared to 57.1% if they're BEV-naive. And then, if they had both PARP inhibitor and prior BEV, still high responses at 43.9%. And the most recent PFI, if it was greater than 12 months, response rate was 64.7%. So, I want to take a look at that. So, I want to also point out, these are small groups. some of these groups have a very small number of patients, so we have to just acknowledge some of the limitations in our interpretation of this data. But I think overall, it's important signals and very promising. And with that, I want to turn our attention to that PARP inhibitor exposed group. So can we go to our next slide? I want to isolate this group further, because as we were talking about, Wendell, this is a really important group to evaluate as our clinical practices change. And over 50% of my patients are going to receive a PARP inhibitor in the maintenance setting in the frontline treatment of their disease. So I want to turn your attention first to that bar on the left, where patients are PARP inhibitor-naive with a 75% response rate, which is really exciting. And now I want to turn your attention to the treated patients, and specifically that group that has the red square around it, because that's a group that I think is at highest risk and urgent need for novel therapies. These are patients who progressed on a PARP inhibitor, and 59 patients met criteria for this evaluation, and the response rate here was 45.8%, so really still a strong response rate. And if they had a PARP inhibitor but didn't progress on a PARP, the response rate was 60%. And now I want to turn your attention to that table, because it shows the duration response. So even if they had progressed on a PARP inhibitor, and they responded to Merproteximab, their duration of response was still strong. It was 7.3 months, with a range all the way up to 10.8 months. So very similar to the overall group, which was approximately eight to nine months. All right. Any thoughts there? We were surprised by the high response rate in the BRCA patient population, since this is not a DNA damaging agent. I was. About 75%, was it? And I know they tend to be chemosensitive, but we tend to use DNA damaging agents, as opposed to other types of chemotherapy. Yeah. I was really surprised by this, because the payload is really targeting tubulin. And I don't have an explanation for the mechanism of action here, in terms of why it's so much greater in patients who have a BRCA mutation. But it's very interesting, and it's very exciting to see these results, and I think this is something we can continue to build on. Okay. So the safety summary is also really reassuring. There were no new safety signals. There was a treatment discontinuation, about 16%, as well as dose modifications and delays, which is no surprise. And there were two deaths on the study. One was attributed to Mirvotexamab, and that was due to pneumonitis. And the other one was due to sepsis, which was not attributed to the study drug. And let's go to the next slide, which I'll be able to share a table with you. And as you can see from this, that greater than or equal to grade three treatment emergent adverse events were actually fairly rare. The highest percentage here was 10%, was blurred vision. So most of the adverse events were very mild GI-related or neurosensory or reversible ocular toxicity. The big overlying point here is that there's no new safety signals, which is very reassuring. And next slide. All right. So overall, after reviewing all this data with you, I think it's notable efficacy seen here in this heavily pretreated patient with platinum-sensitive disease, including those who had progressed on a PARP inhibitor, which may be indicative of PARP inhibitor resistance. In fact, 75% of our patients had progressed on a PARP inhibitor. The investigator says objective response rate was 51.9%, including six complete responses with a median duration of 8.25 months. The upper limit of that confidence interval is close to 11 months. And in those who progressed on a PARP inhibitor, a very reassuring signal of activity with an objective response rate of 45.8 months. The median duration of response was 7.33 months in these patients. And the median time to response overall was 1.58 months. So the other thing I wanted to note here was the safety profile, which consisted primarily of the low-grade side effects that we mentioned, as well as resolvable ocular toxicity. And so overall, mirabatexamib remains to be a safe therapeutic option. And I really believe that mirabatexamib is a potential treatment for patients with heavily pretreated platinum-sensitive ovarian cancer who may not be suitable candidates for platinum reinduction for several reasons. We mentioned hypersensitivity already. But I think this really also provides the foundation for the studies that are ongoing. There's two studies evaluating mirabatexamib in the platinum-sensitive space right now. One is the Immunogen 420 study, which is a study of mirabatexamib with carboplatinum followed by mirabatexamib. And then the other study is the GLORIOSA trial, which is a maintenance strategy. So patients who have platinum-sensitive disease retreated with platinum induction combination therapy may enroll in the study, and they're randomized to either mirabatexamib with bevacizumab or bevacizumab. So thanks again, Wendell. I'm so happy to be on IGCS 360. What a great program, and to share these exciting trial data with you. Yeah, that was great and very exciting data, obviously. I think one of the questions that we're going to get is about, obviously, a very active drug in platinum-sensitive. What do you think about the maintenance strategy in terms of active treatment? We had this entire argument back in the GOG 178 data, where we had using taxane as a maintenance agent. And now we're looking at doing that in second line. Obviously, we have to weigh toxicity versus efficacy. What do you think about that data? There are pluses and minuses of early pretreatment versus later pretreatment. Any thoughts on that? Yes. I do have thoughts on that. Well, I would say it wasn't truly an argument per se, but rather a thoughtful discussion. So the GOG 178 study was very provocative, but it did show that in order to obtain that disease control, it also came at the cost of quality of life, and namely with neurotoxicity. And I think that we have become more open to maintenance strategies at this time now With PARP inhibitors and with Bevacizumab, they're fairly easy to give. I think it's important to conduct these studies. You know, Wendell, I tend to be a less-is-more person, right, rather than a more-is-better. We talk about this often, back and forth. And so I think it's really valuable when doing these studies to take into consideration the side effect profile, the ease of administration, and the quality of life. Yeah. Well, and obviously, with Bevacizumab, the toxicity is minimal. With PARP inhibitors, you do have some nausea, but generally that gets better. And I think we've become more accustomed to maintenance therapy, but I agree it's going to be very interesting to see what the long-term outcomes of the studies, particularly Gloriosa, which looks at earlier treatment. And I was not a believer in maintenance, but I've slowly changed as more maintenance strategies have come out. So we probably use Bev in the first-line setting with PARP in the HR-deficient patients and in the HR-proficient patients, obviously. The maintenance PARP probably doesn't help quite as much, but we have the Bev option. And then we use Bev as maintenance in the second line. So it will be very interesting to see how these studies play out. Right. Yeah. And as you mentioned, I was impressed with the efficacy simply because many of these patients probably wouldn't respond to platinum in the third-line setting, and so I was very excited to see these things. Well, there's a paucity of data in this space, really, right? When you think about what do you compare this to, well, you can't really compare to the other platinum-sensitive trials because those patients, we don't have the biomarker data on. So as we mentioned, this may be a more patient population that has more aggressive disease. And those other trials, patients weren't treated with a prior PARP inhibitor therapy, so they're less likely to have that increased level of chemo resistance. So what's your comparator? You really can't. We have the space of discovery is going so quickly that we're just trying to keep up clinically with all the new data that's coming forward. Yeah. So obviously, with the ongoing Gloriosa trial, we may have this in maintenance, but what would you say would be the next trial design in this space? I mean, are we going to compare this to a platinum combination? You're going to compare it to platinum, or are you just going to let this data speak for itself as another choice? Oh, I think they can move up and compare directly to platinum. You know, 420 is now completed enrollment, so I look forward to seeing that data. That was carboplatinum and rifotexamab followed by MIRV maintenance. So I think that's a really exciting opportunity to explore further. Now, whether that's a two-arm trial design versus three-arm with incorporation of Bev remains to be seen, but honestly, I think we can move this up into the front line. Taxanes are really valuable drugs, and since the 1990s, we've been very fortunate to have them in our clinical treatment for our patients. You and I, like, we were treating patients before taxanes were available, right? And think about how horrible those regimens were and how much more toxic they were until we got all the supportive drugs to care for these patients, and now we have these different smart drugs. So I think, first line, this should definitely be moved into that space. But can we go back one second, because I think that there's also a really important point that you made, and that's about, you know, different patient populations and how much better patients are doing today and how we've become more accustomed to maintenance therapies or different treatment options. There was that really provocative study that Dr. David O'Malley presented, and you shared it with me, about the long-term survivors of patients who've been treated with mirvotexamab. And I believe in that study, the patients who were long-term survivors, those individuals at two years, was it 60% were still alive at two years with recurrent platinum? Some of them had recurrent platinum-resistant disease, right? And then at three years, I think it was about 40%. It was 66% at two years and 40% at three years in the patients who survived more than 15 months. So there was a subgroup, and 80% of those patients were folate receptor alpha-high. This was David O'Malley's presentation at ASCO this year, looking at long-term survivors. So I think there is clearly a subgroup of patients that does very well on this drug, but it has a unique set of toxicities. And as you pointed out, there is the interstitial lung disease that you have to be aware of, as well as the eye toxicity, which is generally reversible, but not trivial. And I know the added burden of eye exams and some of the prophylaxis stuff is an issue to take into account when you're putting patients on these trials. Oh, I think it's so important to have a good friend who's an optometrist or an ophthalmologist. We fortunately have somebody here at Duke that we rely on heavily, and he's just been fantastic helping us with our patients. Yeah, I think that's more common if you have more blood. The other thing we should talk about, and you brought it up before we started the meeting window, was the NCCN guidelines right now. So it's Mervitex-MAB for patients with platinum-resistant ovarian cancer, for those individuals with high expression of at least 75% based on the biomarker testing. And then the other NCCN guidelines also include Mervitex-MAB and Bevacizumab for patients with platinum-sensitive disease. And for that, it's a lower protein expression at at least 25%. So I think that it's important to remember what are options and what are the treatment settings for Mervitex-MAB currently available in the clinical arena. Absolutely. Any further thoughts on drug development and where we're going? You mentioned going to the front line. We have a number of agents now. We are looking at the high-risk patient population, the HR-proficient patient population. In Prima, we did have some signal with norepireb, but again, the median PFS in that patient population, and again, they were suboptimally debunked, HR-proficient patient population, but the median survival in that in the control arm was 5.4 months. So the majority of those patients in that setting are going to be platinum-resistant. Do you see any movement in that patient population in terms of either maintenance strategy or more aggressive treatment strategy? Oh, that's the group that desperately needs it. There is a huge, urgent, unmet patient-driven need to identify novel therapies for that group of patients. And I'm very hopeful that the ADCs will be helpful in that patient group, really to identify what is the underlying molecular biology for those patients, and some of it appears to be driven by CCME1 amplifications, but what are the other underlying mechanisms we need to better understand? Because those studies were predominantly high-grade serous cancers, right? There's other rare ovarian cancer groups that we need to consider, clear cell, mucinous, so we really need to not be complacent and really focus on pushing the envelope further so we can improve outcomes for all of our patients. Well, that's great. And just thanks so much for sharing that data with us, and very exciting, and congratulations on your trial. Well, it was my pleasure. And I just want to say that I got to share that data with you on behalf of all the other wonderful collaborators and colleagues who enroll patients on the trial, and to our lovely patients who are willing to participate in these studies, as well as ImmunoGen and AbbVie for supporting the study. And thank you all for having me.

PICOLO trial

mirvetuximab soravtansine

ovarian cancer

folate receptor alpha

objective response rate

clinical practice