Welcome to the IGCS Journal Club. Today we have a great episode for you. We're going to discuss the highly anticipated Phase 3 trial of Tisotamabidotin in second third line cervical cancer. And today I have with me, I'm Leslie Randall, by the way. I'm a GYN oncologist in the United States, and I have with me, I'm going to introduce yourself. Yeah, sure. Hi, Leslie. Thanks. I'm Brian Slomovitz. I'm a gynecologic oncologist in Miami Beach at Mount Sinai Medical Center. And I served as the PI here for the GOG, working with Dr. Vergoot and the GOG and NGAT team. And really it's an honor and a privilege to be here today. And most exciting is the data that we're going to be able to discuss. Absolutely. And the follow-on activities that have happened since this data has been released. So thanks for joining me. It's really a privilege to have one of the actual PIs of the study here to discuss the paper. So tell us a little bit about why the study was done. Yeah, sure. So Leslie, we know that, and you and I treat, and a lot of us treat many patients with cervical cancer. Fortunately, many of those patients do well with their initial treatment, whether it be surgery or, for the locally advanced disease, chemosensitizing radiation. And they may even do better with the new advances. But we know those patients who have recurrent disease, there are not a lot of good treatment options. Chemotherapy in that setting really hasn't done much, unfortunately. We did have immunotherapy in the second or third line setting, but based on the great work of you and your team through the GOG and NGAT, we moved immunotherapy to the first line. So while this is a second or third line trial, the great unmet need has been in the second line setting. And we needed to come up with better treatment options. As we know, antibody drug conjugates, or ADCs, have been changing a lot of what we do, a lot of advances in gynecologic oncology. And Tizotamabdotin was the antibody drug conjugate that goes towards tissue factor, which is overexpressed in cervical cancer. And that's- In almost all cervical cancers, right? Well, you may show some of that data. Yeah. Almost all cervical cancers. And based on preliminary data that we were involved with, and we led to an accelerated FDA approval, we were fortunate enough to do the confirmatory trial here, the randomized phase three trial, to determine if it truly was better than chemotherapy. Yeah. And I think that's a really important point, academically, to know that this was a confirmatory trial for an accelerated approval in the United States. So tell us about the design of the study. So this is a randomized phase three trial. It was looking at those patients, obviously, with recurrent or metastatic cervical cancer after disease progression. They had to have less than two lines of therapy, because we were looking in the second or third line. Right. Relatively a good performance status, which, as we know, it's tough in cervical cancer. Can be. Right. Because some of these patients don't do well. 500 patients. It was a large trial. Again, an international effort with a one-to-one randomization. Tizotamabedone versus investigator choice chemotherapy. The end point, the primary end point here being overall survival, with the standard list of secondary end points, PFS, response rate, and obviously safety. Great. What would you say were any strengths of that design, any weaknesses in that design that you can think of? Yeah, so in general, whenever we do a trial that's overall survival, that's a tremendous advantage, and it's something that we really need to look at. Now more and more, a standard is Bevacizumab, and a standard is the checkpoint inhibitors, anti-PD-L1 or PD-1s. So it wasn't required, but it was stratified, so we are able to see the differences between those two groups. Other than that, there's nothing perfect, but we thought it was a very good strategy moving forward. I agree. I think overall survival does get a little bit tougher if patients cross over to the therapy if they're living longer and we have better supportive care than we used to. So I think at this point, we don't know what the crossover hasn't been published yet. And the good or the bad, you're right about the crossover. Unfortunately, we're working on this more and more now. We want to make this globally available. So when there was crossover, it wasn't as easy to get. Great. And then tell us about the statistical design. So this is, again, primary endpoint here was overall survival. The secondary endpoints, we're looking at progression-free survival and overall response rate. They did an interim analysis, but overall, for a phase three trial, it went relatively smoothly. One thing I will add, and we mentioned about this a little bit, it was a global trial. However, once we got the accelerated approval, then we closed the trial in the United States because to your point, crossover, a lot of patients had access to TV. We were working on the assumption it was better, so we didn't want to withhold that therapy to half the patient population. But it still accrued nicely globally. Right. And I had it open at my site, and I was glad to see that we could just give patients to Zotamab, Podotin, off study. So in the end, we evaluated, we enrolled 600 patients were evaluated for eligibility, 502 were randomized. But in the end, we had about 500, we received, it was 253 in one arm and the TV arm, 249 in the experimental arm. The median follow-up for the population was almost 11 months. Great. And who enrolled in the study? Who, as far as the patient characteristics? The patient characteristics. Yeah. The mean age was around 50, as mentioned. We had around a 50-50 split between performance status of zero to one. Because of the closing in the United States, about 6% of the patients from the US, but a large percent of the patients from Europe and Asia. When I present this data, and we're super proud of the data, I also want to mention one of the weaknesses, which we're working to improve, and that's that it really lacked a little bit of diversity or a lot of diversity. This is before some of the FDA guidelines statements and before we made it more of a priority. So while this study itself was, I would say, limited by that, it's something that we acknowledge and looking forward where we're trying to make better. You mentioned a tissue factor progression. It's not 100%, but over 90% of cervical cancers overexpress tissue factor. Of these common histologies, right? The squamous, adenosquamous, and the adenocarcinomas. The other thing is I didn't mention that now most of these patients are using Bev and are using some checkpoint inhibitors. In this study, 65% or so of the patients had prior Bevacizumab. At this point, the PD-1s weren't as actively in the armamentarium that we use, but about 30% of the patients did have prior checkpoint therapy as well. That's unique, right? This is the first study to really have this level of prior anti-PD-1 therapy in a subsequent line of treatment, especially in a phase three setting. Exactly. Especially to that point, especially because now in the real world, these patients are getting checkpoints, unless there's another contraindication towards that. So in terms of the overall survival primary endpoint, what was found with this study? So the primary endpoint was overall survival, and we're super excited that it met its overall survival endpoint. The hazard ratio for this trial showed about a 30% decreased risk of death for those patients treated with TV versus chemotherapy. The hazard ratio was 0.7. Super exciting. The difference in time is something that sometimes we question, 11.5- Being the median overall survival. The median overall survival. Between the experimental and the control arm. Exactly. The difference in approval. So it was 11.5 versus 9.5. But one of the things, and you and I talk about this a lot, the treatment of cervical cancer and the progress is going to be baby steps. So sometimes we don't see such of a difference, but this is clearly a statistically significant overall survival bump. 30% is statistically significant. And we're looking to create a greater difference in medians, and we're working towards that. We're going to get there. And this is Journal Club. So it's really important to know that a median PFS, or a median overall survival in this case, is a point estimate. It is not reflective of the totality of time for all the patients. And really the more appropriate measure of the effect is the hazard ratio. So here, what did the hazard ratio tell us? So it showed that there was a 30% difference. And you could see here, we're showing the Kaplan-Meier curves here. They're completely separate. It's a traditional, what we call a banana-shaped curve. They start together. There's a separation. They come back together later on. But looking at this, there's no doubt that the TVR inpatients have an overall benefit. And one of the nice things is now the article here is available for open access. Yes. We want to reconfirm to the audience, hear what we're saying, but go back to the article and really take a deeper dive because we feel that there's some information there that we'll probably not be sharing here. And not only that, we probably should share here that this is the data that led to the FDA approval in the United States. This is also the data that has led to an update in the NCCN guidelines where this is listed as a category one medication supported by phase three data, prospective phase three data. And the nice thing, as we know, taking a step ahead, we're using TV now in the control arm of future trials. That's right. So this is a standard. We're applying for use of TV because it has an effect on survival. Exactly. Because it is prognostic. The use of TV is now prognostic because it does work so well. Exactly. It's not the one option in ongoing trials because it's not available worldwide, but it's the option in those areas that it is available. Yeah. Hopefully we'll see it have more uptake globally. This is a global trial. These global patients responded to this treatment. This had an advantage in a global population. Cervical cancer is a global disease. The hope is that this could get distributed to the patients who need it. Exactly. Yeah. Exactly. What about secondary endpoints, progression-free survival, for example? You know, we always want to make sure that the secondary endpoints are aligned with the primary endpoints. And we see that in the progression-free survival, the hazard ratio was 0.67 or 33% improvement in those patients who received Tizotamab, the dotin, as compared to the standard. The median difference is here, 4.2 months for those patients receiving TV and 2.9 months for those patients receiving investigator's choice chemotherapy. But again, looking at the curves, we're seeing those banana-shaped curves that clearly show a difference between the two arms. Here's another Journal Club question. So is this adequately powered, because this is a secondary endpoint, is this adequately powered to be a definitive statement that it's a positive PFS? Yes, there was some statistical power that was translated down to the second line. Because of the hierarchical design. Exactly. So we did see that here, which is exciting. We also saw at six months, there was 30% of the patients on TV who didn't progress versus about 19%, 20% of those patients who received investigator's choice chemotherapy. So it's a difference. And I always really like to say this because we're always passionate about our patients doing better. Traditionally, when I was in fellowship, when we were in fellowship, we said, you know, these patients, they're really not going to do well, and maybe they're not going to make the next holiday season or the next birthday or the next wedding. I remember those days. So we're seeing the curves come together at the end, but helping these patients live longer, albeit maybe it's not as long as we want, are getting those patients to spend more time with their family, which is so important, and which is why we do what we do. Live longer, feel better, right? Exactly. So when we looked at, the other thing that's important, when we looked at the different subgroups, which is something we like to do, there was really no difference. So, you know, a lot of times we analyze different groups to see if, in fact, there was differences in some of the subgroups or others, but here there's no difference. All the data in the subgroups was aligned with the primary endpoints of the trial. Great. And it didn't matter what prior treatment they had had, if they had had, because it says in the MMAE payload, a prior taxing, prior chemotherapy, no difference, prior checkpoint, no difference, prior BAB, no difference. Really saying that when we're trying to globalize a statement, it's for these common histologies, it's really a treatment option for all of those patients. Yeah, that's a really good point. When we looked at response rate, that's another of the secondary endpoints. This is something that we did see a great difference, about 18 to 20% of the patients receiving TV responded to therapy, versus about 5% of chemotherapy. One thing we like to say in clinic is chemotherapy really doesn't work in these patients, which we're seeing here, 5% is relatively low, and we have a treatment that is working, which is pretty cool. Not as many CRs, complete responses, as we wanted to see, but the progression-free survival was 15% or so in those patients receiving Tizotamabidotin. Finally, we always think about clinical benefit. Not only are they responding, but the disease prevented from growing, and over 50% for Tizotamabidotin, really exciting data. Yeah, it is a high bar for the response rate, and I think that that's what patients want. They want their tumors to shrink. But the stable disease has a lot of value, especially in those who aren't so symptomatic. The patients who are symptomatic from their disease, we're really looking for that response rate. So then again, you're going to go for the treatment that has the best response rate if you're going to subject your patient to more side effects of treatment, which we're going to get to next. And the disease control rate, 76%, 75%, 76%, which is really exciting for our patients. So let's talk about the treatment-related adverse events, the side effects that are associated with Tizotamab. It's got a different sort of profile. I think a lot of folks are now familiar with the ocular side effects of the TV. How do we manage that, and what else do we look for? So if we see ocular side effects, which is something we'll talk about more in a second, we also see the peripheral sensory neuropathy. One of the things that's important in practice is to note that the neuropathy that we see is not the same as the neuropathy that we see with taxans. So and our patients tell us that. So not in the paper, but more like clinical experience, which is so valuable for using this new treatment. Exactly. Exactly. And we'll see, you know, it does require eye exams, which is something, you know, part of the ocular mitigation strategy. The users of this, as you know, we do eye drops, we do steroids, we do close examination. Contact lenses, a lot of people wear, but they should stay away from contacts while they're taking this drug. And, you know, a lot of these side effects, we're able to, leads to very, very few discontinuations. And a lot of them go away once we employ the treatments that we use to prevent. How did the side effects of TB compare to chemotherapy in this study? Yeah, so we saw more of the, you know, the ocular, the neuropathy, and the bleeding. There's some nosebleeds that we saw, some hematuria. But overall, of these side effects, there's much more in the TB, but remember, chemotherapy, without going through it, chemotherapy has its own toxicities. Well, that was my review of the paper, is there was maybe even a little bit more toxicity, especially the obvious, the heme toxicity, the cumulative neuropathy from reintroduction of chemotherapy in this population. So that gave me a little bit more comfort in adopting TB as a therapy. Exactly. Yeah, I agree completely, which, and our experience, I mean, now, at this point, you and I have used it a fair amount, patients, you know, sometimes you, the same patients don't get both therapies, but, you know, in my practice, I see the TB patients, it's so much well-tolerated. I'm allowed to give a lot more cycles for those patients who respond. So it's really exciting from that perspective. Great. And I think that's interesting because it's not exactly reflected in the numbers for the median duration of response in this study. But I think that that's, you know, it's just complicated when you roll out a treatment to a global population, sometimes you see, you know, a little less efficacy than what you've seen in the earlier trials or in your own patient population. So I think that, you know, my interpretation of the data is that patients deserve a chance, and then we just need to be educated on how to manage the side effects. Exactly. You know, I completely agree. Outside the scope of this paper, the other thing I want to mention when we're talking about responders, you know, there's good data, a lot of this you led with TV and pembrolizumab, there's other data with carboplatin. You know, we're looking forward to further studies on that, hopefully, to expand the use in this combined, with a combination setting. Yeah. That's really important data. I mean, we're a very naive population, but immunotherapy is so active in cervical cancer, it's curious and, you know, we'll be doing subsequent studies to see if we can retreat with immunotherapy. And I think cervical cancer may be the one situation where we can actually do that with some benefit. Yeah, exactly. So it's exciting. I mean, we just went through some of the efficacy, we went through the toxicity, you know, we're proud, really excited that the medical community accepted this, the FDA approval, July 4th publication in the New England Journal. So, you know, that doesn't happen every day and it's, you know, it's a team effort, here with a global effort, it was a global team effort, which allows us to do future trials using that team. Again, overall survival, progression-free survival, safety profile aligned with the previous studies, with the mitigation strategies, maybe even better. So it's exciting and, you know, I think you and I are in agreement, we use it. The big problem, as you mentioned, we need to get it more available globally. We need to get it more available globally because the patients can really benefit. This has been a great journal club. I mean, what a treat to have, again, one of the investigators to get sort of the context and the background around how the study was conceived, done, performed, interpreted, and then again, you have the open access to this paper. So please, again, study it in the context of our discussion and hopefully we'll work on getting this drug available in the rest of the world. Likewise to be acknowledged, Leslie leads the cervical cancer portfolio for the GOG Partners Group. So I can't emphasize enough the team effort and the portfolio that you're bringing forward. As I said, baby steps, right? So this is a step forward. Put those trials that you're doing together, put an I.O. into the first line setting. Really, you know, it's exciting to see what we're doing for our patients. It's all about patients. The patient who inspired me to be a GYN oncologist could have benefited from this drug and is not here. Yeah. So, yeah. Yeah. It's a great story. So it's all about patients. Yep. Yeah. So thank you for having me. Thank you very much. Thank you. And we hope to see you back in January as Cervical Cancer Awareness Month. The best immunotherapy for cervical cancer is an HPV vaccine. I was just going to say prevention. You know, Leslie and I, if we never have to treat another patient with cervical cancer, that would be our career goal. That's right. Prevention, pap smears, vaccination. Yeah. It's all. Yeah. We continue to be excited about these data, but we look forward to the day where these treatments are not necessary because of vaccines. Spot on. You and I are in complete agreement. As usual. Thank you very much for having me. Thank you.

Tisotamab Vedotin

cervical cancer

clinical trial

treatment efficacy

HPV vaccination

side effects