Welcome all, I'm Flora Backus, I'm a gynecologic oncologist and professor in the Division of Gynecologic Oncology at The Ohio State University Medical Center and James Cancer Center. I'm honored to be one of the co-chairs of the IDCS Education Advances and Updates workgroup and excited for our webinar today titled Changing the Standard of Care in Second Line Recurrent Cervical Cancer, which is in part sponsored by CGen and GenMAP. IDCS is committed to providing meaningful education opportunities through a unique year-round educational engagement program. This platform provides the level of strategic engagement and exposure needed to educate and inform gynecologic oncology professionals on current and future treatments to optimize patient care. Now it's my honor to welcome our speaker, Dr. Brian Slomovitz, Brian, will you please introduce yourself? Yeah, sure. Hi, everyone. My name is Brian Slomovitz. I'm the director of gynecologic oncology here at Mount Sinai Medical Center in Miami Beach, Florida. I also serve in GOG Partners as a uterine cancer trial lead, but most important for today, I served as a GOG principal investigator for this important trial that we're going to be discussing. So, Flora, thank you for having me and I want to thank the IGCS for hosting this and obviously the sponsorship from CGen and GenMAP. I'm really excited to be here. So thank you. Well, yeah. Thank you for joining me. I know you were just at ESMO and are doing a lot of traveling, so thank you for making the time and sharing this very, very important information with us today. So before we can get started, I want to mention a few housekeeping items. Please know that a recording of the webinar will be available on IGCS Education 360 Learning Portal within one business day, and we encourage you to submit questions via the Q&A feature at the bottom of your screen, and we'll do our best to address as many questions as possible. Brian, I will now turn this webinar over to you. Great. Thank you very much. And I think the best way for us to start is really to spend some time and go through the presentation. So let me pull this up on my... Now, Flora, can you see this okay? Yes. Yeah, absolutely. Great. Again, thank you very much. This was... For me, it's an honor that I represent the GOG, and we were honored to work with our colleagues in NGUT on this important trial. As mentioned, I was a GOG principal investigator. The global principal investigator was Ignace Vergoet, who presented the trial during one of the presidential sessions at ESMO, which by itself is sort of unprecedented in GYN type of GYN studies, so we were excited to be here. But it's an important trial. It really, I believe, is going to change the second and third-line management of this disease. Innovative 301, NGUT CX12, GOG 3057, it's a randomized global open-label phase three study of tezotamab vidotin. Going forward, I'm going to refer to that as TV, versus investigative choice of chemotherapy in the second or third-line management of recurrent or metastatic cancer. It's really led by NGUT with GOG participation, but more importantly, really a global effort, and a lot of the global investigators are part of our co-authors. So just for some background, again, a lot of us know this information, but I think it is important to go through. Recurrent or metastatic cervical cancer is a devastating disease globally associated with a poor prognosis and a high mortality rate. It's the fourth most deadly, cervical cancer is the fourth most deadly cancer in female patients worldwide. Despite the addition of immunotherapy in the treatment of this disease, those who progress on or after first-line therapy continue to have an unmet need for better treatments. TV, or tezotamab vidotin, is an investigational antibody drug conjugate, ADC, composed of a tissue factor-directed human monoclonal antibody covalently linked to the microtubule disrupting agent, MMAE. TV received FDA approval in the U.S. for the treatment of adult patients with recurrent or metastatic cervix cancer with disease progression on or after chemo based on a phase two trial, Innovative 204, GOG 3023, and NGOT CX-6. Now as you know, when we get an accelerated approval in the United States, it's required that it's a confirmatory trial, and that's what this study served as a confirmatory trial. In addition, we needed to do this trial in order to get global use and global acceptance of this treatment, if in fact, and as I'm discussing, that it is positive. Here's the study design. Innovative 301, again, is a randomized open-label trial enrolling patients with recurrent or metastatic cervix cancer whose disease progressed on or after chemotherapy. Patients had doublet chemotherapy plus bevacizumab if available and eligible, and plus a checkpoint inhibitor if eligible and available. Patients were required to have two or less prior lines of therapy, measurable disease according to resist, and a performance status of zero to one. 502 patients were randomized in a one-to-one randomization to receive either TV at two milligrams per kilogram or the investigative choice chemotherapies listed here. Primary endpoint was overall survival, and the key secondary endpoints, which I'll go through, progression-free survival, overall response rate, and safety. Patients were stratified by performance status, prior bev use, prior checkpoint therapy use, and geographic region. The data that were presented here are planned interim analysis with a positive outcome. When we looked at our statistical considerations, the planned sample size was 482 patients. The sample size was powered at 90% with 336 overall survival events. The interim analysis was planned for 252 overall survival events. The assumption was a hazard ratio of 0.7, a dropout rate of 5% per year, and the overall statistical level of significance was defined as 0.05. Based on the actual number of events at the interim analysis, the p-value boundary for overall survival was 0.0226, PFS 0.0453, and overall response rate of 0.05. Simple testing was performed, first looking at primary endpoint. If in fact that reached its goal, then key secondary endpoints were PFS, followed by the overall response rate. Here's a look at the patients who were enrolled. 660 were assessed for eligibility, 502 were randomized. In the experimental or TV arm, 253, of which 250 received at least one dose of therapy. Patients on study or continuing study are 21. In the chemotherapy arm, 249 patients, 239 received at least one dose, and there's 16 patients currently on trial. The discontinuation rates are listed here for both arms. Most commonly progressive disease, followed by adverse events in the TV arm, and patient decision in the chemotherapy arm, followed by patient decision in the TV arm, and adverse events in the chemotherapy arm. On patient characteristics, of note, the baseline characteristics are similar, very similar between the two groups. Asia had a very high proportion of patients accrued in Asia, 33% and 35% across the two arms. Most patients had squamous cell carcinomas, approximately 63%. Pelvic recurrence was only seen in about 10% of the patients, making most of these patients systemic recurrence. For a prior systemic regimen, 60% had one. Bevacizumab eligible and available, 65% and 63%. About a quarter of the patients had prior checkpoint inhibition. And 92% to 94% had positive membrane expression of tissue factor. And we knew this, and one of the reasons why we're going after cervical cancer here is the high rate of tissue factor noted on the cervical cancer cells. Here's our primary endpoint, and this is what we're very, very excited about. This is the Kaplan-Meier curve. The median overall survival for Tizotamab-Vidotin patients in that arm was 11.5, investigative chemotherapy 9.5, the hazard ratio of 0.70, demonstrating a 30% decreased risk of death due to this disease in the study population. At 12 months, 49% were live in the TV arm versus 35% in the control arm of investigative choice chemotherapy. The next slide here is one of the secondary endpoints. Progression-free survival, the median progression-free survival in TV was 4.2, followed by 2.9 in the investigative choice chemotherapy. For a hazard ratio of here, of 0.67, or a 33% decrease in risk of recurrence or death in those patients with TV versus the control arm of investigative choice chemotherapy. Six-month PFS, 30.4% were progression-free in the TV arm versus 19% in the control arm. When we look at the key subgroup analyses here, overall survival and progression-free survival benefit was generally consistent across the key subgroups. Those patients with a performance status of 1 didn't cross 1, while it did in the performance status of 0, overall survival. We can see here that as well, the prior bevacizumab was significant for both overall survival and progression-free survival, if in fact the patients had prior bevacizumab therapy. Antitumor activity, another secondary endpoint to this trial, 18% of the patients receiving TV had an overall response, with 6 patients, or 2.4, having a complete response. There were only complete responders seen in the TV arm. Overall the disease control rate was 75.9% versus 58.2% in the control arm, with a median duration of response of 5.3 and 5.7. We could see from the waterfall plots here that many of the patients receiving TV did in fact have a change in baseline of tumor shrinkage in their cervical cancers when treated with TV. You can see here the complete response rate, as mentioned, the disease control rate. Let's look at some of the most common treatment-related adverse events, and this is something that's very important when we look at this therapy. Of note, grade 5 treatment-related AEs occurred in 2 or 0.8, and 1, 0.4% of patients in the 2 arms. The median relative dose intensity was 96 and 90% in both arms. When we talk about any event, the 87% or 88% versus 85%, those side effects that were more common in the TV arm, peripheral sensory neuropathy, alopecia epistasis, and a slight increase in decreased appetite and diarrhea. Of note, the grade 3 adverse events for TV were seen in 46% of the 26% peripheral neuropathy. Very few had grade 3 adverse events. Similarly, the number of grade 3 events was extremely small, low, in those patients receiving TV. In the control arm 43, for 4% of the patients had anemia. You can see there's a significant number of grade 3 events there, as well as with neutropenia. These again are the ones that are most common in the TV arm, and the gray arrows here are more common in the control arm. When we look at those adverse events of special interest, the three most common preferred terms for each adverse event is ocular, which includes conjunctivitis, keratitis, and dry peripheral neuropathy, which includes peripheral sensory neuropathy, paresthesias, muscle weakness, and peripheral sensor motor neuropathy, and finally, bleeding, epistasis, hematuria, and vaginal hemorrhage. We can see here the percentage of those patients with these side effects. There was no grade 4 or 5 adverse events of special interest. Post-discontinuation due to ocular and peripheral neuropathy events occurred in 5.6% of the patients each. The low rate of ocular discontinuation is most likely due to the aggressive ocular mitigation strategy that was employed in this phase 3 trial, based on our prior experience of TV. In conclusion, Tizotimab-Vidotin showed a statistically significant and clinically meaningful improvement in overall survival, with a hazard ratio of 0.7, demonstrating a 30% reduction in the risk of death. Consistent benefit was seen in progression-free survival, and confirmed overall response rates were also observed and supportive, consistent with the overall survival benefit seen with TV. Safety profile was manageable and tolerable and consistent with previous experience. And based on these data, Tizotimab-Vidotin should be considered a potential new standard of care for patients who progressed after first-line systemic therapy. Most importantly, the study couldn't have been done without patients and their families. The study, as mentioned, was funded by GenMab and CGen, and it was co-developed by both of these sponsors, GenMab and CGen. And we're listed here all the investigators, again, who can't do the study without their active participation and accrual of these patients. Thank you very much. And Flora, I look forward to our continued discussion during the session. Excellent. Yeah, such a nice presentation, and great news for our cervical cancer patients who really are in high need for this. So Brian, I do have a few questions after seeing your presentation. So what do you think about the survival difference between those two groups? Thank you for that. When I look at the survival difference, I think the right statistical endpoint to look at is the hazard ratio. And it demonstrated a 30% decrease in risk of death in patients treated with TV. This was statistically significant, obviously. In addition, that's consistent with progression-free survival. And also, it's almost about four times increase in response rate when compared to the controller, so which is very exciting. One issue that has been brought up is the difference in response rates between this trial of the TV and the previous trial that was reported on. And truthfully, Flora, we see that across phase three studies. Normally, there is sort of a drop-off from phase two to phase three studies. And oftentimes, that's really used to observing these patients a little bit more closely and trying to see when they're progressing or not, because this, in fact, is a registration trial. So I'm not concerned about seeing that. I'm more concerned about the statistical significant endpoints. Yeah. Do you have any explanation why it seemed like when we look at the plots that in the patients that were previously treated with Bevacismab that it looked like the benefit was a little greater than non-treated? Yeah, that's a great question. In short, we're not sure exactly why is the case. The good news is, as far as the standard of care here, based on the results of Dr. Monk and Dr. Torres to GOG240, Bevacismab is part of the standard of care if, in fact, they're eligible. But the mechanism itself, I'm not sure how to explain it. But I'm sure that we're going to further try to elucidate that in future trials. Yeah. And how about the side effects? When we looked at those side effects, we see definitely differences. You pointed out those ones that are the AEs of special interest. Well, we still see some alopecia, of course, with this also, as we do with chemotherapy. But the neuropathy is certainly a great one, too, is a difference. Are you comfortable with that? And how do you manage that with this agent? Yeah. So first, I'll answer the first question first, am I comfortable with it? Yes, I'm comfortable with it. Cervical cancer is a deadly disease. We don't have a lot of good treatment options. I think the choice of investigator chemotherapy, I think that is the standard of care. And we could see the response rate there was 5%. We could see that there's a low discontinue rate versus these adverse events, particularly those of special interest. So I'm OK. I'm more than comfortable in giving those side effects. I think as far as the major one that we're concerned about, well, we're always concerned about all side effects, but the major one being ocular side effects. As mentioned, well, I didn't mention there's a warning in the accelerated approval label. In this trial, we were really aggressive, as mentioned, in our ocular mitigation strategy, requiring patients to go to ophthalmologic exams, to if there are any changes to catch things early, aggressive steroid drops, saline drops, keeping the eyes moist. So I think if you employ this aggressive ocular mitigation strategy, handling the side effect is, or the incidence of timing of the side effect is much, much less and much more manageable. As we can see in the low rate of grade 3 side effects there. Yeah, I agree. With the addition of the eye cooling and the vasoconstrictive drops, that really seems to have made an improvement here, and that's encouraging to see that there's low discontinuation rate for this as well. So how are you going to manage recurrent cervical cancer in the future? Now we have this data available. Now that's a great question. I think that the landscape of cervical cancer is changing, continues to change. If you were at the ASMO meeting, or if not, you could see that there was a lot of cervix being presented. A18 interlaced on this trial. If we move, one of the exciting things about A18 is a positive trial moving IO, checkpoint inhibitors, into the first line therapy of locally advanced disease. In systemic disease, in the first line setting, as you know, the A26 data encourages the use of both IO with Bevacizumab. The second line treatment options represent an unmet need, and I think this is a very exciting agent to put into that setting. We have a benefit of overall survival. We have the benefits of progression-free survival. So I'm pretty sure that we're going to see a lot of patients using this as we move forward. Yeah, and so what do you think about this as a single agent? We have this now as an option as a single agent, but recently we also saw the presentation of TV, and that's a phase two trial, an earlier trial, but it's not a confirmatory trial, but that TV is being used as a combination agent with very encouraging responses in that population also. How do you see this being used in the future as a combination, as a single agent? Yeah, no, that's great, and Flora, as you know, a lot of times that when we're getting a positive result in the recurrent setting, similar to IO in cervix cancer, similar to Bev in cervix cancer, and in ovarian cancer, we sort of move it forward. We start in the second or third line and we move it forward. So I think that given these positive results, I think it would be nice to move forward into earlier lines of therapy, and the data that's given with pembrolizumab, the data that's given with bevacizumab is promising, and I think there will be opportunities as we move forward to investigate these combinations more in the first line setting, particularly looking for the benefit there. Excellent, excellent. If it moves there, it's great. If it stays in the second line, again, overall survival, either way, I think it's going to be used. Yeah. And so we have one question in the Q&A also that asks, why did so many patients abandon treatment? And I think that was on one of your first slides by patient choice. Yeah, so it's interesting. Most of the abandonment in this trial happened in the control arm. We really worked hard not to let that happen. Given the fact that it's an open-label trial, and given the fact that the control arm is readily available, a lot of times patients go the distance. They travel far. They really want to do whatever they can to get into the treatment arm of the trial. When not selected, unfortunately, we see some numbers, a really relatively low number, but some patients withdrawing and going closer to home to get their care. Yeah. Okay, great. Thank you. Well, I think we're kind of at our 20-minute sequence here, and so I don't see any other questions in the Q&A. Brian, any final comments that you'd like to make sure that people know? Yeah, no, just again to highlight, we're thrilled that we were able to do this as a collaboration between NGOT and GOG. We're looking forward to future trials to, again, always improving the standard of care. Obviously, we're happy with and we're content with the hazard ratio that we've seen in this trial, but we need to continue to do more. And finally, a lot of times when we're talking to patients, sometimes it's baby steps. Putting this together with two or three other trials than this, we go from a smaller difference in median overall survival to a larger difference. So I think it's exciting. We need to continue to move forward, and I'm excited for our next steps. And most importantly, thank you very much for joining me here and for your great moderating. You made it easy for me. Thank you. Oh, well, my pleasure, and I'm so glad that we could share this data, very important data, with the rest of the world and for everybody who wasn't able to be at ESMO. So with that, I thank you, and thank you all for attending. Thank you for sharing your knowledge here. The recording of today's session will be available in the IGCS Education 360 Learning Portal within one day. We wish you continued health and safety. Thank you very much, and have a great day, everybody.

webinar

Dr. Brian Slomovitz

tezotamab vidotin

cervical cancer

overall survival

progression-free survival