Well, welcome to Novel Combinations for the Treatment of Recurrent Cervical Carcinoma. My name is Wendell Mellon. I am the Associate Director of Clinical Trials at Levine Cancer Institute in Charlotte, North Carolina, and I'm the moderator for this session. I would like to welcome Dr. Brad Monk, who's going to join us for this. Dr. Monk is the Director of the GOG Foundation and a board member. He has been instrumental in developing drugs for gynecologic malignancies, is well-known, and has really had an impact on cervical cancer, and he's going to discuss many of the advances in cervical cancer, which have been quite, in terms of advancing the treatment for recurrent metastatic cancer, have been just unbelievable. This recording will be available on the IGCS 360 website as of tomorrow, and if you have questions, please use the Q&A feature at the bottom of your screen. Dr. Monk? Yeah, thank you, Dr. Nauman. I'm going to call you Wendell. It's been my pleasure to be friends and colleagues for many years, and thank you for having me. I haven't done anything. You have done it, and so it's very exciting for me to report and summarize what you have done in the clinical trial landscape, and many of you have been papers, had co-authors on these papers, and it's exciting to sort of summarize. We're only going to be here for 30 minutes, so we'll have plenty of time for Q&A. I just sort of want to review and, quite frankly, celebrate your achievements. These are my comprehensive disclosures. Thank you. This is my deck. No one has contributed to this other than me and my colleagues. If I am sharing your slides, I want to thank you, because, again, this is a group effort. Cervical cancer really hasn't changed in the U.S. as far as incidence goes. In fact, it's decreased by less than about 1% in women over 50, so we still need to focus on vaccine and screening. If we've learned anything from COVID, if you don't get vaccinated, you might die, and if you want to figure out what your risk is, you should test for the virus, and all of that applies to cervical cancer. So I want to now talk about recurrent cancer. We don't treat or consider chemotherapy and radiation as a line of therapy, although I think all of you have seen the press release for Keynote A18, which is adding Pembrolizumab to chemotherapy and radiation in locally advanced cervical cancer. I have it on good authority that this will be presented at an upcoming meeting, and you know when the upcoming meetings are in the next several months, so we can talk about that. But it's ultimately going to move Checkpoint into an earlier line of therapy. So the first landmark discovery, of course, was chemotherapy and radiation. I just described that that's changed, I think. The second landmark discovery was GOG204 platinum taxane. But the third discovery was the addition of betacizumab to chemotherapy, which led to an improvement in overall survival and a global approval, and many of you are listed here as co-authors, and it was a good time, was the first targeted therapy that was approved in a gynecologic cancer. It's hard to imagine that we're coming up on 10 years, so that was great. The next achievement was Pembrolizumab, only in a few countries, conditional or accelerated approval based on only 77 patients, a 14.3% response rate. But those were durable, and that was exciting, again, because the response rate was so low, it's the durability that led to the approval, again, in June 12, 2018, and I appreciate your contribution to that. But it was really the regular approval in the New England Journal and the ESMO simultaneous publication at ESMO of keynote 826. And that led to the full approval, again, in PD-L1, CPS greater than or equal to 1. It was about 90% of patients. So we had chemotherapy and radiation, 204, 240, Pembrol, four amazing accomplishments. And I can't even believe that in our short lifetimes, we are now talking about sequencing, and that's very exciting. So that was two years ago. I want to talk about the fifth and the last landmark discovery, and that's Tizotamab V. dotan, which is an antibody drug conjugate against tissue factor. It's a very exciting opportunity. The payload is MMAE. The payload and the linker together are known as V. dotan. So that's where the name comes from, Tizotamab V. dotan, and it's a microtubule disrupting agent. I point out to you here that this is also very prevalent on uterine cancer and ovarian cancer, so stay tuned. We're here to talk about cervical cancer, but I hope to, with you, bring this or other tissue factor ADCs to endometrial and ovarian cancer. So this received FDA approval on September 20th. It was just before the PEMBRO approval, because remember, if PEMBRO would have had full approval in the second line, you would have had to have beat PEMBRO. Remember, PEMBRO came in October of 2021, so because this was before it, we were able to get accelerated approval, and again, that was a big, big milestone, and again, landmark discovery number five. So this is an iterative increase, again, 204 platinum taxane, Bevacizumab, and then triplet or quadruplet. Look at the iterative change, 12.9 months, 17.5 months, and now 28.6 months. And now look at the response rates, 29, 48, 69. Cervical cancer is a chemotherapy-sensitive disease, period. So you'll see someone with a symptomatic lesion in the neck or something, I'm going to radiate. No, you're not. It's a systemic disease. You're going to give that individual systemic therapy because their response rate is 70%, assuming their CPS greater than or equal to one. So remember these numbers. The topic for today really is combinations. What we do is, what you do is you get generally approval in a late line, and then you do three things, combination, earlier line of therapy, and other tumor types, and that's sort of a tenant of drug development. So this is a trial that we've worked on, our European network, NGOT, GOG, you'll see my GOG background, most of these studies are GOG. We really collaborate well. We're not territorial. Our passion is not to compete against each other, but to beat the cancer. And that's what we do. So this is the safety presentation that was presented at IGCS 2021, and then we followed it with the efficacy at ESMO. So there's a safety component, there's a phase two efficacy component, and then ultimately there's an RMH, which I'm not going to show you, which is taking the keynote 826 and replacing taxane with tezodamabidotin. Now whether we'll go into that space as a randomized phase three is up to the sponsor. As you know, the sponsor is being acquired by Big Pharma, Bigger Pharma, but this was really an exciting opportunity and something I'm very passionate about. So this trial, 205, except for the RMH, the quadruplet, the doublets will be published together in the Journal of Clinical Oncology any day. So, and the data in the paper are a little better than what I'm going to show you because as you follow patients longer, the patients continue to respond. But I'm going to share with you sort of a general overview that was reported. So this is the efficacy here, as you can see, of TV-CARBO in the first line. So remember, TV-CARBO in the first line was studied and inferentially compared to the results of 204. And I showed you what the results were of 204, right? The response rate, do you remember? 29.7%. Small numbers here. But the confidence interval excludes the 29.7% of 204. So TV-CARBO has synergy, preliminarily, phase two data, small numbers, that exceeds carboplatin paclitax. So that's exciting for me and hopefully exciting for patients. One of the adverse reactions related to TV is ocular. We require that patients have a baseline exam, generally by an optometrist, it doesn't have to be an ophthalmologist. We have a mitigation strategy, which includes three types of drops, vasoconstricting drops, steroid drops, and lubricating drops. And the vasoconstricting drops are to limit the exposure to the eye. And also there is a cooling pad over the eye. So that's the intention. I get the sense that the adverse events here are a little lower because we sort of learned how to do it. These are reversible. It's a surface toxicity, it is cornea, which is called keratitis, and conjunctiva, which is called conjunctivitis. And it's not as complicated as some of the other adverse reactions related to the eye from other ADCs. Again, it's surface. So if you examine a patient and there's no red eye, there's no conjunctivitis. And if you ask the patient, can you see your visual acuity, there's no corneal or keratitis because that's what you've looked through. So this has been something that we had to become familiar with. Because tissue factor is in the coagulation pathway, we looked for bleeding. And there was some bleeding, so the cooling covers the external layers. But there was some hematuria, could have been radiation cystitis, there's some vaginal bleeding, could have been cancer, but definitely there was epistaxis. Based on the mechanism of action, we look for neuropathy. So people ask me, what is the contraindication to TV? Well, the answer is grade II neuropathy. Most of these patients are young, haven't had a lot of treatment like our ovarian cancer patients have, generally cisplatin at low dose with radiation, then six doses of carboplatin and paclitaxel. So we monitor this and we treat the neuropathy just like we do when you have a paclitaxel related neuropathy with interruption and dose reduction and supportive care. So that's what you get here with carboplatin TV. Again, this has been presented at ESMO. You will see this in the Journal of Clinical Oncology. The numbers are a little better because we followed the patients longer, but we're excited about that. In addition to combining it with carboplatin, we combined it with the other two active agents, Bevacizumab and Pembro. I want to focus on the Bevacizumab and the Pembro opportunity because I get asked all the time, well, if I have a second line patient who is checkpoint naive, because checkpoints don't really work after checkpoints generally, but many of the patients around the world in the second line are checkpoint naive, so which do I do? Pembro or TV? And the answer is yes. These molecules can be combined and that's what this study shows. And you remember that the Pembro was 14%. The accelerated approval for TV was 24%, 14 plus 24 is 38. So at least they're additive and I can tell you this number is better in the publication. So this speaks to not only the additive at least activity of TV Pembro, but also speaks to the tolerability and there was really no new safety signals in the TV Pembro, again in the second line. TV Carbo is an opportunity in the front line, okay? And that is good news for patients and I'm excited to see this in print and so proud of what you guys did together. Now when you get conditional or accelerated approval, you got to do phase three. And that study is called 301. It's again, second line or greater than first line, one or two priors, measurable disease. TV at the dose, two milligrams per kilogram, again, it's every three weeks intravenously versus physician's choice chemotherapy, which is exactly the same interventions in Empower with Simiplimab. So it'd be interesting to cross trial compare, although we shouldn't do that. With the primary endpoint being overall survival. Now the sponsors have said that we will hear in the latter half of this year, maybe even the third quarter, which is where we are, okay? So we'll see what this shows. For those of you that don't have access to TV because you didn't have an accelerated or conditional approval like Germany, like US, Switzerland, other countries, this will enable you to have access to TV. And that's really exciting. And I can't wait to see what this shows. And I'm confident, although I don't know, that this will evolve and allow other countries and settings to have this medication. So I'm excited to see all of you in Seoul. The IGCS is a wonderful organization. The first IGCS that I ever attended was in Seoul. So I'm excited to have this come full circle. So I'm going to stop sharing and turn it over to you, Wendell. Thank you for having me today. Thanks, Brad. That was just a great overview and very exciting data. I mean, I remember the days in the early GOG where we ran the phase two trials for cervical cancer. Most of them had a median survival of about eight months. And so to now have a primary combination that goes 28 months, it's unbelievable. And some of these patients are going to be cured because you see that tail on the A2-6, which you've shown. And that's just unbelievable. Let me just address that because that's I didn't say it, but you did. And I just it's so important. Half of the patients are CPS greater than 10. OK, so 90 percent are CPS greater than one in the CPS greater than 10, which is half. Forty percent of the patients are progression free in three years. In other words, they finished their two years of Pembroke, they go a year and nothing happens. So I can't say you sort of inferred it, but I think we're hoping imagine if you could cure 40 percent of the C of the CPS greater than 10 and some of the greater than ones. I think there are patients that are being cured just like just like. PARP inhibitors and BRCA, just like checkpoint in MSI high endometrial cancer. Wow. Sorry to interrupt you there. I just get so fired up. Oh, no, I think that's a great, great point. I and you hit on this a little bit. One of the issues comes because the frontline trials upend all of the data we have in second line. I know there's a lot of discussion, a lot of sort of confusion, I think, in terms of what do we do. Second, I knew you pointed out there are different patients. There are checkpoint naive patients. There are, you know, and I assume that we will have compendium listing for some of these combinations when the publication comes out. So, you know, I think it's going to be interesting to see how we we choose these combinations. I guess the question is, you think, you know, we have a lot of pushback, I think, to Sodomab because it's a new drug, it has new toxicities. Do you see this as a combination, second line, or do you see it as front line? When would you want to add chemotherapy to the TV if that's available based on the publication? Yeah, what a great point. And I've known you for a long time, and you always ask the toughest questions, so thank you for treating me the way you always treat me. And so I think that the TV Pembro is pretty easy because there's no increase in toxicity really to speak of. I get it, you can have immune-related adverse events. So in the checkpoint 9, I think TV Pembro is probably the best path if you can get it paid for, and I love your comment about the NCCN. TV Carbo, I think that was the proof of concept to try to move it earlier in a line of therapy. So for now, I probably wouldn't utilize that, but that's a good question. So if you were advising somebody to do the next generation trial, what would you like to see in terms of improving the front line treatment? Obviously, the removal of taxane eliminates some of the neuropathy that these patients get, also the hair loss, although you do have a little hair loss, I think, with TV. That's right. So the first thing is, again, A18, adding Pembro to chemotherapy and radiation, which is a study that many of you participated in. Once that sort of is shown, and once that is approved, and it will be, then these patients in the first line, over time, probably two years, will become checkpoint exposed. And again, checkpoint doesn't work after checkpoint. And then we'll basically have as the control arm, GG240, platinum taxane Bev. And we'll be able to switch out some of those components, I think, just as you said, particularly the paclitaxel. And we have probably at least three options to switch that out. And you can switch it out with trope. You saw some of the data that's been recently presented, very exciting. You can check it out, switch it out with a HER2. You saw pandestiny tumor recently in ASCO. And then you can also switch it out with tissue factor TV or another anti-tissue factor ADC. So I think, because these are, many of them, tubulin active, some of them are topoisomerase. And as you know, topotecan works in this disease as well. That's what I want to do. I want to switch out the paclitaxel. One of the other questions, can we switch out both carboplatin and paclitaxel? One of the probably, other than what I've shown, and I apologize for not showing it, one of the most exciting data sets is your study, Wendell. So CTLA-4 PD-1. This is a transformational combination. The reason that I didn't mention it, because I think the intention is to move that to chemotherapy and radiation. So we really haven't been able to get traction from a PD-1 CTLA-4 sponsor in first line. But we are getting traction with chemotherapy and radiation. And people get anxious, oh, 18 is positive. We can't do it. Yeah, you can. Because now you've shown that immune therapy and chemotherapy and radiation works. And what you told me, Wendell, and I've used it based on your leadership, adding CTLA-4 to PD-1 is transformational. So thank you for that. And I hope that that's also maybe even a chemotherapy-free regimen, even in the first line, depending. Yeah. So hopefully that publication will be out soon as well. Well, and we have seen responses in PD-1 negative patients, which is unmet. Both in Checkmate-358, as well as GOG-3028 with the rapid straw. But anyway, I think those are interesting combinations. And we have a whole host of new molecules that are coming out. Other ADCs. The TIGIT molecules and TEM-3. We don't know how those are going to play out in patients with metastatic cerebral carcinoma. But clearly, there's an immune problem in terms of dealing with HPV and development of cancer. I think that's a very exciting project. We did have a question on the TDXD. So, and you mentioned the Pantumer Destiny-03 trial that was presented. Very exciting trial in addition to a 2-plus or 3-plus HER2 expression, not even by the traditional criteria, by the FISH criteria that we use in breast cancer. What do you think? And do you get HER2 testing on all of your patients with cervical cancer? And if you had a positive HER2 patient, what would their second line be if they were treated with the 826 regimen up front? So, let's go through the tumor testing. So, first of all, you know, PD-L1. And again, it's CPS. Remember, if you start using, and that's 22C3 antibody. If you start using SP-263 and others, you're going to get a lot of negatives. So, let's utilize the companion diagnostic. And if you do 22SP-263, you'll get a lot of positives too. But let's focus on the companion diagnostic. Don't give up on a checkpoint if they're PD-L1 negative, because many of those are adenos. And some of those are TMB and MSI. So, when I say that it's CPS, you know, 10% or negative, it's probably closer to 5% or 6%, because you're going to pick off, you know, four or so of TMB, MSI. The next most important biomarker is HER2, and that's your point. And because it's sort of unproven in those small subsets, I'm not sure what I would do in the second line when I got TV in my pocket that is paid for, and I have it, it's in my electronic ordering system. You know, there's no, you can't go into my ordering system and say, oh, you know, trustee doesn't have drugs to count. My pharmacist is going to say, no, you would, no, you're not. That doesn't mean I can't get, you know, battle through it. But I am testing. We also had a NIRATNIB publication in the Journal of Gynecological Oncology, which is a TKI. Those also work. But yeah, we need to start testing. I think that the trick is really going to be HER2 is going to be studied in a phase three trial, period. Who does it? There are lots of anti-HER2 ADCs, and trope is going to be studied. Again, there are multiple trope ADCs. And whether tissue factor is studied, I hope it is. I'm passionate about it. And that would give us three ADCs in the first line to study. Good question. And obviously, and you know this, we're seeing ADCs with multiple different warheads. And what do you think about sequencing the patients who don't respond to one, let's say we have another tissue factor antibody, do you tend to think that they're going to be resistance or is the mechanism of resistance to the warhead? I think you're obviously very smart and you're right. The challenge has been that, at least myself, I'm interested in the topoisomerase warheads. But the vidotin, again, it's the linker in the MMAE together, vidotin is very well validated. And so you say, well, it's not sexy enough. Well, it has multiple indications, vidotin. So I think you're going to see some other vidotin antibody drug conjugates that are undisclosed, made by, you know, CJEN, who owns the vidotin platform. But I think it's all about the payload, just what you intimated. And if you're resistant or the patient is resistant to a tubulin, you can come back behind and do a topoisomerase. You also saw from this mirsana epifidumab, UPRI, that you really got to follow the science. And it starts saying, oh, you know, NAPI 2B and dololoc, all of that, you got to prove it. And when the question was called, it didn't work. In fact, it was toxic and caused some treatment related deaths. So we just have to follow the science. And that's why I'm a fan of the vidotin platform, because it's validated. Although some of these other platforms are also validated, such as just using MebDrux to can. Well, and you never retreat with an IO, or do you think that there's not energy between an IO and chemotherapy in terms of somebody who had basically an IO and recurred late? I look at it as like PARP after PARP. So, you know, if there's a patient that had two years of PARP, and then a long time when I'm going to use a PARP again, yes. The challenge is that those patients are so exceedingly rare, that the answer is basically almost never. The same thing happens here that if I treated a patient on 826, and she completed her two years, and she went a long time, yes. But the typical patient, most patients progress on 826, not all, I told you. And if you don't progress on it, and you have a substantial amount of time after, those patients are probably cured. So these patients who get two years of checkpoint in 826, and then go a long time, and then recur are so rare, that I think we should talk less about IO after IO, and more about these sort of novel ABCs, which is what the discussion you've led. So not never. Well, my hope is that we're going to cure a large percentage of these patients. What do you think, now you mentioned RMH, and that data is, as I understand, not in the manuscript that is eminent. Do you have any idea when we're going to see the safety and efficacy results? Yeah, so that's carboplatin, TV, Pembro, and Bev. So that's interesting. It sort of is challenging to interpret, because when you replace one of four active agents, and then try to make a discovery in a small subset, it becomes very difficult. It's true that the safety is the primary endpoint, and that will be informed. I don't know when that will come, but quite frankly, because those patients are doing so well, which is good, it's not anytime soon. Well, and I guess the other issue is, it is going to change again, as you mentioned, as we move toward IO with chemo in the patients with advanced disease. So now we have another paradigm, and we have to adjust that. So maybe we're back to the 240 regimen. That's right. Here's the challenge with A18, I only know what's in the press release, is that PFS was clinically meaningful and statistically significant, but OS was not mature. So now we have a sequencing issue, because we're probably not going to get reimbursement until the OS comes, just like Ruby and the PMMR, same thing. PFS was good, but we only filed for the DMMR, because that's where the biggest impact was. So we're going to have to really wait for A18 to show a survival difference, I think. It'll get EMA approved probably, but the reimbursement will be dependent upon the OS. In the US, when we get approval, we also get reimbursement. As you recall, the approval of 826 came 113 days after the press release. So 113 days, and obviously that's less than four months. So you know when the press release was for A18, it's the same molecule, it's the same people, it's the same FDA, and you can reverse engineer four months since then. And I would hope that we would get FDA approval in that four month range after the press release, and you can do the math. They haven't said, oh, we filed it. They haven't said, oh, this is the action date, which is called the PDUFA date. But they don't always tell us, because you only have to report that if it's going to change your stock price. And because cervical cancer is such a small component of Merck, they may not tell us when it was filed and when the action date is. But they're obviously working on it. Well, one last question, because I want to put you on the spot here, just to see what you think. So why was the A18 data positive and the CALA trial negative? And do you have any concern that we're perhaps downregulating the immune response with the radiation in a pulsatile fashion, unlike with chemotherapy? In other words, I guess the basis of my question is, and you alluded to the survival in A18, but the question is, do you think there's more synergy between chemo and IO as opposed to radiation? The short answer is yes. I think to kill the cells that you're trying to educate with radiation sort of creates this internal contradiction. But it's still positive. So was it positive because A18 probably had a higher risk group of patients? The eligibility for A18 were larger nodes in size and number, which leads to aortic nodes being more positive, and then ultimately a positive result. You saw that in CALA, there was a trend in the aortic node positive patients. You also saw that in CALA, that the PD-L1 positive patients did a little better. Or is it PD-L1, right? Dervalumab versus Pembro PD-1. So you've got a higher risk group of patients, and you also have really sort of a different mechanism, although related. There were 270 events in CALA. There were 270 patients that recurred and that will ultimately likely die. So there was plenty of power, plenty of power to show, and we weren't even halfway there. So if we would have doubled the sample size, we still wouldn't have got there. So I think it's twofold. It's the risk of the patients, and it's also the PD-1, PD-L1. I think it also begs the question, if you look at how we develop medications, we study in a high-risk group, and then it get approved in Alkemer. What do I mean? If you look at GOG218, they had to have residual disease. It's everyone. Pebicizumab. If you look at Prima, we did high-risk, and then we got Naraparib and Alkemer. If you look at RUBY, it was mostly what was 50% recurrent, 50% adjuvant. Yeah, they just gave it all advanced and recurrent endometrial cancer. So it'll be interesting to see if the A18 approval is in high-risk, locally advanced disease, or if it will be adopted broadly that every time you give chemotherapy and radiation, you can give PEMBRO. And that's another question. But I can't wait to see the A18 data. Again, it's been since 1999, since chemotherapy and radiation has been unseated, and we beat it. We got better. That's great. Well, I'm going to wrap it up. First of all, I want to thank you, Brad, for coming on and lending us your expertise. And this was sponsored in part by a grant from CGEN for education and for the IGCS's help in putting this together. Again, I want to emphasize the IGCS meeting. Can we put the slide up there? In Seoul, it's going to be November 5th through 7th. So we hope to see you there. It's a great meeting. I think the quality of the abstracts has increased every year. It's really my favorite meeting now. And again, this recording will be available for viewing on the IGCS 360 platform within 24 hours. That is our education platform that has a very robust assortment of lectures and educational material. And I really encourage you to check that out if you haven't seen it before. So thank you, everybody. And we're going to conclude this. Thanks, Brad.

recurrent metastatic cervical cancer

treatment options

clinical trials

early detection

radiation therapy

immune response

IGCS meeting