Hello? Yeah. Can you hear me, Matt?
Hey, Jen.
Hi. I think Don's on as well. I don't see him yet, though.
I am here. Unfortunately, I don't have my camera with me.
Oh, no. And Dave O'Malley is jumping on. I just finished speaking with him.
All right. Sounds good. So who will you share slides, Jen? Or will Dave? Or do you have?
The our I'm happy to. You mean our corporate deck?
I guess I just didn't know if Dave wanted to refer to some of his slides, like kind of the start.
Oh, sure. You know what, I have them ready in the case that he wants to do that.
O'Malley, how are you?
Good. How are doing, man?
Pretty good.
Let me change let me change my lights around here. Sorry. Just finished up seeing patients.
Dave, you know what I'm going to do? So we were just chatting before you came on. So I have the slides. Let me just pilot these. If you wanted to refer to some of them, let's just see if you guys can see them.
Can you see those, Matt?
Yes.
Okay. Great. So, Dave, if there's anything you wanna refer to, I'll be prepared to just pull these up.
Yeah. I'm just trying to get so the light's not terrible here. Great. I can't can't have my head any shinier than it already is. You know?
I understand.
Alright.
Should I hide the slides for now, Matt, or do you want them do you want them on?
How do you wanna
I mean, it's up to you guys. I don't think it's matters too too much. Because I figured we'd kinda start with, you know, kind of a quick run through of the data and maybe anything you think are worth pointing out, and then, you know, have a kind of write a questions on the data and just how it fits in the the broader landscape, I think.
Yeah. Yeah. I mean, I think it's and so how Matt, are you gonna facilitate, or are we gonna go right how's it gonna work?
Yeah. I'll intro. I'll introduce you and Jen and Dan, and I think then kinda turn it over to you to maybe flip through a couple of the slides and provide some maybe high level thoughts, if that's okay.
We're being monitored. You just came in to
say hello.
How you doing, brother?
Good to see you, girl.
Gonna have fun.
Doctor Malley said
I'm gonna be a spectator.
Oh, spectator. Doctor Malley, a a fellow DOMer here, so always always excited to
Oh. Think I have you by a few years. What what what year were you?
I I was o eight.
O eight? Yeah. Where did you live?
What's that? I was in Stanford Hall.
Where'd Stanford. I went to Kenan.
Battle of the channel. Love it. Yeah.
There we go. Let me see. Try to get the love it. Love it. Love it.
Love running the domers. I actually had two medical student domers this past month. Couldn't believe it.
Nice.
Yeah. Couldn't believe it. But, yeah, good kids.
Really young ones.
Well, I will tell you that I lived in Baden.
Oh, yeah.
That's
right. Before both of
you. Also, look at that. I love
And also had a daughter who just graduated a few years ago.
Oh, really?
We're Keeping the train
of thought. Awesome.
Yeah.
I love it.
Yeah. Yeah. Name is a professor there, actually. He's a physicist.
Who was?
My dad. Really? Yeah. So that's home for me.
I guess so. I like it.
Nice to
back in ages.
Cece, your dad was a physicist?
Yes. He's nuclear physicist and then most of his time spent
in the math department, though. Wow.
So he was literally a rocket scientist.
I know.
Kind of a
hard act to follow there.
So
we're at the we're at the go, Mark. So what I was gonna do was, because Dan doesn't have a camera, Matt, his icon might not show up. Can you just kind of announce that he's on the call, but we don't have video? So like that way, if he's part of the conversation, people know that he's there. And also just it's a better way to to allow people to view the slides.
So we're in the practice room right now. I'm gonna count you down if you're ready to go.
Yeah. I just turned off my emails. Let's make sure this email's off. Tell me if you hear, dangling, will you? Jen, text me or something.
I don't think it will be. Okay. Alright. Let me turn speaking with you. Let me turn this on silent.
Alright. I'm there. Got my water. Background looks okay.
He looks beautiful, Dave. Absolutely. You're worried
about this stuff, man. Didn't tell you. If you're as ugly as me, you gotta make sure your background's okay. You know what I mean?
I love the flowers. Special ordered.
Oh, look at that. I can even move those. There we go. A little bit of class.
Wow. Look at that.
Yeah. Does
it look like a flower coming from my head down? Alright. I'll move it back. Flower child.
Okay. So I'm gonna mute my video so I don't show up on this call. So let me just mute that, and I'll mute my audio in a second. We'll go three, two, one, and live.
All right. Hello, everyone. Thank you all for joining. My name is Matt Phipps, a biotech analyst here at William Blair. I do have to first point you all to williamblair.com for a list of disclosures.
But I'm happy today to have both management from Agenus Bio and Doctor. David O'Malley, a professor in the Department of Obstetrics and Gynecology at The Ohio State University to discuss the really important results presented over the weekend at ESMO combining the PD-one plus CTLA-four inhibitor, bowel xyl combo monotherapy and combo in second line cervical cancer. So today, we'll kind of review the data, go over some questions, both specifically about the data and how this combination could fit into the cervical landscape, also talk about a couple of the other kind of key things being studied in this tumor type and then finish up with more of a kind of corporate look at what's going on. We do have Dan Chan here as well, Head of Drug Discovery at Agenus to chime in for some of that later Q and A. But Doctor.
O'Malley, I was wondering if we could kick it off just by kind of giving a high level overview and maybe just your overall opinions of the data set.
Thanks, Matt. Pleasure to be here today. I really appreciate you taking the time to introduce us and exciting results with regards to these two independent independent Phase II trials, I think it's important to think about. Overall, we need better options for recurrent cervical cancer patients. The current landscape, as you as we all know, the checkpoint inhibitor pembro was approved for a fourteen percent response rate, fourteen point five percent response rate in PD L1 positive tumors.
But I was looking for more options for these patients as they really don't have anything beyond the first line therapy. First line therapy is considered a platinum doublet with bevacivimab or Avastin. I'll refer to bevacivimab as bev throughout this talk. Because if I say bevacivimab too much, I sound like an idiot. So we'll do that.
And really beyond that triplet, what we consider the GOG two forty regimen, there's really not any options for patients. And so pembro was approved on a small subset of patients accelerated approval for this, as I said, fourteen point five percent response rate. So this trial is really looking at that recurrent cervical cancer patient population. I'm happy to go through some of the slides if you like.
Great. And I think there's obviously going to be comparisons amongst the data sets that are initially made. You have similar drugs with overall similar results, but some slight differences. So I guess one of the biggest things that jumped out was the ability of abastolumab did get some responses in PD L1 negative patients, which wasn't seen in the cohort of KEYNOTE-one hundred fifty eight. So and that's why KEYTRUDA only got a label in PD L1 positive patients.
So I guess, Doctor. O'Malley, do you think that this is enough of an effect that was shown in PD L1 negatives to warrant a broader label for balstilimab?
I think the option is definitely there. I mean, obviously, the precedent for PD L1 positive, and we know that the KEYNOTE-one hundred fifty eight zero responses in those, I think, seventeen patients that were PD L1 negative. So to see this eight percent to ten percent response rate in patients who were PD L1 negative, I think it offers some hope that, though it's modest, that there may be a pathway for regulatory approval moving forward. Obviously, as you know, that will ultimately be a it will be a review question. But there's definitely option here since we saw a zero percent response rate in the KEYNOTE-one 158.
Yes. Okay. And I guess the other difference being that this separate study also looked at the combination with CTLA-four inhibitor, selifrelimab, and not surprisingly, I think showed an increase in overall response rate, kind of similar to what Opdivo and Yervoy had showed. But I was actually a little surprised that the response was seem to be really more driving better responses in the PD-one positive patients and deeper responses there, because they showed kind of similar response rates in the PD-one negative patient population. Were you I guess, was that surprising to you?
Or did does that kind of what you might thought happened based on the Opdivo plus Yervoy results?
It's interesting. I think as we're seeing these biomarker negative patients and still seeing the responses, how do we make these can we make these cold tumors hot with the addition of CTLA-four? And I'm not sure that's there. But what we do see is the duration of responses with the combination. So I marked difference in the overall response rate.
I wasn't that surprised. But ultimately, the duration response and drivers in this select group of patients or the biomarker negative patients, I think, is an opportunity again. And we see this in both the single agent where we did we did see a duration response reach, which is an important differentiation that we had two months longer follow-up than the KEYNOTE-one 158. Some people had asked me that previously. Well, they didn't see their duration response.
Well, in those two additional months where you actually see now up to fifteen percent fifteen months, excuse me, in a combination, we don't see that duration response reaching a similar follow-up. So really, when we look at the combination, suspect we'll continue this response rate is not going to get worse. But we know with immune therapies that we can have some late responders. So will we see that improve? I'm not sure we'll see it a marked improvement, but definitely the duration.
And we see these patients potentially cured. And that's a really important differentiation. If we see the cure rate go from two percent to six percent and that's the difference between cytotoxic agents and immune therapy. A complete response in cytotoxic agent is not going to be curative. A complete response in a immune therapy may be curative, unheard of in previous experiences in cervix cancer that you'd have a cure in recurrent setting.
So though modest at six percent in our BALZAL trial, If we have an option to cure one out of twenty patients, that's going to be pretty exciting to the practitioners who are prescribing the option for the combination.
Absolutely. And I'm kind of some of that talk of continuing to follow us over time. I guess, just in general, do you have an idea, either you or Jen, how many patients remain on therapy at this point, so potential to get deeper responses over time, continue to increase that duration of response. Involve And
do you have those numbers on where we are on those who are still on therapy? I can't remember off the top of my head. You're muted.
All
right. Now we can hear you.
For the bound monotherapy, we have forty seven patients who remain on therapy and for the combination, fifty three.
Wow. Okay. So still a meaningful
patient remain
on treatment for both of those. It's great. One thing that's come up
Yes, over a third. So that Yes.
That's impressive. One question that's come up is, does prior Avastin and prior Bev, as you all as well referred to it, make a difference here? Have you been able to tease that out for these drugs and, I guess, other combinations going forward? Do you think that will play a role?
Yeah. So that's a really interesting question. One little of aspects of KEYNOTE-one hundred fifty eight, which was not discussed much, is that only two of the responders had had prior BEV. So when you think about that, it is something that has not been looked at more closely by the regulatory agencies. But we have an opportunity to educate them with regards to we are receiving responders in bev prior treated.
And think we'll and the final manuscript will attest to that. Obviously, that's not publicly available right now, but that is something that will be further described. Now, it is important to say that we also are will have that broken down in bed prior treatment. The other interesting part is this the KEYNOTE-one 158, the pembro approval was the emphasis on the squamous cell patients. And I think that's really important because those are going be a higher chance I think that was one of the questions, Matt those are going have a higher chance to be PD L1 positive.
But we're seeing those responses across. And really, when you look at the squamous cell population, it's really interesting data to see the marked response rate in using squamous cell as a biomarker, which is probably a better biomarker than PD L1 status. But we know the regulatory agencies love the nonhistology biomarkers.
Yes. No, that's interesting. I was wondering that. Okay. I would like to touch on the tolerability of the combination.
Not surprisingly, you do see a few increases in AEs, mainly around like lab abnormalities and endocrine disorders. But overall, I would say it appears tolerable, but I appreciate your opinion on that. And also, there's been this viewpoint, especially in the community setting where PD-one plus CPLA-four is too toxic. I think that's been driven by the melanoma experience, which is obviously the first one and used the high dose of ipi. And so to me, going forward, it's been much more manageable.
And obviously, physicians we talked to have gotten more used to it. So I guess, first, two questions there. One, just talk about the combo in this study specifically. And then more broadly, do you think it can be viewed in a new light as opposed to just getting bucketed under the old ipi toxicity basket?
The most I didn't mean to cut you out there, sorry. The most important differentiation here is the high dose ipi versus low dose. And when we are looking at the design of this trial and future designs moving forward, the toxicity and the tolerance of the high dose versus I shouldn't call it the low dose, but the more chronic dose, would call it, is an important differentiator in the tolerability. Look at the older nivoipididia from the melanoma, you just see an extremely high rate of colitis, as well as other immune associated toxicities. So when we're balancing which dosing to use and how to move forward, obviously, the efficacy was a main characterization.
But also, as we look at the safety, particularly in these patients in cervix cancer who are often challenging patients to treat from a toxicity standpoint. The majority of them have had radiation. They've had at least one line of chemotherapy, if not more. So the tolerance is really important as we look at this. Now, the combination clearly will have more toxicities.
And that ultimately will need to be balanced with the patient sitting in front of the practitioner. But I think with the information we have here, having both a accelerated approval for the single agent bowels with this combination of Balanzale, allowing practitioners and allowing patients to make that decision based on a slightly increased risk of side effects versus an increased ability for curative intent, longer duration response. And balancing those two things will be important ultimately in the marketplace. How many patients will get started on val versus valzal? I'm not sure I can make that prediction.
But clearly, clearly, having both drugs in the marketplace, feeling comfortable dropping one of them, valxal, if we start having toxicities. But clearly, we have to continue to educate the community about these toxicities and that they are manageable by the by far the majority. And when I counsel patients, I usually counsel thirty percent to forty percent chance of immune associated toxicities. Of those, five percent to ten percent will require hospitalization. Of those, about one percent to two percent could be life threatening or life altering.
And I don't see we definitely don't see any difference in these across both of these trials.
That makes sense. And yes, I mean, you really did touch on this right then. But okay, these agents are out there and you have a new patient that just had a recurrent disease. What are you going to look at from that patient to make a decision what to start them with, whether it's monotherapy or combo? And we'll get in a second to maybe some of the other options, but first specifically, Balz Allen.
Well, I'm glad you're giving me the break and letting me start with Val versus Valxol and not throwing in the competition yet. I think we're seeing an extremely changing landscape in the treatment of cervical cancer. And this is it's going to continue to change significantly over the next three to ten years. So there will be options there. I think some of it will be obviously prior treatments.
We're seeing more and more checkpoint inhibitors in the upfront setting. They previously have received a checkpoint inhibitor, then obviously single agent, then we'd go to combination. And we'll look to move forward and gain more data on that in the future. In a patient who is young, healthy, and wants a one out of twenty chance for again, I don't want be too dramatic here. I want to be fair to the data.
But again, complete responses in immune associated therapies offers an option for curative intent. And so when you're talking about this, about the toxicity versus the efficacy, I suspect more patients will be started with the Balzac, and then drop the ZAL if the toxicity is evident. There may be people out there who say, if they haven't had previous immune therapy, I'll start with the bowel. I'll see how they do for the first couple of cycles and then add ZAL. It's usually not the way we do it because we like to get the response earlier on.
But I think both options are viable.
And you brought another part of that is there are frontline trials ongoing that are looking at it's mainly PD one plus chemo radiation, I believe. Correct me if I'm wrong there, but that's mainly what's being looked at as a frontline option. So if you have a
Well, as advanced well recurrent where combined it with chemotherapy.
Yeah. And so I guess if a patient gets treated in one of those studies and then obviously doesn't have response or loses that response, you would be willing to say, okay, we'll try them now with P1 plus CYPLA-four, even though they got that P1 plus chemo, right? You would view that as kind of
I think right now, I don't let there would be no data to hinder me from doing that. Obviously, what the approval will look like and what we can do is the question. Obviously, we'd like to see more data in the future. As we design the confirmatory trial, as we move forward, looking to see what options are available. You know that we already have RAPIDS enrolling, which is a randomized Phase II looking at bowel versus bowel zeal in a placebo controlled trial.
And that is really to add to the Phase II data to assure we have enough patients in these subgroups to justify moving forward and accelerate approval with the final data set. So that is not the confirmatory trial. I think that's very important. And in the current time, we're moving forward with how can we bring these agents to the marketplace, both for our patients in the current setting, but is there an option elsewhere too?
Okay. So not surprisingly, questions coming in about the data that was just presented not too long ago with the tissue factor antibody drug conjugate. Yeah. With mavidotin.
Nice. I call it TV. I call it TV. So Rob Coleman just presented that data, and I would've been in my phase one clinic here. So I was not a coauthor on that paper, so I'm just seeing the final data as we came into this meeting here today.
I think TB efficacy looks similar. Similar patient population treated, again, about one hundred patients. And so in this single arm, I mean, this reported was the Phase II. So, and what's interesting there is a similar complete response rate, think it was seven percent in what he presented. But that's why I made the point at the very beginning, when we're talking about cytotoxic or antibody drug conjugates, complete response rate really has not been associated with potentially curative intent.
So I think it's a pretty important differentiator. But what's the most important differentiator? Listen, TB is a good drug, man. And I'm moving forward and participating in those clinical trials. And I would love to see that drug also in the marketplace.
But as I look at the ultimately what's available in the recurrent cervix cancer, there are some challenges to the toxicity profile with particularly for neuropathy and the inflammation of the conjunctiva can always be a challenge. So I think you need to look at that. Obviously, with regards to some of the bleeding issues, which I think are not that worrisome. But yet, again, if you have a patient who's already having some issues with the central tumor in the cervix, that can also come into play. I'd love to see all three of these drugs be in the marketplace.
And ultimately, how we prioritize the treatment of those and where those are used will just be helpful to our patients. And I think as we see more options available, we're going to see better outcomes and more opportunities for patients to get more lines of therapy. Right now, we just beat them to death. That's a terrible term. I apologize.
We just we really are utilizing chemotherapy and just keep giving and keep giving and keep giving. And I think sometimes the chemotherapy toxicity can be worse than the disease. And then after that, trying to get any additional therapy is really a challenge. In the future, we're going to be able to change that paradigm. And these patients will see three, four, five, six agents.
Like now, they only see one, maybe two.
Right. Right. Yeah. One question, and I don't know if you saw this specific tidbit, but I guess there was a difference again in in in the TV data for whether or not a patient had prior Avastin. And, you know, just kind of interesting here now seeing this, I guess, multiple.
So would that impact, I guess, how you sequence therapies based on whether there's somebody at Avastin upfront?
Well, I wanna make sure I'm saying what's publicly available because I have some other information. So I just I'm flipping over here and looking at what's publicly available.
There was a 32 response rate response rate in Avastin naive versus 19% in Avastin. Thank I'm looking at the right
you. I just want to make sure that I was publicly available because, as I said, I participate in clinical trials for both of these or all three of these agents. So clearly, there's a difference between Bev pretreated here in those patients. And I'm not sure that's completely explained by the mechanism of action and or the mechanism, but also the how to deliver it with the antibody drug conjugate. So, I think we need to continue to look at that in the immune therapy.
It's not as it's probably not as marked of a difference, but yet seeing that in the pembro data, you could argue that the responses were not nearly as wide in pretreated. So another data which is maturing as we move forward, we'll have that answer, especially in the combination in the single agent.
Yeah. Okay. Doctor. O'Malley, another therapy that gets brought up a lot, and just get your opinion on that, is the tumor infiltrating lymphocytes and specifically the process of harvesting and stripping them off, having them kind of reinvigorated and grown back up and then chimp back. I mean, amazing response rates data and also kind of seems to show that durability of immunotherapy, but I'm sure a little bit laborious and burdensome to get.
So I guess just your thoughts on that and where that would fit in with some of the other agents that are kind of getting close.
Great, great, great option for patients. But the problem with the it's a pretty limited group of patients, which are going to be able to undergo that therapy. You need to have a slowing enough progressing tumor to wait for the six to eight weeks process as you go through. You have to have a tumor that's clean that you can resect and send off. So a patient with a central cervix tumor can't be used.
Patient has tumor on the bowel cannot be used. So you have to have the right patient that you can harvest the tumors. Again, a very exciting option for our patients, but it's going be a much more limited population. I already talked about how our patients are really compromised from the amount of chemotherapy they receive and the prior radiation, as well as patients with a lot of comorbidities. And so to undergo lymphodepletion and then the high dose I guess not high dose, the dosing the IL-two takes a unique patient population and group of patients.
So the safety on that obviously is a challenge. The patient selection is obviously a challenge. And again, I hope we have all the technologies available to us for our patients. But this would be a smaller patient population.
So Doctor. Malinow, you're you get the option to run a frontline trial with no regards for corporate incentives. Yes. We talked about there are the PD-one chemos ongoing. To my knowledge, there's not a frontline p d one c two a four ongoing.
And then, obviously, maybe looking at some of the TV plus you know, plus the p d one could be interesting. What do you think you would want to try to kinda deliver the best chance of a long term duration of response to patients?
Yeah. Great question, Matt. How are we going to cure more people? And if we don't cure them, how are we going to improve their quality of life? You just heard me say the option of chemotherapy and continued chemotherapy.
So I think we need to look at, can we replace chemotherapy? That's an extremely high regulatory approval to take on platinum taxane bev versus an immune therapy. And probably not the design of the trial that is going to ever occur because the bar that's set by that triplet combination. But ultimately, having patients be cured with advanced recurrent. And probably most importantly, we have a lot more patients with local regional disease, which are have as high as a fifty percent recurrence rate with treatment of chemoradiation.
So I'd really like to see us improve upon that. I think the option of single agent checkpoint inhibitor, in this case PD-one is already being done, as you know. But looking at the option to bring combination therapy, can we do a better job of curing more patients? And then on that same note, can we do a better job of curing more patients with combination immune therapy in the advanced recurrent metastatic first line? I think those are two great options that we continue to look at in our design of our and moving forward.
I think just one more question that I get is, okay, KEYTRUDA is approved in second line for PD-one positive patients alone, used ubiquitously across a lot of other tumor types now. So just very familiar with that. You have a new PD-one drug that comes in, I guess on the one hand physicians often do follow labels, especially more in the community setting. And so that could kind of drive which one they reach for, but also maybe they just kind of bucket in PD-1s as PD-1s. And so I guess what do you think is going to be kind of things that will influence which drug on the shelf a physician reaches for, particularly if you're, I guess, looking mainly just at pembro versus bowel or the bowel's outcome, I guess.
Yeah. So, you know, the PD-one inhibitors are more similar than they are different from a prior efficacy and tolerance standpoint. But what do we can you guys still hear me?
Yep.
Sorry, I'm getting a little so what do we really look at? When I set out in this adventure working with Agenus and the team there, I want to applaud them. We really challenged each other to say, how are we going to do better? And do we want just a me too drug? And that wasn't the goals here of Agenus.
It sure wasn't my goal. So as we look to say, where are we from a single agent standpoint, absolutely do I want that option? Absolutely do I want to potentially expand and label to include adenocarcinomas, to include PD L1 negative? I hope we get that. Ultimately, we'll see.
But the combination is really where are we going to make a difference in the treatment of these patients with recurrent cervix cancer is the combination. And that is not going to happen with pembro. We haven't seen BMS pursuing approval, which was surprising to many of us. And there's been haven't heard any plans for that to move forward nor is publicly available at least.
Okay, great. So I think with that, I would like to bring in Dan and Jen to kind of get some steps next steps and talk about where the company wants to go from here. So congrats also, by the way, of initiating that rolling submission of the BLA. That's really exciting for Bell. And I guess just any high level thoughts, Jen, on how long will that process take, do you think?
And kind of if there's other things that need to be really completed, and then particularly the next steps for the combination.
Excellent. Thanks, Matt. And thank you again for joining Doctor. Omali. Great presentation this weekend.
So what's next? First thing, of course, would be to fully publish these data. So Dave did a fantastic job presenting the data to date, where we've already prepared we're in the process of preparing a manuscript of the information. The BLA submission is already being initiated. We've initiated this submission with some of the components already submitted.
As you can recall, we received Fast Track designation for these agents, which makes us eligible for priority review. So with our filings plan to be fully submitted this year, we would expect to be have a decision by the latest would be midyear next year. So balstilimab monotherapy will be the first submission in, and we are planning to nearly immediately, if not in parallel, get the combination in.
Great. And actually, I want to take one other question that I think will involve Doctor. O'Malley, if I I know you're kind of part of the NCCN guidelines or committees. And so also while you're going through this process of that, how are you working on talking to the societies and making sure this data, I guess, gets in front of people and needs to get in front to get into guidelines and such inclusion there?
Well, you know, as you know, Matt, that the NCCN guidelines, unless a drug is approved in the marketplace, they're not going to include it. So if it's included in another disease site, would that be an option? Potentially. I sit on the ovarian cancer guidelines. I do not sit in the cervix nor uterine.
So the precedent for us is obviously usually it has to be a large in ovary, I can't attest to cervix. But across the NCCN guidelines, it has to be a well powered Phase II to garner a compendium listing. That bar, because the number of trials being done, seems to be raising a little bit more in the future. But I wouldn't expect a compendium listing or NCCN guideline listing unless a drug is approved in the marketplace. With regards to how do we get this out?
Well, I think that ESMO, IGCS, SGO, ASCO, all being remote has been a challenge. We continue to find ways to disseminate and discuss this as we're doing a Zoom call here today. We're also working I've put Agenus in contact with our CME groups to make sure that they're working with education with regards to recurrent cervix cancer. And we have this information out as a thought leader in the immuno oncology space in GYN cancers and as part of the GOG Partners mechanism. That's meant much of our emphasis is placed on educating the other GI oncologists and medical oncologists who treat cervix cancers across The U.
S. And across the world involvement in these societies. So we continue to look for ways to better educate during these challenging times.
Sure. And so I guess, Jen, on your side of things, how are you helping Doctor. Amal here? I guess, how are you thinking about approaching the market sizing that infrastructure appropriately to help get this out there.
Samad, maybe just by way of just recognizing that these trials move from Phase I in multiple solid tumors, generating data across a number of different tumors, including complete responses in angiosarcoma, very lengthy durable responses in ovarian, and then we expanded into the cervical cancer. So all of those data are being prepared or have been presented at conferences or published under different mechanisms. We've already started speaking through our contacts with the NCCN And based on the size and scope of the trial and the conduct of the trial and the rigor of the data and the independent review, we meet the requirements for NCCN issuance. Of course, that will require a couple of things that are still pending, such as publication in cervical cancer, which will be our first priority.
The submission and approval, Dave's right, we will need the required the requisite approvals for submission in cervical cancer. There are some other tumors for which we have some data, generated some data, that may be more rare than cervical that we could be eligible for expanded NCCN inclusion, and that being tumors like angiosarcoma. So we have a series of tumors that we will be planning to approach NCCN with cervical being our highest priority, and the planning being to make sure that we line up all of the data and the publications and submissions in parallel. At the time of approval, we would hope to be included in the guidelines at that time.
Great. And Chad, I guess just on a broader view and a longer view, how do you kind of balance further development of the BALZAL combo and other tumor types or maybe other pipeline combination versus kind of pushing forward with November and kind of replacing ZAL, not to say it needs to be replaced, but I think we're both pretty excited about eleven eighty one. Doctor. Malley, I don't know if you want to get your hands on eleven eighty one cervical as well, if you're familiar with that, the next gen C284. But just how are you thinking about that, Jim, far as you got to pick where to start these trials and can't necessarily do all of them, right?
Well, that's right. I think part of this is November is telling us where to go already. So with respect to Balzelle, these are mature assets now with a significant and a robust safety database and an opportunity really to be second to market, maybe first to market in cervical possibly and second to market in a number of indications. And as we've spoken about previously, Matt, we could be second to market in some relatively large indications, even pursuing 5% or 10% of the market in tumors like lung melanoma RCC, for a significant upside for us. And we're talking about $700,000,000 to about $1,000,000,000 in revenue, which would be very meaningful for a company of our size, right?
We're quite efficient. And so I would say that's an important piece. These trials are effectively, these agents are so far along that we have a big opportunity to take advantage of some of those markets now. The November, it is we look forward to presenting some additional data at a medical conference this year. I'm really excited about how the data continue to evolve.
We presented early data, one mg per kg monotherapy CTLA-four showing complete responses in microsatellite stable, so very difficult to treat tumors previously known to be unresponsive to IO agents, and we're seeing activity. We've now expanded our profile of clinical benefit in a number of different solid tumors that we're pursuing. Now what we've looked to do, there are a few paths here. We are seeing activity in patients who are homozygous for the CD16 allele polymorphism, which is very important. These tumors are unresponsive to anything available.
While we continue to keep our trials open to all allele status patients, right, homozygous and heterozygous, We are expanding and enriching in tumors such as colorectal, microsatellite stable, endometrial, as well as in tumors like lung melanoma. We will be telling you more as we share some of the data that will be coming out later at a medical conference. We'll be sharing a summary of where we'll be taking these agents with you. So stay tuned. It won't be very long, but we have a pretty exciting plan to talk to the markets
Matt, you're killing me, man. Let's stay we're this close. You're trying to get me to switch and use eleven eighty one? I mean, come on. So I think what we need to I applaud Agenus.
Their pipeline is quite impressive. And actually, the opportunity to partner with them moving forward with their pipeline and the options, which are quite limited in other pharma partners that I work with. So having this option for our first generation PD-one and CTLA-four inhibitor, getting it to the marketplace, getting approval, and utilizing that is the stepping stone into further indications with the new agents, is exactly where they should be. And we look forward to continue exciting data from the next generation of CTLA-four in these immune therapies.
You are absolutely right. And that you know, I think that we when we look at our pipeline right now, we've got we have eight programs in the clinic, right? These are it's so critical that we get these over the finish line. Plus or minus Sally are going to be the foundation for everything else that we do, November, 12/23, 02/1973. I mean, it is just but ideally, what we'd like to do is to give all of our compounds to Doctor.
O'Malley. Every time a patient walks in to see him, he has something for them, right? That's the complete That's what we want. We never want him to say, protocols do I have access to? We want him to be able to drive that treatment decision, having all of these options at his fingertips.
But the base of this all will be Valley's Alley. So looking forward to getting this through to
the finish. Well, I mean, I I think it's a great transition to talking about a few of those, you know, here in the last couple of minutes that you just mentioned. So Dan, I'll bring you on now. You know, I think, if you don't mind, you know, first, there was some data over the weekend about targeting TIGIT from Merck. You guys are obviously, right on the cusp here of getting your own TIGIT molecules, if have two of them.
And so I guess over the past six months now we've seen, not even six months, we've seen data from Roche and Merck that have generated some polarizing opinions on is is TIGIT a real target? Is it just a little bit of a step? Is it really going to be anything beyond like high PO1 expressing non small cell lung cancer? Obviously, that's not an important opportunity, but curious to Dan, what your opinions are and how you guys are thinking about the next steps with, with your own molecules.
Matt, thank you for that question. I take it you can hear me well? Yes. Good. Well, I would say that, you know, we remain, you know, very encouraged by the data coming from Merck and from Roche.
I would say there's three things to note here. You know, the first is that, you know, both Roche and Merck are showing that adding a TIGIT on top of p d one is expanding responses. In the case of, you know, Merck's p d one naive population, you're you're seeing evidence of deeper responses with TIGIT therapy. Yes. It is incremental, and, you know, we've articulated many times why that would be the case.
We've demonstrated preclinically that these current generation of TIGIT molecules are not optimally designed to really target TIGIT. Now we like TIGIT as a target. I think many people do because they recognize the importance of TIGIT. In fact, you have to go all the way back to p d one and CTLA four, to see the first IO plus IO combination. And and and, you know, outside of p d one plus CTLA four, there's no other IO plus IO that's really starting to emerge as a validated approach other than perhaps TIGIT plus PD-one.
You know, we've said we've stated very early on that, you know, TIGIT is an ideal combination partner for PD-one, but you need the right TIGIT molecule. And and, you know, we published on the importance of Fc. You'd recall from our presentation at AACR last year how our Fc engineering approach gives you monotherapy activity, which is not something you see with the current generation of TIGIT molecules, both preclinically and not clinically, but also better combination activity. So that's a very important point to make that the clinical data is encouraging. But like what we've seen preclinically, we were starting to see the same thing clinically.
It's not optimal, right? And then lastly, we as you're aware, at R and D Day, we mentioned that we're pursuing a TIGIT bispecific as well. And we haven't disclosed what that second arm is, but we have articulated that it addresses a major, or potential relapse or resistance mechanism to tissue therapy, and we are seeing in our preclinical data responses in PD one refractory models. That's that's what we've shared with you last time we spoke about this. But, you know, I would say that, you know, the data is very encouraging.
It certainly bolsters our position in TIGIT therapy, and we remain very encouraged by that data and, of course, enthusiastic with moving over TIGIT therapies to the clinic. We believe we have a better designed molecule to address the limitations of the current generation of TIGIT antibodies.
Thanks, Dan. I guess then just based on what you've seen, has that kind of influenced your initial clinical trial designs? I mean, obviously, it'd have to be dose escalation, but will you really focus on moving quickly to that combo in PD L1 positive tumors? Or you guys have thoughts on maybe other places that you can make it work? Yes.
I think
it's pretty interesting that there's a lot of focus on PD L1 positive tumors. Not a lot of talk about TIGIT positivity or PVR positivity. Part of that could just be limitations of the tools available. As you know, when we advance our drugs to the clinic, we take a very laser focused approach to measuring potential biomarkers, both that are predictive of response, but also indicative of activity of the drug. So I think we have definitely an approach that would not only be complementary to what others are doing, but also unique to help identify the right patients for TIGIT therapy, but also identify the right combinations.
I think PD-one is definitely a goal. You know, there's a lot of literature showing TIGIT plus PD-one coexpression, the clinical data support in the combo. You know, Bali, you spoke earlier about where do you take Bali next? Well, you know, as Jen mentioned, Bali is gonna be a cornerstone going forward. TIGIT is definitely one those therapies we add to Bali.
But we also have zalifrelimab. We have eleven eighty one. Right? That's another way we can differentiate, as we advance our TIGIT therapy on top of having what we believe a best as a best in class molecule.
Thanks, Dan. I appreciate that response. And then the other interesting thing at ESMO, kind of from an earlier clinical standpoint is some of the four-1BB tumor localized four-1BB targets. So we saw Pieris and Roche both had updates, one HER2, one FAP. You know, I think some interesting work.
One, I I do think they've shown that they can get over some of the toxicity that urelimab showed and showing signs of activation. You know, Pierre showed a lot about serum four-1BB as well as increases in T cells in the tumor. I know you guys are are in the clinics with two thousand three and seventy three, which is not a tumor specific four-1BB activator. And I know it's partnered with Gilead, so I know there's not too much you can say. But curious just what you think about the data that was showed over the weekend and, you know, how that might influence kinda twenty three seventy three next steps or or how you're thinking about what to combine that with or anything like that?
Yes. So, Matt, you correctly stated that these bispecifics are designed to be tumor specific because they have a tumor antigen as the second arm. I would like to highlight, though, that twenty three seventy three is designed to avoid peripheral activation and an activation in the tumor microenvironment. One thing to point out here is that I think the idea of targeting CD137 or four-1BB has has been, you know, shown many times over, both in the cell therapy space and and most recently now with, you know, these newer approaches. The goal is really to get activity in the tumor.
And and these bispecifics, while they are designed to address safety, they're they're limited to just, you know, tumor that express that particular antigen, right? Whereas AGEN2373 does not have that problem. We designed the molecule to be active in the tumor irrespective of whatever tumor antigen that they present. So while you know that immune editing is a is a real concern, and, you know, what do you give patients who need c d one thirty seven but no longer express HER two and no longer express that? Right?
This is where twenty three seventy three really shines is because, you know, the molecules Fc engineered to only be active or only be agonist to four one b b in the context of, the the right immune cells presence in two microenvironment. So so we're not limited, in terms of indications. And and, you know, we think that we still have a better molecule compared to the bispecific approach with respect to broadening the reach of four-1BB. In terms of the soluble four-1BB, I think that's not a, I think the jury's still out on whether or not that could be a biomarker to predict those. You know, from the Pfizer study, you know, they demonstrated four one b b based on, immune activation.
It's well known activation marker, but there's not really dose response to it and correlating with response. So I think that the jury is still out there.
All
right. Thanks, Dan. Well, Jen, maybe I'll turn it over to you to kind of wrap things up. I guess, just to summarize here, you kind of hit all the marks for the data presentation this weekend, started the rolling submission already for the mono, Talked about soon to come for the combo with as well as the publication. So really kinda getting all the pieces together to show the totality of the data here that, you know, will get you that first indication and then broadening out from there.
But I guess anything else you want to touch on? Or Doctor. O'Malley as well, if you have any things worth wrapping up with. Otherwise, I think I'm out of questions.
I'll just I'll ask Doctor. O'Malley if he has anything else that he wants to say, and then I'm happy to close out the call.
Yes. I think I'm honored to talk about this exciting data. It's obviously a step in the right direction for ultimately gaining access for these both these agents in for our patients. We're going to continue to look for ways and more to come on that with regards to offering them to a greater group of patients and increasing the chances of curative intent in many of these hard to treat patients. So really, thank you for all of you attending.
Matt, thank you for being a great moderator. And appreciate Jen and Dan and their insight today. Thank you.
Thank you very much, Dave and Matt. Thanks very much for the call. And of course, tremendous thanks to all of our patients who have participated in these trials. You know, Dave mentioned this earlier. Cervical cancer has been is a very underserved tumor, and there have been very few treatment options that have been come forward.
And the data that we presented at ESMO present a few different options, right? One, broadening the patients who can benefit from a PD-one inhibitor. And then also potentially doubling response rates, specifically in certain histology groups, like the largest histology that we see, squamous cell carcinoma. That combination with balstilimab and zalifrelimab represents some very meaningful potential best in class treatment benefit to patients. So we're really looking forward to getting those into the market as quickly as practical.
Dan mentioned a few options with respect to our portfolio, our pipeline, the differentiation of some of the novel therapies. And I think an important piece to remember about Agenus' portfolio is we have all of these agents in our own hands. So it gives us enormous flexibility to continue to deliver responses to patients over time. So we can participate in their journey, ideally expanding the number of patients who can be cured. If we don't hit those cures, we continue to give them treatment options.
That's what we're designed to do, and we have a pipeline and a number of programs. So eight of these assets that we've discovered are in the clinic in our own hands, and seven additional are in our partner's hands. And some of those data you also saw at ESMO. Merck presented data on MK4830. That's a molecule that we discovered addressing myeloid biology and ILT4 mechanism.
And there are a number of other discoveries like that that we've partnered with to really expand our opportunity to broaden the reach to patients. So I wanted to just end on that note, Matt, and thank you again for the opportunity to speak with you today.
Thank you all so much. Thanks again. Thanks for bringing up the ALT-four antibody. I can't believe I forgot about that. But yeah, Merck showed some interesting data there too.
So all good things. Doctor O'Malley, thank you very much for taking the time out of your day to go over those results. And and Jen and Dan, I appreciate it again as well, and look forward to seeing more.
Excellent. Thank you, Matt.
Thanks, everybody. Bye. Bye.