Agenus Inc. (AGEN) Earnings Call Transcript & Summary

Good afternoon, ladies and gentlemen, and welcome to the next-generation immuno-oncology therapeutics conference call. [Operator Instructions] It is now my pleasure to turn the floor over to your host, Mayank Mamtani. Sir, the floor is yours.

Thank you, John. Hello, good evening, everyone. This is Mayank Mamtani, I'm a senior analyst covering biotechnology companies at B. Riley FBR. I hope everyone is keeping well and thanks for joining. I'm pleased to welcome you to our expert panel call today to recap an exciting data at ASCO weekend, in particular focusing on next-generation CTLA-4 agents where we saw Agenus present encouraging early data as monotherapy and in combination with PD-1. We have with us on the call, Dr. Steven O'Day, who were the leading clinical investigator who presented that data, and also Dr. Charles Drake, who have -- and both of these guys had -- obviously don't need introduction, but they've obviously pioneered the checkpoint inhibitor biology space over the past several years, including in translational research and clinical development. Before we get started, I need to quickly walk through my disclosures. In the normal course of its business, B. Riley FBR Capital Market seeks to perform investment banking and other services for companies under coverage and to receive compensation in connection with such services. As such investors should assume that B. Riley intends to seek investment banking or other business relationships with any and all of the companies mentioned today. Agenus currently is, within the past 12 months was, a client of B. Riley FBR. The services provided were investment banking services, and we intend to seek additional compensation over the next 3 months. B. Riley FBR has managed a public offering of securities for Agenus and acts as a market maker for Agenus' securities. Dr. Steven O'Day is the Executive Director of the John Wayne Cancer Institute and Cancer Clinic and Director of Providence Los Angeles Regional Research. Dr. O'Day has been at the forefront of new drug development over the last 2 decades, including playing a leadership role in the development of the breakthrough anti-CTLA-4 ipilimumab or commonly known as YERVOY as well as anti PD-1 antibodies, including Merck's pembrolizumab and BMS, nivolumab or OPDIVO. Dr. Charles Drake is a Co-Director of the Cancer Immunotherapy Program and Co-Leader of the Tumor Biology and Microenvironment Program at the Columbia University Herbert Irving Comprehensive Cancer Center. Prior to joining Columbia, Dr. Drake served as a Co-Director of Cancer Immunology Program at John Hopkins Kimmel Cancer Center and has been a lead investigator on several pivotal clinical trials and immune checkpoint inhibitors. We appreciate Dr. O'Day and Dr. Drake spending time with us today. On the call also facilitating the dialogue with me is Jennifer Buell, President and COO of Agenus. We appreciate our panelists spending time with us today. Their opinions are their own and do not necessarily reflect those of B. Riley FBR. We ask them to avoid any disclosure of confidential nonpublic information. We obviously have a lot to go through in the call. We'll be happy to take questions if you want to e-mail them to me directly at [email protected]. So with that said, Jen, why don't you just kick us off and just talk about a little bit about what we saw -- what we learned from you at Agenus and then obviously, we want to hear from the 2 doctors that we have here.

Wonderful. Thank you very much, Mayank, and Dr. O'Day and Dr. Drake, thank you very much for taking the time to be with us. It's always wonderful to be with you and particularly exciting to do so on the heels of ASCO. As Mayank mentioned, you are pioneers in the field of immuno-oncology. And collectively, your work has paved the way to a much deeper understanding of the most validated cancer checkpoint targets, CTLA-4 and PD-1, and also has driven the work that we've been doing here, both in how we're dosing the molecules and combining them to optimize their benefit for patients. The durable and curative benefits that we're seeing in some patients are direct results of your contributions. That includes how to administer these agents, and you're also in the forefront of identifying gaps in these first-generation combinations or therapeutics.

Dr. O'Day, you were the first patient -- the first person to dose patients with YERVOY, a first-generation CTLA-4, more than 20 years ago, and you're now the first to dose patients with our next-generation CTLA-4, AGEN1181, which is a multifunctional T-cell engager that also binds to CTLA-4, and we've designed the molecule to approve upon what we believe to be important efficacy and safety parameters and also to expand the patient population of patients who benefit from the first generation CTLA-4, and as Mayank mentioned on Friday and after you presented exciting data from our Phase I trial on this molecule. So I'd like to start the conversation by asking you, what have you learned from your experience with CTLA-4 and PD-1? And how has your thinking about this combination evolved? And what do you both believe that we need to expand in order to expand the expected and durable responses for patients with cancer?

Well, thank you. This is Steve O'Day. I'm delighted to be on the call today. And Jen, thank you for that lead-in. It really has been an extraordinary 20 years. I was in the field of melanoma where we had very few therapeutics, and about 20 years ago was fortunate enough to work with a small group of investigators that put ipilimumab into human melanoma patients with very advanced disease. And to make a long story short, we've discovered an extraordinary result. Of 1 in about -- 1 in 4 patients who received 4 doses of a CTLA-4 inhibitor resulted in long-term survival. And these were patients with very advanced melanoma, including brain metastasis. It was an extraordinary finding, and it then resulted in almost 10 years of clinical trial research Phase I/II and then culminating in a Phase III trial that was presented. At ASCO, I was able to give the plenary session, then in 2010, showing for the first time in a randomized controlled trial that CTLA-4, any drug in melanoma improved overall survival with remarkable cure in 1 in 4 patients. So clearly, this was an important checkpoint that then launched the revolution of immuno-oncology. Very shortly after that, obviously, the intensity of our clinical researchers and immunologists and oncologists, Dr. Drake being a primary focus in that whole field, discovered that there were other checkpoints. And you all know the story, PD-1 then became front and center. I think what I'd like to say just at the outset is that I really felt that there was a misunderstanding of mechanism very early on. Obviously, CTLA-4 helped a very small subset of patients with melanoma, but it was so dramatic, and it produced durable responses suggesting memory after very few exposure doses. But very soon after that, the thought was that the T-cell life cycle had other checkpoints and that PD-1, obviously, seemed to have a lot more activity. And then CTLA-4 sort of got looked at as the poor stepchild or the inferior version of PD-1. I think that was unfortunate because, in my mind, there are 2 very separate targets. They do share in common a T-cell, but as we know now, T-cell life cycle is very different in how antigens are processed in the periphery of the immune system, the army is built, sent to battle, then they encounter the tumor microenvironment, and the battle even begins there. And then they get exhausted. And then they -- then they upregulate exhaustion markers like PD-1. And so PD-1 responses were remarkably more common than CTLA-4 responses but -- and so it deserved its front and center. But with time, the durability has been less, and we had -- we neglected CTLA-4 for a while. What I'd like to reiterate though is I think that in the last 2 years, it's extraordinary how CTLA-4 has been brought back, a better understanding of the distinction of the 2 targets. And now across many solid tumors now 6 indications, CTLA-4 has been shown in combination at lower doses and even more less frequent doses has been an important background, not only in melanoma, but renal cell, non-small cell lung cancer, hepatocellular, colorectal. So I think it's here to stay. I think -- so the combination, we obviously need better, and then I'll let Chuck and others, we can talk some more about why we need better versions, but the existing CTLA-4 that we have, ipilimumab, is a very front and center platform now in combinations. Having said all that, I think we -- let's go back to what we learned initially as monotherapy with ipilimumab. And remember, where you may not know, but it really did have a dose escalation, dose response at higher doses in melanoma in the metastatic study. And up to 10 milligrams, it was superior in a randomized study than 3 milligrams, but toxicity also increased with dose. And because at the time the toxicity seemed overwhelming, if you really put it in perspective now that the gain that we get with the toxicities with CTLA-4 blockade are much more reasonable. It's just that it was a huge toxicity paradigm shift for oncologists back in to 2000, 2010. Now we're very facile at managing these toxicities, and it's changed things and allowed us to do combinations. But having said all that, we still want to reduce immune-related toxicity, not necessarily completely get rid of it because there is a correlation between mechanism of toxicity and response, but we certainly want to mitigate severe toxicities and obviously, there is a limiting factor to first-generation CTLA-4 regarding that. What I'm excited about in the next generation, which I will talk about is that we need to re-explore the dose if we have a less toxic drug, and that's the hope with 1181, because single-agent activity may be still dose related. And secondly, we never really got to study very many tumors with CTLA-4. We got a little signal in prostate cancer, a little signal in renal cell. And then it sort of left us as PD-1 was launched. And so we really don't have a good idea of CTLA-4 across solid tumors, particularly with more potent drugs that I think we have in second-generation and less toxicity. So for those reasons, I think both CTLA-4 monotherapy and combination is coming back. And I think it's very clear that this is a critically important target and the most important target at present in combination with the PD-1 background. I've probably spoken more, but I wanted to give that background, and we can move into biology.

That was outstanding. And I'll just say that I'm glad that you mentioned the new approvals where ipi and nivo now have been able to be dosed tolerably and effectively and now over 6 different tumors -- they have a label and approval in over 6 different indications. I'm hoping and looking forward to Agenus' contributions to that in that we have a first-generation CTLA-4, as you know, as well as a PD-1, advancing in 2 BLA path trials, monotherapy PD-1 in patients with refractory cervical cancer and the combination in refractory cervical cancer as well. And we presented some data demonstrating that patients with PD-1 monotherapy have response rates of about 14.3%, and that's quite comparable to the 14.3% that pembrolizumab was approved on via accelerated approval in this indication. The combination, however, is what we're thrilled by. We're seeing 26%, maybe a little over that, of response rates and that's showing near doubling of responses in patients with refractory cervical cancer, which shows a potential best-in-class benefits for these patients. And these responses, what we're seeing now are durable. So we have 4 complete responses, 10 partial responses, and these responses are very long-lasting. Maybe I'll turn it to you, Dr. Drake, now to speak about some of the learnings about CTLA-4 and PD-1, the mechanism, in terms of T-cell modulation, effector memory cells and some of the underlying immune activity that is helping to drive these durable responses.

Sure. I am happy to do all. First of all, I would like to just start off by agreeing with Steven, actually, on his -- on the basic point that he made at the very end, saying that the immunological pathways mediated by PD-1 and CTLA-4 are very, very different at the molecular and cellular levels. I actually had a similar experience. I was lucky enough to treat the first kidney cancer patient in the world with anti-PD-1 in 2008. And they had a complete response. And so we were all excited this was going to be the next generation. It looked like PD-1 was more effective and then maybe less toxic than anti-CTLA-4. But I think that as time has emerged, there are actually -- and also the field was accelerated greatly by a series of animal models, which show that if you add PD-1 to something in mice -- sorry -- so I think the field got a little bit overexuberant about the idea of using anti-PD-1 in combinations, but really the clinical data hasn't so far borne that out to the degree it has, at least with CTLA-4 in that CTLA-4 blockade is approved with PD-1 in 6 different indications. And it's actually the only immune checkpoint that reliably combines with anti-PD-1. So I think that's kind of what the field has taught us. The one -- I would take slight exception to one thing that Dr. O'Day said, in prostate cancer, I was actually fortunate to be the -- one of the international PIs on our pivotal-- potentially pivotal Phase III trial. And what he's right about is that we had to use a higher dose, right? So definitely, with CTLA-4, there's a dose response relationship, but we almost won. In prostate cancer, we had a hazard ratio of 0.8 and our p-value was just on the edge, it was 0.53. And so we really came pretty close with a high dose of ipi in prostate cancer. And that's not what you see with PD-1 monotherapy in prostate cancer. So I think the other thing to keep in mind is from an immunological basis, studies from Rafi Ahmed's group and then several other groups really, Steve Reiner, and actually, we repeated some of these studies in our labs and that we really, really believe them. And the idea is that actually, PD-1 blockade is important in T-cell biology in that it basically really exploits the effector phase. So basically, T-cells have 2 jobs, one is to go ahead and kill, and the other one is to turn into memory cells. And so PD-1 definitely augments the effector phase, and that's why you see a nice response rate, but that does come at the expense of forming memory, and that memory phase is actually more strongly supported by CTLA-4 blockade. And I think that's really kind of an easy way to think of why the combinations are usually additive. And sometimes even if you're synergistic, actually. So I think that all those things together do suggest that -- Dr. O'Day, and I totally agree that CTLA-4 has been sort of marginalized to some degree for a while, but I think the emerging data really pointed out that CTLA-4 is an important checkpoint and then why new approaches to -- versus standard ipilimumab might be advantageous.

Thank you very much. Dr. O'Day, do you have anything to add to that?

No, I'm -- Yes I -- sorry, I may have slighted the prostate group, but I remember that, that was very close. And in fact, I was so disappointed because essentially, there was a 94% chance that, that was a positive study, so to speak. So -- and cold -- relatively cold tumors like prostate cancer with very few infiltrating T-cells normally, it just makes the strong point that CTLA-4 may work better in some diseases than PD-1. And it makes a strong point, and it's based on biology, and the 2 together always seem to be a little better. But there are diseases where CTLA-4 by itself may be the best drug of the 2. I don't think that's fully appreciated by the wider community, but I'm just delighted to see it now back front and center and to be involved with the -- sort of full circle for my career to put the first CTLA ipilimumab be involved with that group in around 2000. And then this year or last year to put really the first 1182 second-generation from -- in a person. So that was exciting.

Well, that's a perfect segue and an opportunity to start talking about some of the next-generation approaches for CTLA-4. And I also want to ensure that we cover, in this category, the opportunity to potentially really build on the learnings that we have to date and how there may be some monotherapy opportunities for anti-CTLA-4 given our enriched understanding of the biology now as well as other non-PD-1 combinations that we can contemplate as well. So transitioning to the next-generation CTLA-4, where there has been quite a bit of activity and notably also at ASCO. Our 1181 is Fc-engineered, and we've designed this to increase the dwell time or the time between the engine presenting cell and the T-cell interaction to increase immunogenicity, of course, to activate T-cells, but also to improve priming. We -- also with the Fc engineering, we believe that we can now dose and benefit patients who have a polymorphism in their CD16 allele. And those patients appear to have had no response or suboptimal responses to first-generation CTLA-4s. The molecule is now in the clinic. And perhaps I can ask you, Dr. O'Day, just to highlight a few key features a number of your patients have been treated with the therapeutic and give your perspective about this molecule and perhaps then we can turn it over to Dr. Drake to talk about how this approach may differ from some of the other approaches that are in the clinic.

Yes. So I've been fortunate to be involved and sort of to lead the initial Phase I trial. And what I like about it is sort of an adaptive design. We're doing sort of parallel Phase I monotherapy 1181. And then as we clear doses, we are then starting that lower clear dose into the combo. So I think we've treated a little over 20 patients with these and what we've seen, obviously, it's early days for efficacy and all that. What you really want to look at, obviously, early on is toxicity signals, both with the monotherapy and the combination. We've seen -- what we might expect with the CTLA-4 blocker was skin and some GI toxicity that's been manageable. What we're particularly interested in based on Fc engineering and the complement aspect of this is the neuro-endocrinopathies, particularly hypophysitis, which is one of the more significant endocrine toxicities that you don't typically see with PD-1 inhibitors. You tend to see more thyroid in other, but with CTLA-4, with ipilimumab, anywhere from 10% to 15% of patients could knock out their pituitary glands. Where it's not life-threatening, it does produce lifelong need for hormonal adrenalin and thyroid and testosterone in men, replacement. So it's not a trivial issue since these tend to be the long-term survivors. So anyway, we're -- based on preclinical models and the Fc engineering, there was a hope that they really didn't see these neuro-endocrinopathies. And so far, again, in 20-plus patients, we have not seen any of these neuro-endocrinopathies. So that's encouraging. Otherwise, it's been a fairly reasonable toxicity profile without any new signals. And then, of course, we have seen some responses. One, in monotherapy at a very low dose and in a disease endometrial that doesn't have a track record in CTLA-4 and had the haplotype, the low affinity haplotype that you would expect to have a very low response based on melanoma data with ipilimumab or the first generation. So for all those reasons, low-dose disease that had not previously been a CTLA-4 disease, so to speak, and a low affinity haplotype, that's really exciting. And it was a complete remission, and it happened within 12 weeks of starting. So very dramatic, and it's been durable. So that's, again, one patient but exciting. We had another patient at the very lowest dose of the monotherapy that's had an ovarian cancer and had now almost 1.5 years now of prolonged stable disease. And so that's been -- she's tolerated it beautifully. And then we've seen a combination patient, again, low dose of CTLA-4 of 1182, 0.3 milligrams with full-dose PD-1, and we've seen a very nice response rate, multifocal ovarian disease that was progressing through chemotherapy after multiple regimens and now having almost an 80% shrinkage with most recent scans. Again, very dramatic, very early. So we are -- what is nice to see, and again, all of these early studies are let's get to an optimal dose with monotherapy, and let's get to an optimal dose of combination and then obviously expand these cohorts, which we plan to really focus and use our energy, knowing the field where would be the biggest impact to get both a monotherapy on the market or a combination in diseases that traditionally might not be a colder tumor, so to speak. So we have a very well-developed advisory board that is well versed in I-O that is really doing its job to think of where we're going to put these optimal combination doses and schedules and monotherapy in the coming months. We're also looking at both a 3-week and a 6-week monotherapy regimen. So we're looking at a couple of different dosing regimens.

Thank you very much. And Dr. Drake, you've been an expert in the area of tumor microenvironment conditioning agents, Treg depletion as a mechanism of tumor progression, tumor escape mechanisms as well as T-effector activity. One of the features of agent 1181, based on its design, is we're anticipating Treg depletion. And perhaps we could ask you to speak a bit about what you believe these next-generation CTLA-4s may be able to do. And also what your thoughts are on where to bring these forward, both as monotherapy as well as in combination with PD-1?

Yes. It's a great point, actually. So in the lab, we've been fortunate to have an analog of a CTLA-4 depleting antibody. It's a mouse IgG2a, and it depletes brilliantly. And with that drug, we can see activity in tumor types in mice where anti-PD-1 has no activity. And so I'm really very enthusiastic about the ability to optimally engage Fc receptors and potentially deplete Treg. And so the mutation that's in 1181, the DLE mutation is unique. It's actually not in any other antibody that's in the clinic now. And if anybody is -- once we delve into the deep science, we should point them towards the beautiful cancer cell paper actually that shows this molecule compared to native type CTLA-4s and actually several other mutations. So that's why I'm excited about the mechanism, but the other reason I'm excited, I got to tell you, is that when you push a tumor, what you get is an expansion of both number and function of regulatory T-cells. And by that I mean if you radiate a tumor, you think that you're increasing the TME inflammatory status and you do, but that's very well balanced by an increase in the number and function of Tregs and those Tregs express CTLA-4 like highly, actually. We published this in clinical cancer research. We recently published the same thing in prostate cancer, hormonal therapy is immunotherapy. You get CD8 T-cells come in. You're very proud of yourself and then shortly after you see a nearly perfect adaptive increase in Tregs. We call this adaptive Treg resistance. And I have to tell you it probably happens to everything, it probably happens to PD-1, it probably happens to chemo. And so I have to say that I think that there is a very, very broad spectrum of tumors and combination modalities that an optimized CTLA-4 has a placement. I think what Steven said is, which I agree with is the one place to start is just to reexamine the tumors in which we either didn't casually explore or which we saw a width of CTLA-4 activity, prostate is a very good example. But then I think going forward, like, frankly, I mean, there's multiple, multiple applications. I think that in kidney cancer, there is certainly a good chance that a drug like this is more active than traditional CTLA-4 drugs. I do agree with Steven, I think the place to start there would be to look at an optimized antibody in tumors that we think have a chance of being immunologically sensitive. But then I think going forward, I think that the -- frankly, the combination approaches with really most things that are pro-inflammatory in our hands actually benefit from CTLA-4, not blockade by using CTLA-4 optimize depleting antibody. We have another paper that we haven't published yet, in progress, where we combine it with the cancer vaccine, which have lost sort of interest, but I can tell you that it's the same thing. You push the tumor microenvironment with the vaccine, you get more Tregs. If you get rid of the Tregs, then the vaccine works beautifully actually. So I think that there are really many, many applications for a region like this, frankly.

Very helpful. Now maybe I'll just ask for a perspective from your experience. Both of you were at the front edge of using CTLA-4 in tumors. And you've seen the benefit as well as some of the challenges to see responses this early. And at the low doses that Dr. O'Day just highlighted, how common, in your opinion, how common or unusual is it at this stage to see the kinds of activity that we're seeing?

I think -- go ahead, why don't you start with it?

Yes. You've seen more because you do more melanomas.

Yes.

What I'll say, actually, is the fact that you're seeing responses at low dose are very clear evidence that biologically, this is a different molecule than ipilimumab. I think that nobody can argue that, right? I mean, I think that the fact that you see responses at 0.3 and that maybe even spacing it out to every 6 weeks is possible, I think that this is biologically a different molecule than ipilimumab. So I think that's very important. I think that what -- in terms of the true measure of the clinical activity, I once again will agree with my friend, Dr. O'Day in that I think that the key to really understanding that -- certainly seeing responses early is encouraging, right? But I think that the fact that we're getting closer to what looks like a recommended Phase II dose, both as monotherapy and combination really, really means that within the -- a relatively short time, we'll be able to get a better readout for exactly what the activity is. So I think, again, the low dose is -- shows very clearly this is biologically different. I think that seeing responses early is encouraging, and we really very much look forward to like what happens in the expansion cohorts.

Yes, I would agree. And I think the fact that we -- again, it's still some confidence in rules around this statement. But I mean, certainly not seen any neuro endocrinopathies so far in a drug, ipilimumab that we saw a fair amount, 10% to 15%, certainly gives me a hope that this might be different from a toxicity point of view. But obviously, that's going to be really critical, too.

Thank you. And perhaps, Dr. Drake, given your experience with some of the other next-generation approaches, how do you see the profile, the observations of safety, the absence of the neuro endocrinopathies, in your opinion?

I think it's very exciting. I mean, so I mean in terms of full disclosure, I'm actually the local PI on a competing molecule. Frankly, it's the BMS version of ipi. It's the non-fucosylated antibody. And the idea there is similar. There have been no data presented publicly. We treated the first patient at Columbia actually in 2017. Someday those data will be released. So we can't comment publicly. But I think that defucosylation and the DLE mutation are again biologically different, actually, and this is shown in the white paper, which I encourage people to take a look at. The other approaches out there include a molecule called the probody, which this is a very clever joke, right? So you have an antibody, then a probody, right? So the probody has the antigen binding region masked by cleavable peptide. And the idea of this drug is that the anti-CTLA-4 activity only becomes effective within the tumor microenvironment where that peptide is cleaved by the appropriate protease. Hopefully, it's there. That's been going along. That's -- the probody has been going along. They were -- increased the dose to a fairly high level and then saw some toxicity, some CTLA-4 like toxicity. I think that's a very interesting molecule. I think the challenge is that there will always be some tick over for a molecule like that. And so whether that molecule can achieve its promise that is either decreased toxicity with same activity or the same toxicity with more activity, is -- still remains to be determined. Actually, I think it's an interesting molecule, but so far still in development. There's also a couple of other ideas. There's some bispecifics. I think Xencor has -- is in the lead with this. They have an antibody that finds both PD-1 and CTLA-4. And there are several other companies that have a similar construct. The idea there is that you really only work on cells that have both PD-1 and CTLA-4. Yes, that's a blessing and a curse that might increase specificity and decrease toxicity. The tumor microenvironment, the Tregs do have a little bit of PD-1. And so this might help increase some specificity and some of the CD8s also have a little CTLA-4. And so I think it's a reasonable concept that's still early on for that molecule. There's a couple other ones, too, but I think that, again, I just keep saying this over and over, but I think really -- my take-home point is that DLE mutation that alters the Fc gamma RIII binding is different than any other molecules. And I think that this is the lead compound that has that. And I think that's why this one is particularly exciting. I am -- I have to say I'm a little bit jealous for -- of Dr. O'Day being able to present the data a little bit at this point.

We'll make sure that we share in some of the novel innovations that you have in your hands.

We're in the same sandbox.

Well, maybe this is a nice transition then as we -- you referenced the Cancer Cell patient -- the Cancer Cell paper where we actually highlighted the Fc engineering that we modeled into our 1181 molecule for CTLA-4. In that same publication, we also had shared some data on our next-generation, our TIGIT molecule. We have a family of TIGITs, monospecific approach that's Fc-engineered as well as a bispecific approach that we're really -- both of which we're really quite excited about, and they're on the -- moving into the clinic end of this year, beginning of next year. Do you think that this Fc engineering, based in your opinion, with a TIGIT molecule may have a similarly beneficial impact on this type of target? Maybe we'll start with Dr. Drake.

Yes. I think that's for Chuck to address.

So definitely, I think that -- not in terms of addressing, but in terms of it being differential, actually. So I think that basically -- just -- the presence of Fc receptors in the tumor microenvironment, to be fair, has not been very well studied. And it probably actually is a dynamic parameter that changes as the tumor evolves or undergoes treatment, but the fact that this DLE mutation allows stronger binding to the Fc receptors also equalizes binding between the low- and the high-affinity variant, which are both present in fairly reasonable proportions of the population really means that molecules that incorporate this could be different actually. And so I have to say that TIGIT is a very reasonable target going forward. We published a paper in The Journal of Clinical Investigation where we looked at sorted regulatory T-cells from multiple tumor types and did very careful analysis of RNA sequencing. And TIGIT is certainly one of those molecules, actually, and one approach is to try to use a blocking antibody that maybe reprograms those TIGIT expressing cells, but another approach actually is to consider that there might be mostly regulatory T-cells. And once again, attempt to try to get rid of them with depletion. So I think that just like -- just this is the case, where the DLE version of ipi is different than ipi/CTLA-4, I think that the Fc-modified TIGIT is certainly going to be different than the other TIGITs that are out there, actually. And some of them are particularly engineered to not have any Fc receptor binding. So those are primarily designed to be blockers, right? And so I think that you'll see what will happen is much like the CTLA-4 antibody, you'll see very, very stark differences in both activity and toxicity. And I would be -- honestly, this is obviously speculative, but I would be really surprised if the Fc-modified TIGIT doesn't look different than the other TIGITs.

That's very helpful. We've actually been able to share publicly some data preclinically, both with our TIGIT monospecific as well as the combination demonstrating superior tumor control in preclinical models compared to competitive molecules in our hands. So from our perspective, it certainly does play a differentiating role with this particular target. I was curious to hear your take on that. Thank you. Mayank, let me go ahead and open it up. There were a few questions, I think, that you had specifically on the ASCO landscape related to the TIGIT target.

Yes. And maybe -- since we have both Dr. O'Day and Dr. Drake, maybe if you could comment on the Roche's first-line lung cancer study data that we saw from the CITYSCAPE study and just your general comments on the path forward. And then obviously, I know we are still very early with the monospecific and the bispecific approach for Agenus. Just kind of high-level thinking on where this could go. And then you also obviously know there's the Arcus molecule and there's also a couple of other molecules in the TIGIT landscape. Maybe Dr. Drake, if you want to take that?

Yes. So well, obviously, this is not an area that I have been that involved with. But I -- so I don't want to -- I've seen the lung cancer data, and so I'm aware of the target. But I think it's reasonably encouraging data, with response rates that were approximately doubled. I think response rate in -- when we've done PD-1 plus, we've been through a lot already, not to get back to CTLA-4, but obviously, it is the one player that has held its own, not based on response, but obviously, durability and long-term survival. But so I am a -- we went through the IDO experience with insight and anyway, this is encouraging. It's a randomized Phase II trial, reasonably good 70, 80 patients per arm. The response rates were better. I am much more interested in plateau of PFS curves at 12 to 18 months to really see if the next immunologic manipulation will both recruit, either change ratios like what Chuck said in the tumor microenvironment of pro -- antitumor effects as well as suppressive effects. So -- or bring in additional molecules that are -- that kind of affect the outcome. So obviously, macrophages and repolarizing them and myeloid-derived stem cells that are all immunosuppressive. So I think the phenotype of the microenvironment is critical to making a big change, and we will see but it's certainly an early signal that looks promising. I know they're launching a large Phase III trial. And whether it's premature or not, in my mind, it may be based on waiting for more durable data, but such as it is. Chuck, do you have some thoughts?

Yes. I mean so I think that the story is not too dissimilar from, I think, what we're learning from CTLA-4 that is careful studies the TME show that CTLA-4 is mostly expressed on the regulatory T-cells. Although there's a fair amount on CD8 to be fair. TIGIT is similar. There's more on the regulatory T cells and CD8. And [indiscernible] have a very beautiful paper in The Journal of Clinical Investigation kind of really in animal models at least suggesting it's almost only on the Treg that matters. And so that gives you sort of an immunological rationale for this combination, a rationale that's not dissimilar from the PD-1/CTLA-4 rationale, actually. And so the response rate difference is encouraging. I guess the thing that bothers me a tiny bit is that there were several other anti-TIGIT molecules in the clinic, BMS had one, and I think 3 or 4 other ones, Arcus. So like did they just miss this? I mean...

I think Merck had one in particular, right?

Yes. Yes, Merck had one. So I mean to be fair, I mean, to be fair, Roche did a fair number of patients. This was about a 60 or 70 patients if I recall correctly in each arm. And it looked like it was placebo-controlled. So maybe this is a little bit more compelling than some of the IDO data. But I think what Steven says is true, obviously. We would prefer to see -- initial response rate can sometimes be a little misleading in these studies. So seeing a longer PFS or potentially an OS signal, I think what we need to see. But to be [indiscernible], we go back to the thing that you guys just said in beginning, right? So if a TIGIT works, right, that's great. Would an Fc-optimized TIGIT work better? And the answer is probably, right? I think so. So I mean this is not a bad thing. I mean, if this is correct, and this is TIGIT activity, I think that exploring the pathway with next-generation molecules more quickly than we did with CTLA-4 might be a good move forward.

Right. Okay. And another question I got in terms of just thinking about the path forward and specific tumor types that -- and keeping in mind the CD16 allele high activity there, I'm just curious if any one of you can take this question on where this can kind of go forward? What could be a path? And I know the advisory board, all that work we still have to see. And there maybe -- also would be helpful as if you could comment, like in CTLA-4 in some tumor types can actually start becoming backbone and we can start thinking about it as PD-1 and maybe there are other agents that would need to combine. And I'm obviously thinking, I think there's some data with [indiscernible], for example, other alternative approaches where CTLA-4 actually works really well, that combination.

Yes. Well, let me take your crack. I mean, I think everyone has historically wanted to combine something with PD-1 that isn't CTLA-4 because they're worried about its toxicity profile and this notion that it doesn't really have much tumor coverage, so to speak. It was sort of a melanoma drug that didn't work elsewhere. So we -- I think like coming back to the beginning, I think of them as very different drugs and mechanisms, and they only share T-cell, but a very different life cycle. So there may be -- as we understand the biology better of how CTLA-4 works, there may be drugs combining with CTLA-4 that are optimal to PD-1. I mean, [indiscernible] and drugs like that, that have activity as a priming agent. And the obvious -- there's data with CTLA-4 with ipilimumab that obviously looked in my mind, better than their combination with PD-1, and yet they went through a large Phase III with PD-1. So there -- so we need to be smarter, I guess, in terms of the combination. The other thing I would just add is I think the -- one of the most exciting areas, I think, is in the microenvironment is with TKIs and VEGF-based therapies. And as people know, lenvatinib is getting more and more interest across solid tumors as a combination with PD-1. And the renal -- and Chuck can comment the renal cell data looks tremendous and melanoma data is probably forthcoming. But with the bar that the resistant PD-1 patients overcoming that secondary resistance, which is a high bar. But my sense is if a new drug can do that, then its benefit in naive -- I-O naive patients is highly likely to be equally, if not better. So some of these drugs, I think, the obvious place to look for benefit is if they can reverse a resistant phenotype after PD-1 exposure and anyway -- so these are areas that we're looking at. Obviously, in melanoma with 1181, obviously, CTLA-4 can be used in sequence after PD-1 or even in resistant patients. And that would be a great area to look at in a single arm to see if you could overcome resistance.

Yes, I agree. I would say that in addition to the phenomenon of Adaptive Treg Resistance, which again occurs probably to many, if not most, on prior therapies rationalizing CTLA-4, there's another phenomenon. I think, Steve, you kind of hit on it. It's adaptive myeloid resistance. So basically, same thing happens with radiation. You see initially a beautiful influx of activated CD8 T-cells killers. You're, again, proud of yourself, but then it's balanced by both Tregs and then later on by myeloid cells, right? And these myeloid cells fall into several categories and 2 macrophages: granulocytic MDSCs, monocytic MDSCs. The reason I think lenvatinib is a nice partner because lenvatinib blocks multiple TK -- multiple tyrosine kinases and some of those are critical for the function of these myeloid components. So I think in terms of combinations another way to think about going forward is to consider that other suppressive component of the TME, in addition to the evil Tregs, for which 1181 should be a very good drug, to consider some of the myeloid targets that might be involved in mediating that resistance. It's certainly -- as you mentioned, I mean, certainly the TKIs, not only lenvatinib, cabozantinib probably does similar things as well. We have a paper in review where we looked at the immunological effects of cabo and find reasonably similar effects of myeloid compartments. And there's other drugs that fall into that, too. But I think that thinking about a little differently, thinking about pushing the tumor and then worrying about the Tregs, 1181 a good idea, and I'm thinking about what are you going to do about the myeloid component is another way to think about combinations perhaps.

Yes. I can't wait to get CTLA-4/PD-1 and TKIs in combination because I do think it's just very delicate ratios of effectors and suppressors that can just turn it into full -- particularly if they can keep the regs away and keep the myeloids away and then drive the CD8s. I think the dynamics of that's going to be really exciting. But CTLA-4 both drives fresh T-cells, right -- the primed, expanded T-cells as well as PD-1 is really focusing more inhibition on these exhausted cells that have gotten out there but are losing the battle. So there's tremendous mechanistic opportunities to hit this at multiple sites and I just hope I'm here in the coming years to really witness this because I think there's going to be some dramatic forward. I mean, it's going to be exciting this next 10 years.

We absolutely need you. We absolutely need you to think that.

I'm trying to stay healthy. I'm trying to stay healthy or Chuck will take over for me.

It won't be long then. It's going to be faster.

No, I'll be fine. In the next 6 months, they'll not even remember what they saw in this time frame looked like and we ever had a virtual ASCO. [indiscernible] But quickly, maybe, Dr. O'Day, as you think about this next leg of innovation, and I'm thinking more orthogonally, like you start with melanoma, I mean that's kind of the typical line of thinking, which is obviously easier to explore and -- for the mechanistic reasons that we just discussed. Like is there a new paradigm that -- with what maybe we learned in stages seems like a more high-risk approach. But like how do you think about these agents that are obviously coming along in large volumes? Like how do you develop them differently going forward than what was our understanding maybe 10 years ago? Could you just comment on that?

So I guess I had a little trouble. My phone was -- had trouble. What was -- could you repeat the question?

Yes, sorry. So a little orthogonal question, which is basically asking you, as we thought about clinical development like 10 years ago, we obviously start out with melanoma and then we think about other tumor types depending on the immunogenicity, but what we know about all these TME suppressors, it's all very tumor-specific and the targets obviously are guiding us in different ways. So how do you think about drug development maybe in 2020 as you think about a newer target coming along?

Yes. I mean, I think obviously, melanoma has been a prototype as a very -- its UV signature, its mutational burden, and kidney cancer also to a certain extent, but melanoma has just been such a prototype of a tumor that's visible to the immune system. And we now know that it does recognize it as foreign and it also battles. And then -- but so each tumor type though really depending on its source and its mutational and neoantigen signature and it is really going to be different, but there are common methods like Chuck was talking about. I mean I think we're understanding the players, the orchestra that the tumor is involved with. And that [indiscernible] is really, really interesting. And there's both common elements and then very unique elements. So I still think disease-specific biology and clinical experts are going to be critical to figuring the targets out because there will be differences. But I'm also encouraged by when we find targets that are effective like PD-1 and CTLA-4, how broadly they can be applied. I think the bigger issue will be once the immunologic sort of understanding of the tumor and its microenvironment are understood, we may need direct cytotoxics, whether it's radiation, chemotherapy, targeted drugs for brief burst to disrupt and allow that platform to take over. And colder tumors may need more work than warm tumors, but warm and hot tumors still kill people because of these ratios, and so we're just getting a lot more sophisticated. It's going to be a really exciting time to -- I think we need our disease specialists, but our immunologists and biologists, too.

Great. And maybe Dr. -- sorry, Jen, go ahead.

No problem. I'll just say one comment. And thank you and thank you very much for your vision and your leadership in this space, both of you. I'll make a point that optimizing combinations is so critical in the underpinning as to how we've designed our portfolio, and we will have some very exciting data that we'll be reporting out on in just a couple of weeks at AACR that may help us to elucidate the best ways of approaching some of these combinations, and we're looking forward to doing them together with you. Mayank, please go ahead.

Yes. I guess my final question, actually, you said that up nicely, Jen. Maybe if, Jen, you want to start the first end of this question, and I want to ask Dr. Drake also essentially for the upcoming -- for the remainder of 2020, what are some of -- some data sets that we should be looking out for, specifically in the checkpoint inhibitor space? And obviously, mostly now combinations because a lot of monotherapy activity is kind of -- at least for PD-1 is out of the way, but obviously, CTLA-4 monotherapy, I think, we'll learn more. So maybe, Jen, can you just set the stage us -- for 1181. What sort of -- we should expect through the remainder of 2020? And then maybe Dr. Drake for the -- broadly for the space, it would be helpful, what should investors focus on?

I'll just take a moment. I want to make sure we turn it over to Dr. Drake. We have -- for 1181, we have some interesting data, as I just mentioned, coming up at AACR, looking at best ways to optimize combinations for patients with cancer, looking for those long, durable, curative responses and broadening the patient population to do so. We'll have some data at AACR. We're also going to have some additional clinical data as the trial matures. And as you know, we've been very aggressive at getting these data out. So you could look for data at upcoming major medical conferences. Beyond that, our BLA filings are actively underway, and we're planning on filing those this year. So we're -- ideally, once we've secured the filings, we'd be looking to release an update on the data to date. So I'll turn it over to you now, Dr. Drake, to address the remainder of the question.

Sure. I mean, I think that some of the other combinations are going to have some more mature data towards the end of the year. LAG-3, which I have a vested interest in went, into the clinic a long time ago. So hopefully, we'll see some data from BMS from for lenvatinib. And there's a couple other anti-LAG-3s in the clinic. There will be some TIM-3 data as well. In terms of the TIGIT pathway, I think many people forget that, that TIGIT pathway is a parallel pathway. So it's TIGIT binds to PVR, but there's another pathway PVR actually binds to molecule called PVRL2. And there's an antibody against PVRIG in the clinic from a small company called Compugen that gave a little bit of data I think at ASCO, and there will -- they're going forward with their triple combination. But the other thing I think that investors -- if I was an investor, the other thing to keep an eye out for to combine -- and I think Steven said this very well, actually. So the idea is you probably need something to treat the tumor and radiation chemotherapy. Those are good things. I think that in addition to -- for something to combine with I-O, the drugs that are really seeming to really be rising quickly in interest is the antibody drug conjugates. So we saw data from -- anti-B7-H3 from -- ADC from MacroGenics in prostate cancer with some nice responses. There is a similar drug from Daiichi Sankyo in the clinic. And in bladder cancer, this is going to be a lead actually. So we're going to have enfortumab as the backbone in first line, and then we're going to add checkpoints to that actually. And I think that -- unfortunately, not CTLA-4, which is what we should be adding at this point. But still I think that what Steven said is the basis for many combinations will include something to get rid of the tumor probably, in many cases, PD-1 blockade still but CTLA-4 blockade as well. So I think that's what we'll see over the next couple of months, I hope.

Great. Lots to come. It looks like you're just starting out 2020. And from Dr. O'Day's vision, we are like just scratching the surface here on the immuno-oncology innovation that's ahead of us. I think with that, we are out of time, Jen. Are there any questions at your end or any closing remarks? Otherwise, we can close the call.

Thank you very much. No closing thoughts from me. Just great appreciation for your time and participation in the call. Thank you.

Thank you. Thank you, Dr. O'Day. Thank you, Dr. Drake.

Thank you.

We really appreciate it. And thanks, everyone, for joining us. And please, everyone, stay well and healthy. And back to you, John. Thank you.

Thank you, ladies and gentlemen. This does conclude today's conference call. You may disconnect your phone lines at this time, and have a wonderful day. Thank you for your participation.