Regeneron Pharmaceuticals, Inc. (REGN) Earnings Call Transcript & Summary

Good day, and thank you for standing by. Welcome to the Regeneron Investor Event ASCO 2021 Conference Call. [Operator Instructions] Please be advised that today's conference is being recorded. [Operator Instructions] I would now like to hand the conference over to your speaker today, Justin Holko, Vice President of Investor Relations. Please go ahead.

Thank you, Gigi. Welcome, everyone, to Regeneron's Oncology Investor Webcast. Joining me on the call today are Dr. George Yancopoulos, Co-Founder, President and Chief Scientific Officer; Dr. David Weinreich, Executive Vice President and Head of Clinical Development; Dr. Andres Sirulnik, Senior Vice President, Translational and Clinical Sciences, Hematology; Dr. Israel Lowy, Senior Vice President of Translational Sciences and Oncology; and Marion McCourt, Executive Vice President and Head of Commercial. After our prepared remarks, we will open the call for Q&A. Before handing the call over to George, I'd like to remind you that remarks made today include forward-looking statements about Regeneron, including those relating to Regeneron's business and research and development programs, anticipated milestones and regulatory matters. Each forward-looking statement is subject to risks and uncertainties that could cause actual results and events to differ materially from those projected in that statement. A more complete description of these and other material risks can be found in Regeneron's filings with the United States Securities and Exchange Commission. Regeneron does not undertake any obligation to update publicly any forward-looking statements, whether as a result of new information, future events or otherwise. With that, let me turn the call over to Dr. George Yancopoulos.

Thank you, Justin. And before turning it over to our oncology leadership team, I'd like to make a few introductory remarks. As I'm sure many of you know, Regeneron has developed some of the world's leading biotechnologies, which have allowed us to develop one of the broadest and most diverse pipelines in the industry. And we have been increasingly applying these technologies towards oncology. Our velocity in technology allows us to create some of the best antibodies against select targets of interests, such as checkpoint inhibitors. And you will hear about our PD-1 and LAG-3 antibodies today. And we have built on our velocity in technology by creating 3 new classes of bispecific antibodies. The first is our so-called CD3 class of T cell engagers. Our second is our costim class of T cell activators. And today, we will also introduce you to our third class of tumor-targeting bispecifics. Importantly, our portfolio combines to allow precise mix-and-match opportunities with which we can successively build on antitumor efficacy for a particular tumor class. And today, you will hear how we are doing this for lung, for prostate and ovary as well as for hematologic malignancies. Our development pipeline of over a dozen clinical candidates has the potential to address unmet need for many of the most important cancers. And many of these candidates have already demonstrated important proof of concept with several showing potential to be first and best in class. And we will be adding a similar number of additional clinical candidates over the next couple of years as part of a very ambitious effort in oncology. Today, with our updates presented at ASCO, we will focus on some of our oncology pipeline highlights for select programs and advancements. I'm joined today by our leading physician scientist, David Weinreich, Israel Lowy and Andres Sirulnik, who together are leading our clinical oncology efforts and working to make a difference against some of the most difficult-to-treat cancers. David will discuss our broad oncology strategy and approach and what makes Regeneron unique with our combination of homegrown pipeline and mix-and-match capabilities. Izzy will provide select updates across various solid tumor programs. Andres will provide select updates across our leading bispecific platforms in hematologic malignancies, including our potential best-in-class CD20 and BCMA programs. And then we will all be pleased to take some of your questions. So with that introduction, let me turn it over to David, who is our Executive Vice President of Global Clinical Development. David, take it on.

Thanks, George. As we've previously stated, our strategy centers around competing, enhancing and extending in the large and rapidly growing immuno-oncology space. First, compete. The anti-PD-1 market is large, more than $27 billion and can support multiple competitors. Demonstrated by our monotherapy data that we have reported out in multiple settings, we have what appears to be a very good drug with Libtayo. Libtayo on its own is going to be a meaningful contributor to our business as we compete in this large market. As revolutionary as anti-PD-1 treatment has been for the field of cancer, even in the best settings, objective response rates are generally less; than 50%. There are many patients who do not benefit solely from PD-1. We aim to enhance these benefits by combining PD-1 with other directed agents to potentially reach more patients. Finally, there are tumors that do not respond to anti-PD-1s at all. And unfortunately, that list is quite large, prostate cancer, pancreatic cancer, multiple hematological malignancies. We are looking to extend the benefits of IO to a broader set of cancers those addressed by PD-1s today. If you look at Libtayo, it continues to build a vast and maturing clinical profile across many cancers in the monotherapy setting. Most recently, we announced data for an overall survival benefit in second-line cervical cancer. The first -- and we were the first PD-1 to demonstrate a survival benefit in this setting. Libtayo was the leader in the Dermato-oncology space as the #1 systemic agent in cutaneous squamous cell carcinoma. And most recently, we received FDA approval in advanced basal cell carcinoma. Importantly, at this ASCO, we are presenting data for Libtayo in combination with our own anti-LAG-3, fianlimab. And it's an example of us delivering on our combination strategy that we discussed for the last year or so. In non-small cell lung cancer, Libtayo was recently approved in February as a monotherapy option in PD-L1 high expressors. And if you look at our clinical profile, which Izzy will touch upon, we believe we have a really good agent with a competitive and differentiated profile. With that, we believe we can compete in this very large lung space. Further, we expect a data readout in the second half of 2021 for the Libtayo plus chemotherapy combination study. Despite the advancements in this field, there are many cancers that don't respond to anti-PD-1 monotherapy. Even for those cancers that are responsive, many patients unfortunately do not benefit. An example of PD-1 is in advanced melanoma with very low objective response rate. Our clinical development pipeline currently has more than 12 candidates to potentially address unmet medical need of the most prevalent cancer types providing a significant opportunity to advance the science, utilizing our vast technologies and capabilities. What makes Regeneron unique is the platform by which we can generate and combine antibodies against many cancer targets. While others in the field aspire to extend treatment benefits to more patients, nobody in the industry has the toolkit that offer the complementorial flexibility that we have. With this powerful toolkit, we are well positioned to compete, enhance and extend the benefits of immunotherapy to a broader patient population than those who benefit in today's large and rapidly growing immuno-oncology market. As our updates throughout the year and highlights at ASCO, we continue to advance our broad and deep pipeline. Now we are showing meaningful data in the combination settings, which highlights the powerful and diverse pipeline we possess. Now I'll turn it over to Izzy to go into more detail about our progress in solid tumors. Izzy, take it away.

Thank you, David. Let me start -- review a set of impressive clinical data across a number of cancers with Libtayo, but I want to reemphasize that our work with Libtayo is just the first of outputs from a long-term plan to develop a broad and deep pipeline which has been thoughtfully imagined to allow for flexible and complementary combinations. Libtayo is a foundational piece to Regeneron's oncology strategy, with expanding and maturing clinical data across many cancer settings. We're sharing some important clinical updates today that have just been presented at ASCO as well as a few weeks back at the ESMO virtual plenary. And over the next few slides, I will showcase some of the compelling and maturing data for Libtayo in non-small cell lung cancer, the second-line setting in cervical cancer and in combination with fianlimab, our own anti-LAG-3 antibody for advanced melanoma. Next slide, please. Thank you. We have shown -- let me remind you that in first-line lung cancer, Libtayo demonstrated a significant clinical survival benefit versus chemotherapy, which served as the basis for our FDA approval this past February. And now Libtayo provides physicians and patients a potent new treatment option against this deadly disease. Importantly, the strong survival benefit that was demonstrated was remarkable because the -- first, was 70% crossover built in -- crossover was built into the study. And second, we included in this study patients representative of real-world settings who are typically not well represented in registration trials, such as those with brain metastases or locally advanced disease. Next slide, please. At ASCO, we're showing additional data on lung cancer patients with stable brain metastases at baseline. Brain metastases are found in approximately 10% of patients with newly diagnosed non-small cell lung cancer and around 1/4, 26% of patients with advanced stage IV lung cancer have these and have generally been underrepresented in lung trials. And the prognosis for them is poor. In a post hoc analysis, Libtayo demonstrated a market improvement in survival, progression-free survival and objective response rate versus chemotherapy, demonstrating a meaningful benefit of Libtayo for these patients. Next slide. Another interesting and important piece of clinical data is the correlation of PD-L1 expression to the key clinical outcomes in the same registrational EMPOWER-Lung study. An exploratory analysis emphasize that PD-L1 positivity is an effective tumor biomarker for the patient group with increasing PD-L1 expression correlating with even better outcomes with Libtayo. You can see the largest benefit in reduction in tumor size was observed in the tertile of patients with PD-L1 percentage greater than 90%. That's the bottom curve on the right. It was markedly superior to chemotherapy with a more limited benefit in general, was not driven and was independent of PD-L1 expression. These data serves to deepen and enhance Libtayo's clinical profile, supporting the use of Libtayo in first line, especially in those patients with high PD-L1 expression. We are eagerly looking forward to our Libtayo plus chemo combination study to read out later this year, where we hope to show clear benefit across all levels of PD-L1 expression. Next slide. At the ESMO virtual plenary last month, we were pleased to present our clinical data for the survival benefit afforded to patients with second-line cervical cancer by Libtayo monotherapy in comparison to a choice of commonly used second-line chemotherapy regimens. This was the fourth example of the strong clinical profile for Libtayo in yet another devastating disease, and the first immunotherapy to demonstrate an improvement in overall survival in advanced cervical cancer compared to chemotherapy. Libtayo reduced the risk of death by 31%. Patients were enrolled regardless of PD-L1 status, and benefit was observed across both squamous cell and adenocarcinoma subgroups. Regulatory submissions are expected in the second half of this year. Next. In conjunction with this efficacy, the safety profile of Libtayo in this study was exemplary. No new Libtayo safety signals were observed. And despite a longer duration of therapy on Libtayo than on chemotherapy, and therefore, longer exposure, overall, there were still fewer treatment-emergent adverse event. Next, please. So now turning to fianlimab, our anti-LAG-3 antibody. This is an example of our long-term plan to develop complementary combinations with Libtayo. At ASCO, we have shared compelling early clinical data from 2 expansion cohorts in both PD-L1-naive and PD-L1 experienced patients with advanced melanoma. LAG-3 is an immune checkpoint receptor that delivers an inhibitory signal to activated T cells. Its expression in melanoma biopsies has been shown to be associated with therapeutic resistance to anti-PD-1 and suggesting that LAG-3 immunosuppression and blocking it may be complementary to blockade of PD-1. This double IO combination has the potential to be a viable treatment option with additive activity as opposed to PD-1 monotherapy for patients. And this may be a welcome alternative to the current option of PD-1 plus CTLA-4 blockade, which, while having better efficacy than single-agent PD-1, does have significantly more toxicity. Next slide. From these 2 expansion cohorts, there are compelling objective response rates, in particular, in the naive setting. The response rate by investigator assessment was nearly 67% for naive patients and 13% to those who were experienced. Importantly, the results are durable, and the median progression-free survival and the median duration of response has not yet been reached but are each clearly better than the year-to-date. A Kaplan-Meier estimated progression-free probability at 12 months was 61% and 10% for naive patients and 10% for experienced patients, which compares favorably to other approved and clinical combinations. And in the first-line setting, these results are even more impressive with at least 80% of patients on our study having at least 12 months of progression-free survival. Next slide shows that the safety of this combination is quite attractive. Fianlimab and Libtayo demonstrated lower rates of treatment-emergent adverse events compared to the currently approved anti-PD-1 and CTLA-4 combination therapy. These data will expand our dermato-oncology portfolio to include both melanoma as well as non-melanoma skin cancers. And in conclusion, we are very excited about this clinical data and are moving this asset forward into a Phase III pivotal program in first-line melanoma in 2022. Now I'd like to turn to our bispecific. Next slide. So beyond Libtayo monotherapy and combinations with other regular antibodies, we are sharing new updates across our bispecific pipeline, which we believe have multiple opportunities for antitumor activity as monotherapy in combinations with Libtayo, combinations amongst different types of bispecifics, and of course, as well with other therapeutic modalities. I'm going to discuss the progress we've made in our solid tumor bispecifics, and Andres will come up on the heme malignancy programs. Next slide, please. Our MUC16xCD3 program is our first CD3 bispecific in solid tumors targeting ovarian cancer, and we have been observing early efficacy signals in this disease and expect to report Phase I data next year, if not sooner. It's also the first indication in which we are now clinically testing 2 different types of bispecifics for this tumor target, a CD3 bispecific, as well as a CD28 bispecific, the costim. The CD3 bispecific is being tested as monotherapy and in combination with Libtayo. And the CD28 bispecific, the costim, will be tested in combination with Libtayo where dose escalation is ongoing. And subsequently, we will begin combinations of both bispecifics together, the CD3 bispecific and the costim CD28 bispecific. We believe these have potential to be game-changing approaches to the treatment of solid tumors. We're not stopping there. Next slide. We now have a trio of CD28 bispecifics in the clinic, PSMA for prostate cancer, MUC16 for ovarian cancer and other MUC16 expressing tumors and eGFR. The PSMA costim is being studied in combination with Libtayo for prostate cancer and is progressing through dose escalation cohorts, and we expect some initial data next year or sooner. As we've seen in our other programs, we're also planning on introducing a potentially complementary CD3 bispecific for PSMA, rounding out a powerful and unique tool kit for prostate cancer, which is currently considered relatively nonresponsive to immunotherapy. Our eGFR by CD28 costim is currently undergoing dose escalation in combination with Libtayo. eGFR is widely expressed on epithelial tumors. Therefore, our combination of this costim bispecific and Libtayo represents a potentially game-changing approach for quite a few tumors in general and in lung cancer, in particular. Next, please. I'd like to discuss now METxMET, which is a novel bispecific mechanism targeting non-small cell lung cancer. We've got a number of shots on goal in lung cancer: Libtayo monotherapy, Libtayo plus chemo, eGFR costim plus Libtayo as well as combinations with other collaborations. And now we have a targeted mechanism in MET and our unique tumor-targeted bispecific known currently as REGN5093. Our METxMET bispecific has a unique and elegant mechanism of action. It targets 2 distinct epitopes on the MET receptor, which enable rapid internalization of the surface protein rather than activation. You can see a depiction of this interaction on the right side of the slide, 2 antibodies grab on to 2 MET receptors at the different epitopes. And in this way, they lock them in a separated state so that the dimer cannot signal. And at the same time, it sets it up to promote their rapid internalization and clearance from the cell surface. Our bispecific antibody has shown that it is highly effective in MET-driven cancer models,and promotes very efficient MET degradation and cancer cell death. The next slide shows an ongoing study exploring the METxMET antibody in patients with lung cancer. It is progressing. It has reached the dose expansion stage. And we are enrolling lung cancer patients with a broad selection of MET alterations responsible associated with their tumor. We have high efficacy bars for these patient populations, and we will only move forward with the regular antibody for those that meet that high bar. But because of this, promotion of rapid internalization, this bispecific is a natural and attractive candidate to think about for using with antibody conjugated chemotherapy. Next slide. We have been working for a while developing our opportunity to develop antibody drug conjugates. And so we're also highlighting another important advance. We've developed a broad ADC platform with proprietary technologies and capabilities that adds to our already unmatched toolkit and pipeline. But we will take the ADCs into the clinic when they make the most sense to use. So what's the rationale for the METxMET ADC? As we've shown, REGN5093 promotes efficient MET internalization and inhibits recycling, distinguishing it from other conventional MET-targeting antibodies. This is a great bispecific antibody. Combining this antibody with a novel linker payload takes advantage of the unique trafficking properties of the same bispecific antibody, which allow for internalization of MET-expressing cancers and promoting cell death. Further important to our design is that it has a very poor -- the linker payload has a very poor cell permeability, therefore, reducing the potential for off-target effects seen typically with other ADCs and hopefully limiting toxicity. MET is expressed in many cancers, and we hypothesize that with the targeted MET ADC approach, we can enhance efficacy, particularly in cancers that don't respond well to other MET-targeted therapies. The Phase I/II study in MET-overexpressing advanced cancer is about to initiate in the second half of this year, and this represents a large opportunity as nearly 25% of lung cancers overexpress MET. Now let me turn the call over to my colleague, Andres, to update you on our efforts in hematologic malignancies. Thank you.

Thanks, Izzy. Let me take a minute to discuss some of our recent updates across our bispecifics for hematologic malignancies. For odronextamab, our CD20xCD3 T cell engager currently under investigation in non-Hodgkin's lymphoma, we recently announced that we are of partial clinical hold in diffuse large B cell lymphoma and follicular lymphoma in the monotherapy trials, and enrollment has resumed. Odronextamab, as a single agent, demonstrates efficacy across both aggressive and indolent lymphomas in what we view as a best-in-class therapeutic. We presented data at ASH 2020, and our program is currently advancing, and we have a very robust development plan, which provides a tremendous opportunity to bring this therapeutic for many patients. For REGN5458 and REGN5459, both BCMAxCD3 bispecifics currently under investigation in multiple myeloma, we recently obtained exclusive development rights across our BCMAxCD3 programs, which are -- we are very eager to aggressively move forward. We are very pleased with the data presented from our ongoing Phase I trial in refractory relapsed multiple myeloma, which was also presented at ASH in 2020, and we have a robust program, which is again advancing rapidly. All in all, both our CD20xCD3 and BCMAxCD3 programs each have shown promising single-agent activity, and we are progressing these programs in potentially pivotal trials, exploring these agents in early lines of therapy and in combination with standard of care and other novel agents within our pipeline. Let me bring you back to George.

Thanks, Andres, and thanks also to David and Izzy for those overviews. We believe that we have an exciting and robust ongoing strategy to help produce leading therapeutics in the cancer space. Our first foray Libtayo, as you've seen, has demonstrated broad efficacy across multiple cancer populations with differentiated data in first-line lung cancer as well as first-in-class data, leading to first approvals in 2 different dermato-oncological settings that is cutaneous squamous cell carcinoma and basal cell carcinoma and now our recent first-in-class overall survival data in cervical cancer as well. We are now able to hopefully add to this benefit of Libtayo, particularly in the melanoma space with our anti-LAG-3 antibody, which is showing early, very exciting activity and in which we are going to be entering into a Phase III within the next year. Izzy also reviewed for you our combination program of both CD3 and CD28 bispecifics in combination with each other as well as with Libtayo in numerous cancer settings, such as lung, ovary and prostate, but he also introduced you to a third new class of bispecific as exemplified by our MET bispecific, which is advancing in the clinic, both as a naked antibody and also as an antibody drug candidate, which we think has a lot of exciting promise in MET mutated and overexpressing cancers, including lung cancers. Andres briefly updated you on our progress with our CD20 bispecific in the lymphoma setting and our BCMA bispecific in the myeloma setting. But I think one of the most important aspects of these programs are these are just the first steps for us. While each of these individually have exciting and perhaps best-in-class activity on their own, they are soon to be combined with costim bispecifics in both of these settings that we hope can enhance and extend the potential leading activity here even further, which is an ongoing theme for us. Next slide. So all of these are going to produce a number of upcoming milestones over the next 12 to 18 months. We've touched on most of these. And as I said, in some ways, it's the combinations, which are going to really show the power of our mix-and-match strategies across so many different tumor settings. So I guess with that, well, thank you for your attention, and we'll open up the call to Q&A.

Gigi, we'll now open the call to Q&A. [Operator Instructions] Please go ahead, Gigi.

[Operator Instructions] Our first question comes from the line of Geoffrey Porges from SVB Leerink.

So I appreciate also the call and the detail, and there's a lot to talk about. But perhaps we just talk about the LAG-3. George and Izzy, you're fairly specific that you're developing this only in melanoma at this stage. And some of your competitors are, of course, developing their LAG-3s in a number of other indications. So could you talk a little bit about this? Is this just the melanoma medicine? Or does it have broader potential? Is it just a replacement for IPI? Or can it be more than that? And then just related to that, can you talk about your competitive profile because we can all see that you have a much higher dose or greater frequency of dosing, et cetera. So is it really a competitive molecule?

Well, first of all, I thought that what we've discussed is that what we are moving into Phase III is in our combination program in melanoma. That does not preclude -- and of course, we are looking at numerous other applications and settings for this. And where we'll see activity in early studies, we'll be willing to go forward, of course, in pivotal programs as well. I think that in cancer, we believe that efficacy rules. And we think that, that's what's exciting about our profile right now is that looking at the data that we've produced, particularly in the naive first-line setting, it really has the potential to be best-in-class data. And we believe that's the most important focus, of course, in the cancer setting. That said, of course, just as we are with Libtayo and all of our other oncology assets, we are simultaneously also considering and exploring more convenient dosing regimens as well.

Our next question comes from the line of Terence Flynn from Goldman Sachs.

Great. It's a 2-part question also on LAG-3. Just was wondering if there's anything in the PD-1 experience patients that you've seen that predict response. And then on the Phase III melanoma trial design, how are you thinking about the control arm here given, obviously, there's a change in landscape?

Go ahead, Izzy, on that.

Sure. So we've been impressed with the patients that -- who were PD-1 progressors. We reviewed them very carefully, and they indeed are bonafide PD-1 progressors and the durability of their response. We have yet to nail down a clear reason as to why these patients responded versus others. We're actively investigating that. And of course, if we can figure that out, that will be great. In terms of the Phase III design, we will be discussing our ideas about this with regulatory authorities. And we recognize that cemiplimab is not yet approved for -- as an agent in melanoma, but we will work out and approach.

Our next question comes from the line of Matthew Harrison from Morgan Stanley.

I was wondering on the MET drugs that you're working on specifically, maybe if you could just comment a little bit on, do you think there's something unique about the epitopes that you're targeting that allow you to target sort of broad range of these various MET issues, whether it's mutated exon 14 or amplified tumors or even MET overexpression? And then maybe just talk about how you're going to develop both the ADC versus the bispecific.

Izzy, why don't you take that also?

Okay. So these epitopes are expressed regardless of the genetic abnormality driving the MET signaling, whether it's an exon 14 or whether it's amplified or just overexpress. We believe that if the MET signaling is absolutely required to drive the tumor, then the naked antibody may be quite sufficient to block the tumor. If there are other pathways involved, we believe the ability of this bispecific to promote rapid internalization makes it an ideal candidate to deliver an antibody drug conjugate chemotherapy agents to the cell that overexpresses MET. So we think there will be room for both. And we will be developing both in parallel and figuring out which is the best option for which patient.

And just to add to that, for those of you who may not be aware, historically, there's been a great challenge in making MET antibodies that are not activators. And our unique bispecific approach in which a single bispecific targets 2 distinct epitope allows our bispecific to literally position the MET receptors apart and in a position in which they cannot be activated, but in which internalization is promoted. And we -- our guys have done an incredible job understanding the entire structural relationship between this. So this is a very unique reagent in terms of its ability to very efficiently bind but separate and keep from activating the MET receptors while promoting their internalization. So that acts as an ideal agent both to prevent any potential activation through this MET pathway. As Izzy said, that's one set of tumor targets, which are reliant upon MET activation. But it also can be used to officially internalize the antibody drug conjugate, which should allow killing of cells which have higher expression of these MET receptors but do not actually require the MET receptor for their survival. So we believe these will be complementary populations. And as Izzy outlined, he has a program to be exploring both these potential uses.

Our next question comes from the line of Mohit Bansal from Citigroup.

Congrats on all the progress. Maybe a question on costim. I don't know whether I caught it, but do you have any thoughts on when could we start to see the data from your costim? And when we see the data, I know these are early trials, but what exactly are you looking for in terms of responses, but more importantly, biomarkers, which will inform you that these are good data and we can move forward?

Well, Izzy, why don't you start and take that?

Okay. So the most advanced program we have right now is the PSMAxCD28 in prostate cancer. And that's advancing in combination with Libtayo. We hope to have data in the coming year that we can present. And the data we're interested in seeing actually clinical responses because PD-1 therapy, on its own, is rather ineffective in prostate cancer. And our preclinical models all support the notion that by triggering the co-stimulatory signal in conjunction with PD-1 blockade, we can augment T cell responses that will otherwise were not sufficiently augmented by PD-1 blockade alone. Similarly, the MUC16xCD28 program is in -- is beginning dose escalation first in combination with Libtayo and then in combination also with MUC16xCD3. And potentially, at some point, we might consider all 3. And we have an eGFR costim that also is in dose escalation. So I think these are still early days where we need to demonstrate the safety of the costim first with Libtayo. And we would hope that in the next 12 to 18 months, we will be in a position to really share some data coming out of those studies.

Just to pause on that. I mean I think that, as Izzy said, the first challenge with these costims, especially with the history in the field using very different reagents that led to nonspecific immune activation and toxicity, there was a lot of concern with that. Right now, these costim reagents are behaving as we predicted from the preclinical data so far so good in terms of not showing nonspecific activation of the immune system. Once we dose escalate to the effective doses, the thing that I think we find so exciting is we will probably have 2, 3 or 4 of these costims ready at those doses in the clinic and in combinations with either Libtayo or with their corresponding CD3 bispecifics, whether it be in solid tumors or whether it be in the hematologic malignancies. And we think that this is going to create a very exciting situation where we're going to really see the potential of this new class across all of these various combination and different type of cancer situations. And if the preclinical data hold at all, this could really change the future of immunotherapy in a really meaningful way. And we hope over the next year or so to really start getting that sort of data.

Our next question comes from the line of Ronny Gal from Bernstein.

My question is about the CD28 costims. You've obviously chosen to go with the first trials in cold tumors. You're trying to add efficacy. And you haven't talked yet about trying them as a way to spare either the use of Libtayo or CD3 bispecific unless it removed side effects in tumors that are responsive to those agents. And at least hypothetically, it seems like they should be able to do that as well. Any thought on this? Why has that not been a path to pursue? Or is it you simply just stepping in the order that makes sense?

So can I -- let me explain something about -- George touched on one of the issues that has to do with safety, which is that we want to be sure we do not trigger a broad cytokine release syndrome. But the other thing to remember is the mechanism of this class. It's unlikely for this to be a stand-alone therapy. Because what we're triggering here with the costim is signal 2. And if you trigger signal 2 on a T cell without having signal 1, it doesn't do much. It's like pressing on the gas without turning on the ignition is the sort of general analog -- metaphor that people use for cars. So either you have an engine running and you want to push on the gas harder with the CD28 or you want to release the brake that's going on with PD-1. So we don't see the CD28 costim as a stand-alone. We see it as augmenting either anti-PD-1 or CD3 bispecifics or, as I also commented, in principle, like there's no reason to think that couldn't all 3 be used. But the point is they will require most likely a partner. I hope that answers your question.

Well, I think another part of Ronny's question, which maybe I'll try to take on, is that we are certainly trying them. So for example, let's say, if we have a heme malignancy. Andres showed the pretty impressive data in advanced aggressive lymphoma, where we're getting near 60% response rates with similar complete response rates. That's great. We are trying them initially in the nonresponsive patients or we will be trying combinations initially in the nonresponsive patients. But presuming that we see activity there, of course, we would want to then move it in upfront combination because that would imply that if you are helping the people who either don't respond or don't respond completely, then it makes sense to be giving that upfront. So for sure, we are thinking eventually of employing these upfront with either the PD-1 combination or with the CD3 combination to make their initial activities even more impressive than where they are now in terms of both the numbers and the depth of the responses. And of course, I mean this is all pending things going well, these would then be used together in these earlier lines of therapy, but we will initially be exploring them in the patients who have probably failed the single therapies.

And I'd just add in addition that you asked also whether we're specifically going for tumors that don't typically respond to PD-1, well, that's an easy place to see a signal. But eGFRxCD28, for example, can be tested in lung cancer, in head and neck cancer, in a number of tumors where we know that there are responses that could augment what you already see with PD-1 blockade. So that's certainly on the table.

Our next question comes from the line of Geoff Meacham from Bank of America.

This is Alec on for Geoff. So a 2-part question on odronextamab. Curious whether you've seen any COVID-related disruptions in enrollment or follow-up in the Phase II or in launch of the Phase III study. And you said that the Phase II is potentially registrational. You're launching multiple Phase IIIs. So I guess in terms of your thoughts towards timing of filing with the FDA, do you intend to approach the FDA once the Phase II completes? Or do you think you'll wait until data from the OLYMPIA studies becomes available for the ultimate submission?

Okay. Andres?

Yes. Thank you for your question. So I'll address both parts. The first one I want to address is the timing of our potential filing. As you know, lifted the -- or the agency has lifted the partial clinical hold. Accrual is being resumed. And we still think that if everything goes well, we could potentially be in line for or consider filing in the 2022 time frame, although this may change depending on the speed in which we ramp up accrual. On your question concerning the level of efficacy activity and what data we will be filing with, I would say that we believe that our pivotal study currently ongoing and the data that this emerging, considering what we observed in our Phase I dose escalation study, we remain in line with the depth and durability of those responses, this data may suffice to file and not needing to wait for the confirmatory studies in Phase III. So that's one part. And the other one you asked the question on COVID-19 delaying or not our accrual to the studies. I have to say that we have observed very little impact in this patient population with very high unmet medical need. So to date, that has not been an issue in terms of rate of accruals.

Our next question comes from the line of Hartaj Singh from Oppenheimer.

Great. Just a quick question on just the overall area. We sometimes get pushback from investors about the investments that Regeneron is making into oncology. We've been behind over the last couple of years. Monotherapy trials are now about 15% to 20% of the overall PD-1, PD-L1 trials. Combos are far greater. Also, the pace of recruitment of patients seems to be decreasing in these trials. There's over 4,400 of them. So maybe you could just talk a little bit about how you think about Libtayo mono going forward. Which tumors are important to you? Just -- if you can just frame for us where, from an investor perspective, the greatest returns could occur over the next couple of years.

Well, I think that we're ones who certainly believe in track record. And as you said, there's been thousands and thousands of PD-1 trials using a whole assortment of different approaches, but very few have actually produced first-in-class approvable data in new indications that hadn't been appreciated before. And I think that the track record for the team in terms of making these decisions for the monotherapy indications speaks volumes to this point. Thousands of trials, how was it missed about continuous squamous cell carcinoma, which is a $1 billion opportunity? Well, we think the same may be true for basal cell carcinoma. And of course, now we're extending these positions in dermato-oncology with the key right combinations. It's not just about mass action with combinations. It's about correctly picking and targeting the right cancers and the right combinations. And I think that our team has shown an incredible ability to strategize and pick the right settings in which to do monotherapy trials and the right settings to do combinations. And we have a really unprecedented toolkit for allowing rational combination design. By combining, we have a whole series now of molecules targeting lung cancer, a whole series of molecules targeting ovarian, prostate, the different hematological settings. And these will be rolled out in a very sensible and logical strategy, one that has -- obviously has a great track record for success historically in the past. And we think we will continue to have a great chance of showing that going forward because these will be rational, logical approaches, a team that has shown the ability to really predict the future pretty well and to create these opportunities that allow for these very precise but logical mix-and-match approaches, we think, with a high chance of success. But with many of these mix-and-match strategies, we think it also gives us the right opportunities in terms of numbers as well. So we think we'll learn which approaches work best for liquid tumors, which approaches work best for solid tumors and so forth. And there's a whole pipeline and portfolio behind these of follow-ons and additional mix-and-match opportunities. So I think it really positions us well to really address a lot of unmet need, obviously, in the cancer space.

So we're going to try to get to 3 more callers, but if you can make your questions quick, that will allow us to accommodate as many as possible.

Our next question comes from the line of Alethia Young from Cantor.

I just wanted you to talk a little bit about the first-line data and the relevance of the stable brain METs in that data set you saw there.

Go ahead, Izzy.

Well, the key point for us was that most first-line registration studies have very stringent requirements for what they allow to enroll. And we replicated in our study what is more commonly done in practice, which is if the patients are radiated and they seem stable clinically, we put them on treatment. And what you can see from the data in the slide is very impressive enhanced survival as well as a very enhanced relative response rate. And it was a small percentage of our study. So it's a total of about 70 or 68 patients. But the data for us demonstrated that, in fact, you might do even better with immunotherapy than chemotherapy if you have brain METs. And it was included in our first-line study as part of the patient population because they're an important component of the patients that show up.

I think it's important to add is that typically -- I think it's important to add that typically, these patients are excluded, in addition because they tend to be the ones with the poorest prognosis who unfortunately progressed and died.

Right.

And despite having these patients in our study, we still produce our overall data that was highly differentiated, I think, from almost all of the other data that's been produced for PD-1 agents in first-line lung cancer, despite including these very historically difficult-to-treat patients. So I think it speaks to these patients, but it also speaks to the overall robustness of our study set since we've included these patients that are historically excluded.

Our next question comes from the line of Yaron Werber from Cowen.

Yes. Izzy, I just wanted to follow up on your earlier comments in cold tumors, you need to remove the brake and you got to step on the gas. And when you look at ovarian or you look at prostate, which one is more important in which? Can you tell it all from the preclinical data? Or is it not predictive enough?

I prefer to tell you from our clinical data when we get it. I mean there's a limit to -- at the end of the day, we like preclinical data. We certainly use it, but what we actually see in the clinic is always trumps whatever your preclinical data is. I think there's reason to believe that both are viable, which is why I even -- I am open to speculating about all 3. But I think there's reasons that -- we'll see.

I think the important point to add about the preclinical data is just that -- I mean -- and of course, it's almost total logical, it goes from the basic principles of T cell biology. But the consistency of the preclinical data is really important. Meaning what? Meaning that if you add signal 2 to signal 1 in all of these models, you almost universally and consistently see increased antitumor efficacy. The same thing when you add either that signal 1 or signal 2 to an anti-PD-1, which removes the PD-1 brake, you also consistently see additional efficacy activity. So the fact that we use what we believe are the most predictive genetically humanized immune system mouse models, the fact that they've been very predictive to date of what we've seen in the clinic, in oncology and in other systems and also the consistency now when we combine signal 1 with signal 2 together or we combine either of them with the anti-PD-1 gives us a lot of rationale to have hope that we're going to see these things in the clinic. And as Izzy said, that's why he's excited about pursuing these various combinations in the solid tumor space and why Andres is excited about pursuing these combinations in the hematologic oncological space.

Our last question comes from the line of Yatin Suneja from Guggenheim Partners.

George, you talked about the importance of efficacy in cancer. Can you maybe touch a little bit more on the safety and tolerability of the PD-1 LAG-3 combo relative to the CTL4A? What is driving that? And how do you envision this playing out as a key differentiator for an add-on approach to PD-1 in various tumor types?

I'm going to just briefly touch on, and then I'll turn it over to Izzy for getting more into the details of it. But I think we all know that one of the concerns with combining CTLA-4 with PD-1 was the relative -- increase in toxicity for the relative lack of bang for the buck that you get in terms of efficacy. You don't see that much of an enhancement of efficacy, but you're sacrificing a lot on the efficacy. It seems that we flipped that ratio with the LAG-3 combination and that we're getting a lot of bang for the buck in terms of efficacy,without the sort of increases in autoimmune toxicity that you saw with the CTLA-4 combo. So Izzy, do you want to amplify on that?

I thought I come off mute. What I would tell you so far is that as we've shared in our data, the only real enhanced rate of toxicity that we've seen is in adrenal insufficiency. And that still is -- it's something similar to what you see with the nivo/IPI combinations. But otherwise, we don't see any enhancements in colitis and pneumonitis and severe rashes, hepatitis, all these things that really made -- make the combination of PD-1 and CTLA-4 a bit tricky to manage as well as not sure it's worth the benefit at the end of the day, although you would try it if you had no options. So we think this is going to create a new option. And so far, the -- it's still early days, but the efficacy is looking quite good. And I would venture to say it's going to be at least as good as nivo would be. So I think what we're coming up with is a combination that can be the next standard for an IO-IO combination.

Thank you, Izzy. Gigi, we're going to close the call at this point?

Thank you. At this time, I would like to turn the call back over to Justin Holko for closing remarks.

Thank you, everyone, for dialing in today. We appreciate your time and attention coming off of a busy ASCO. The IR team will be available after this call to answer any further questions. We apologize to those we did not get to on today's queue. Everyone, have a good night and be safe. Thank you.

This concludes today's conference call. Thank you for participating. You may now disconnect.