Regeneron Pharmaceuticals, Inc. (NASDAQ:REGN) ESMO 2022 Investor Event September 12, 2022 8:00 AM ET
Company Participants
Ryan Crowe – Head, IR
David Weinreich – EVP, Global Clinical Development
Israel Lowy – SVP, Translational Sciences & Oncology
Justin Holko – VP, Global Commercial Business Unit
Conference Call Participants
Brian Abrahams – RBC
Christopher Raymond – Piper Sandler
David Risinger – SVB Securities
Evan Seigerman – BMO
Justin Burns – Barclays
Mohit Bansal – Wells Fargo
Robyn Karnauskas – Truist
Salveen Richter – Goldman Sachs
Tyler Van Buren – Cowen
Yatin Suneja – Guggenheim Partners
Operator
Good day, and thank you for standing by. Welcome to the Regeneron ESMO 2022 Investor Event. [Operator Instructions] Please be advised that today’s conference is being recorded.
I would now like to hand the conference over to your speaker today, Ryan Crowe, Head of Investor Relations. Please go ahead.
Ryan Crowe
Thank you, Catherine. Good morning, good afternoon and good evening to everyone listening around the globe. Welcome to our ESMO 2022 Investor Call.
I would like to remind you that remarks made on this call today include forward-looking statements about Regeneron’s business and research development programs, anticipated milestones and regulatory matters. Each forward-looking statement is subject to risks and uncertainties that could cause the 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 SEC filings. Regeneron does not undertake any obligation to update publicly any forward-looking statements, whether as a result of new information, future events or otherwise.
Joining me today are Dr. David Weinreich, Executive Vice President, Global Clinical Development; Dr. Israel Lowy, Senior Vice President of Translational Sciences and Oncology; and Justin Holko, Vice President, Global Commercial Business Unit, Oncology. After our prepared remarks, we’ll open the call for Q&A.
With that, let me turn the call over to David.
David Weinreich
Thank you, Ryan, and thanks to everyone joining today’s call. Regeneron is committed to becoming a leader in immuno-oncology. Before we focus on ESMO updates, we would like to remind our listeners that Libtayo or cemiplimab, our PD-1 antibody, is foundational to Regeneron’s immuno-oncology development as well as commercialization strategy, as highlighted by our recent acquisition of global rights to Libtayo.
In the past several years, we have achieved considerable milestones in oncology, including approvals for Libtayo in skin cancer indications and for an initial non-small cell lung cancer indication. With regard to our developing pipeline, earlier this summer, we have shared initial encouraging top line data for our costimulatory bispecific in combination with Libtayo, PSMAxCD28, for advanced prostate cancer. And today, we will expand on several exciting ESMO presentations, including updated data for our LAG3 Libtayo combination in PD-1 naive melanoma, our first CD3 bispecific data in solid tumors for MUC16xCD3, as well as first data for our novel MET X MET bispecific in MET-altered lung cancer.
Looking forward in the near term, we have a number of potential upcoming regulatory submissions, approvals and data readouts, both later this year and in 2023. We are anticipating the FDA decision on our Libtayo plus chemotherapy application in a broader non-small cell lung cancer population. We look forward to potential submissions of our hematology oncology bispecifics, pending outcomes of discussions with regulators, odronextamab for advanced follicular lymphoma and diffuse large B-cell lymphoma and BCMAxCD3 for relapsed/refractory multiple myeloma.
For earlier-stage programs, we are planning to share additional costim and CD3 bispecific data for ovarian cancer and eGFR-positive solid tumors, as well as data for our first antibody drug conjugate MET X MET ADC developed for MET-altered lung cancer. Taken together, we believe that Regeneron oncology’s future is bright and that our accelerating development is positioning us well to become a leader in immuno-oncology, mainly by unlocking the power of informed combinations we were able to pursue with Libtayo as a foundation with our unprecedented drug candidate pipeline.
Next slide. Anti-PD-1 therapy has become a standard of care across multiple tumor types and settings. Despite this progress, there are many cancer patients whose tumors do not respond to PD-1 blockade and many other tumor types that have not responded to anti-PD-1 therapy in clinical trials, such as prostate cancer, most breast cancers and ovarian cancer. We are aiming to enhance and extend antitumor responses to immuno-oncology treatments with our scientifically based combination approaches.
Our broad oncology toolkit gives us an unparalleled opportunity to mix and match the best approaches, with the goal of broadening and deepening antitumor activity. On this slide, you can see different categories of investigational medicines in our oncology pipeline, which can be combined with Libtayo. Our CD3 bispecifics, our CD28 or costim bispecifics, our tumor-targeted biparatopic bispecific antibodies and additional immune modulators. In order to better understand how these various combinations may enhance T cell activity against cancer, I’m going to take the next couple of slides to illustrate the role of how these agents play in harnessing the immune system.
Next slide. Until a T cell was emerged in order to fight off viral infections and when a virus infects a normal cell, the virus processes the virus and presents on its cell surface in the context of HLA a viral peptide. Circulating killer T cells recognize that peptide in the context of HLA on the T cell receptor. That interaction in and of itself may not be sufficient to stimulate an immune response. So cells also produce on their surface costimulatory ligands designed to interact with other receptors on the T cell to augment the immune response.
One particular example is the cell surface marker B7, which interacts with the T-cell receptor CD28. If this system went unchecked, the body has a natural compensatory break that prevents this system from going haywire and producing autoimmunity. One such break are these checkpoint inhibitors, where a ligand is produced on the cell surface, such as PD-L1, and it interacts with a receptor, PD-1, to shut off an immune response.
Next slide. When we think of a cold tumor, something in this system isn’t working the same way as when a virus infects a cell. One possibility is that an HLA-restricted tumor peptide isn’t being presented on to the cell surface. So there’s nothing for Signal 1 to engage with. Some tumor cells down-regulate the ligands for the costimulatory receptors, preventing upregulation — preventing interaction and upregulation of the immune system through CD28. Finally, other tumors overexpress the checkpoint inhibitor ligand, causing increased blockade of T-cell activation.
Next slide. So functionally, it looks like this. And each tumor could be harnessing one or multiple different of these approaches to evade the immune system. Next slide. What tumors do that viruses don’t is tumor cells put tumor-specific antigens onto their cell surface. Now they are typically not contained within the context of HLA. So natively, they can’t interact with the T-cell receptor. However, they provide nice targets for us to identify tumor cells and differentiate them from normal cells.
Next slide. And this is exactly what our broad pipeline is attempting to do. Our CD3 bispecifics bind to these tumor antigens and directly interact with the T-cell receptor, thereby replicating Signal 1. Costimulatory bispecs can also bind to a tumor antigen, whether it be the same tumor antigen we might be using for a CD3 or a different one and bind to CD28 to augment that costimulatory response and ramp up the immune system. Finally, antibodies such as Libtayo or our LAG3 can be used to turn off the checkpoint inhibition and remove the brake that some tumors have applied to evade the immune system.
Now we’ve shown preclinically that all 3 of these different approaches can work and work in different contexts. In a little bit, what my colleague Izzy will show is the first clinical validation of the costimulatory bispecific in producing clinically meaningful responses in combination with Libtayo.
Next slide. This is just a quick snapshot at the breadth of our pipeline. And as you can see on the slide, we had prebuilt into even the very first trials the concept of testing various different combinations in order to understand for each tumor type what is necessary to turn what is historically a cold tumor, such as prostate cancer or ovarian cancer, and make immuno-oncology therapies applicable.
With that, I’m going to turn the call over to Izzy.
Israel Lowy
Thank you, David, and bonjour, everyone, from Paris, where we are having a banner year at ESMO with 16 presentations, 5 of which are oral. But before I go into the details of the ESMO presentations, I’d like to take a few minutes to expand on the data that we released a few weeks ago on our costim program in prostate cancer, PSMAxCD28.
This is the first or the most advanced of our 3 clinical-stage costim programs, which, as you can see on the bottom right, is being developed in combination with PSMAxCD3 and with Libtayo. And the first data that we’re going to be talking about is PSMAxCD28 in combination with Libtayo. We were eager to share the clinical data in August because of the compelling clinical evidence that a CD28 costim bispecific was able to turn a prostate cancer cell into an antigen-presenting cell.
And on the bottom left of this slide is an example of some of our preclinical data that gave us the confidence to take these into the clinic. In this humanized mouse model of prostate cancer, neither our anti-PD-1 alone or our PSMAxCD28 can affect tumor growth any better than control. But when the 2 agents are used in combinations, they do so in what is clearly a true synergistic fashion.
Next slide. As disclosed in the August 3 press release with the PSMAxCD28 Libtayo combination in late-stage prostate cancer patients, for the first time, we saw evidence that this mechanism potentially worked as the animal models predicted it would, namely obtaining profound synergy with costim bispecifics and anti-PD-1, which provides, we believe, proof-of-concept in prostate cancer, in particular, and potentially for the entire costim program in general.
Why are we saying this? We’ve seen clear evidence of dose-dependent efficacy and safety events in the course of our trial. And you can see this very clearly on the waterfall plots on the right, where within the first 5 dose levels encompassing 17 patients, we observed minimal antitumor activity as well as no grade 3 or higher immune-related adverse events. In contrast, on the bottom right, you can see that when we started treating at dose level 6 up to the highest dose level 8 that we’ve gotten to, we’ve demonstrated a striking increase in efficacy. And you can see this quite clearly by looking at the number of patients that are below the line.
In one case from cohort 6, the patient has maintained an ongoing apparent complete response that’s 100% prostate-specific antigen or PSA reduction and a complete response in target lesions, including both extra osseous as well as bone lesions now for about a year despite the fact that his treatment has to be stopped because of a grade 3 skin IRE after only a couple of months. At dose level 8, 3 or 4 patients had very deep PSA responses. One of the responders had a grade 3 IRE that resolved, and 1 of the responders had an IRE, which unfortunately resulted in death. But no additional grade 4 IREs or greater than grade 2 CRS has been observed in the trial to date. And I want to highlight that any grade 3 or higher immune-related adverse events that we’ve seen have been associated with antitumor activity, suggesting that the 2 are correlated.
Next slide. In this slide, we give you more detailed information about the striking synergy we’re discussing. In the trial, patients are treated with weekly lead-in doses of PSMAxCD28 for 3 weeks. And then Libtayo is added, as you can see by the boxes and the dotted arrows. And the graphs demonstrate rising PSA between the first and third week, consistent with the fact that the costim by itself will do nothing to mitigate the rise in PSA. But once you add Libtayo, there’s a quick and dramatic drop in PSA.
This is exactly consistent with our preclinical data that showed that the costim bispecific has minimal activity as monotherapy. We also know that in prostate cancer, PD-1 blockade has a less than 10% response rate. And in fact, there have now been 2 recently failed large Phase III trials testing PD-1 in prostate cancer. So this 0 plus 0 adding up to much more than 1 suggests true synergy as, again, we predicted from our preclinical model.
The slide also provides more details of the adverse events observed in these patients and these responders. And we continue now at this point to cautiously explore our dosing as well as safety mitigation efforts so that we can enhance the risk-benefit profile of this promising new medicine.
So back to ESMO, where this is a list of the presentations that we’ve had, and in boxes are the ones that we’re going to discuss in detail, which involves ubamatamab, our MUC16xCD3 in advanced ovarian cancer; Regeneron 5093, which is our MET x MET bispecific in MET-altered lung cancer; neoadjuvant Libtayo in CSCC; and finally, our fianlimab anti-LAG3 and Libtayo combination in advanced melanoma.
Next slide. Continuing along the theme of bispecific programs, ubamatamab is our MUC16xCD3 bispecific developed for advanced ovarian cancer. This is our first data disclosure for a CD3 bispecific in solid tumors. We hope to develop ubamatamab as either a monotherapy or in combination with Libtayo or in combination with a costim, the MUC16, as a highly effective and well-tolerated treatment for ovarian cancer and potentially other MUC16-expressing tumors such as pancreatic or endometrial carcinoma.
On Saturday at ESMO, our investigator presented initial ubamatamab monotherapy clinical data, which I will discuss in greater detail shortly. But the next steps for ubamatamab includes ongoing enrollment of a randomized cohort within our — with a Phase II portion of this clinical trial, where we will explore dose-dependent activity with or without Libtayo, and we look forward to providing further updates on ubamatamab in combination with Libtayo next year as well as in combination with our MUC16 costim.
This slide shows the clinical trial design. And I want to point out where you see the asterisks is that ubamatamab is administered in a step-up fashion to minimize cytokine release syndrome, with an initial low dose on day 1, an intermediate dose on week 2 and the fully targeted dose in week 3 and beyond. We are enrolling a second cohort in this study in combination with Libtayo that’s not shown, and that is trailing the monotherapy cohort in terms of the dose levels we have achieved.
Strikingly, the first in-human monotherapy study enrolled heavily pretreated patients, with a median of 4.5 prior lines of therapy and 33% had confirmed visceral metastases as well as 17% of patients who had primary platinum refractory disease, which is a very tough population to treat. Nonetheless, we were able to observe confirmed partial responses by formal RECIST criteria at doses ranging from 20 milligrams up to 800 milligrams.
As shown on the table on the left, the response rate was a little over 14% in this heavily pretreated population, with a disease control rate of 57%. When you started looking at patients without baseline visceral metastases, the response rate was 21%. And when we looked by immunohistochemistry at the extensive expression of MUC16 on tumor biopsies and looked at those who had the highest level of expression in the top 60% of patients, the response rate goes up to 31%.
But most importantly, looking at the spider plot on the bottom right, you see durable responses. In fact, 2 patients had ongoing responses maintained for more than 15 and 25 months, this, in a setting in which the overall life expectancy can be expected to be less than a year.
When we look at the safety, most of the treatment-emergent adverse events occurred with the initial step-up dosing, which was the objective to minimize cytokine release syndrome and make them manageable, and they were basically low grade. And they were not seen when we went to continued full dosing. The most common adverse events in addition to the cytokine release syndrome were of grade 1 or 2 and also included pain. Grade 3 or more adverse events occurred in about half the patients, with the most common being anemia, abdominal pain and neutropenia.
Moving on to MET x MET. This is a different type of bispecific targeting 2 epitopes or biparatopic on the MET receptor, and it’s designed by binding to these 2 epitopes to disrupt the ability of the MET receptor to transmit signaling in 2 different ways: one, by blocking binding of the ligand that interacts with the MET receptor, as well as promoting efficient MET receptor internalization. Our early data that we presented at ESMO showed efficacy in patients with different classes of MET alterations including exon 14 mutations as well as promising trends of higher efficacy that correlates with higher MET expression, as shown by IHC, an addition in the activity in patients who have progressed on prior anti-PD-1s or on prior tyrosine eGFR-targeted tyrosine kinase inhibitors.
On the waterfall plot here, it shows the MET x MET antitumor activity. And the table on — within the graph shows an analysis done by different cuts of tumor characteristics. They were enriched among patients with MET alterations by central lab assessment as MET also shown in the heat map. Among patients who had a MET exon 14 mutation and were TKI-naive, the response rate was 33%, which provides proof of concept that this bispecific antibody can actually target this MET alteration. Responses were also seen in the 30% range for patients with high levels of MET overexpression and seem to further increase to as high as 50% as we set higher cutoffs by IHC.
Looking at safety, there were no dose-limiting toxicities observed, and Regeneron 5093 demonstrated a similar safety profile in both the dose escalation and expansion phases of the study. A well-known adverse event of MET tyrosine kinase inhibitors is peripheral edema. In our study, we saw only grade 1 or 2 peripheral edema occurring in 9% of patients. Overall, 4% of patients had to discontinue treatment due to a treatment-emergent adverse event.
So by selecting patients with significant MET overexpression, our naked MET x MET may be highly active on its own. But since even modest overexpression may render lung cancer susceptible to this mechanism of action that takes advantage of rapid internalization of the receptor, such as using a MET x MET ADC. This is currently in dose escalation, and we expect initial data to be presented next year.
In principle, the naked or the ADC could also be combined with Libtayo in lung cancer. And this is something we have in mind to explore as we learn more about it. And the safety profile of this drug could also make combinations with other tyrosine kinase inhibitors possible and avoid synergistic toxicity.
Coming back to our stalwart Libtayo. As mentioned earlier, Libtayo is a foundation of our immuno-oncology portfolio. Since its approval and the launch of Libtayo in 2018, we have efficiently executed and firmly established leadership in the non-melanoma dermato-oncology space. Libtayo is currently the standard of care in advanced cutaneous squamous cell carcinoma, as well as in advanced basal cell carcinoma patients previously treated with or ineligible for a hedgehog inhibitor. We are enrolling additional studies in various skin cancer indications in order to potentially help more patients in various stages of these lethal diseases and also using the versatility of our immuno-oncology pipeline.
Our third FDA approval for Libtayo was in first-line non-small cell lung cancer for patients with high PD-L1 expression as a monotherapy, where we are building a commercial presence. As a late-breaking presentation at ESMO yesterday, we presented 3-year follow-up on these Libtayo monotherapy data in lung cancer and showed that the survival benefit actually got stronger over time. Moreover, our presentation was the first to report from a Phase III study, demonstrating that continuing cemiplimab beyond progression with the addition of chemotherapy can provide new and durable responses and contribute to enhanced overall survival, a question that faces many practitioners in trying to figure out how to manage patients with PD-L1 that is greater than 50%.
In the past, we also reported positive Phase III results of cemiplimab in combination with chemotherapy in first-line non-small cell lung cancer regardless of PD-L1 levels, and this study was recently published in Nature Medicine. It’s currently under FDA review, and we look forward to hearing their decision in the near future.
I also want to comment on an indication that’s not featured on this slide. Libtayo was effective in the largest study ever performed in second-line cervical cancer, which is another example of success of this drug. We regret we were not able to agree with the FDA on postapproval commitments for this indication and not being able to make it available to the patients in the U.S. Long-term survival analysis of this study was also presented at ESMO in an oral session.
Moving to the next slide. And now talking about neoadjuvant CSCC, which was presented this morning in an oral session and concomitantly published in the New England Journal of Medicine. Our work in neoadjuvant CSCC is an example of our continued investment into our leadership in skin cancer and also presents a near-term substantial opportunity for Libtayo. Libtayo is the leader in advanced CSCC with no curative option, and there are no currently approved systemic therapies for CSCC in the curative setting. Today, we presented encouraging results from our Phase II study. Regarding next steps, we are talking to regulators about possible pathways for registration and potential inclusion in NCCN guidelines.
Next, please. The majority of patients in this study of Libtayo and neoadjuvant CSCC achieved clinically meaningful pathologic responses. In 79 patients in total, 63% achieved a pathologic response, with 51% being complete pathologic responses and 12.7% as major pathologic responses as seen at surgery. In this setting, Libtayo can potentially make surgery less disfiguring. And I think this is nicely illustrated by the photos on the right.
A 59-year-old woman presented with T3 CSCC involving the right eye area. At baseline, the opinion of the investigator was that an orbital exenteration or removal would be required. Yet after 4 doses of neoadjuvant cemiplimab, the preoperative imaging classified the patient as achieving a partial response per RECIST 1.1, which allowed for the patient to be spared orbital exenteration and surgery. Interestingly, this patient, upon review of the pathologic data, showed actually a complete pathologic response according to independent pathologic review. This is the waterfall plot that I think shows a meaningful response to Libtayo in this setting. And interestingly also, most patients were classified as a partial complete response at surgery, were not classified as a complete response on preoperative imaging.
Next. From a safety point of view, there were no new safety signals observed in this setting. Treatment-emergent adverse events of any grade occurred in 87% of patients. The most common were fatigue, diarrhea, nausea and maculopapular rash, and there were 4 fatal treatment-emergent adverse events highlighted in bold text.
Turning now to our foray into melanoma, moving beyond non-melanoma skin cancers. Really happy to talk about our LAG3 data. It’s important to us because after regulatory approvals of Libtayo and 2 advanced non-melanoma skin cancers, we want to expand our efforts in dermato-oncology and address advanced melanoma. And also this showcases the power of our combinatorial pipeline. Combining LAG3 and PD-1 inhibition has shown promise in advanced melanoma, but achieving response rates above 50% has been challenging, as you can see quoted on the slide from the Opdualag Phase III study.
As seen today at ESMO, in 2 independent dose expansion cohort from a Phase I clinical trial of melanoma patients naive to PD-1 or PD-L1 inhibitors, which effectively provides for a test and retest confirmation, our LAG3 inhibitor, fianlimab, combined with Libtayo demonstrated greater than 60% response rates, with a median duration of response which was not yet reached. The median PFS has been estimated at 24 months, and this compares favorably with that of 10.2 months seen in the Opdualag study. The safety profile of the combination appears in line with anti-PD-1 monotherapy.
Here is the waterfall plot of data from the 2 naive melanoma cohorts combined, which shows an overall ORR of 63.8% and with 76% of patients having any level of tumor reduction, and you can also see the details in the test and retest cohorts on the table on the right. Responses were seen in all subgroups of patients, including those with liver, lung and other metastases. This Kaplan-Meier plot demonstrates a median progression-free survival at 24 months, and median progression-free survival at 1 year was 55%. Responses were rapid, deep and durable in patients who had initial stability, and the median duration of response has not been reached.
While not shown on these slides, meaningful clinical activity was observed in all cohorts regardless of PD-L1 and LAG3 expression. The combination was shown to be safe, with the toxicity profile similar to that previously reported for anti-PD-1 or anti-PD-L1 therapies. The rate of treatment-related adverse events of grade 3 or higher among the anti-PD-L1 naive patients was 20%. Rate of discontinuation was 15%. There were 2 grade 5 treatment-emergent related adverse events. One was an instance of colitis, and one patient experienced cardiac shock. There was no evidence, however, of myocarditis. In the anti-PD-L1 naive population, immune-mediated adverse events were usually grade 1 to 2 and manageable, with no novel immune-related adverse events.
So in summary, our initial results in melanoma are just the beginning for the development of the fianlimab-Libtayo combination as we have a robust clinical program ongoing for what we believe to be a potentially best-in-class agent. In addition to the first in-human studies we updated today, a fianlimab plus Libtayo Phase III trial in first-line metastatic melanoma is currently enrolling patients, and a Phase III study in adjuvant melanoma will initiate soon.
Later this year, we will share data from the same first in-human study for a non-small cell lung cancer cohort, where we have the potential to be the first-in-class. In addition, we are exploring several other indications, which we believe is worthwhile to benefit patients. Most imminently, we are expecting data from the I-SPY trial, which explores fianlimab, Libtayo and paclitaxel combination in neoadjuvant breast cancer. Taken together, this robust development program for fianlimab plus Libtayo has potential to differentiate on efficacy as well as safety in comparison to the current standard of care regimens for these indications.
In summary, these ESMO updates and our other recent initial data on the costims that we shared this year help put into perspective the extensive promise of our unique pipeline, which has been designed from the outset to facilitate an almost plug-and-play combinatorial flexibility to benefit patients.
And with that, I will turn it back over to you, David.
David Weinreich
Thanks, Izzy. I want to briefly touch upon our hematology-oncology portfolio. Odronextamab, our CD20xCD3 antibody, has the potential to be the first CD20xCD3 bispec to be approved for both follicular lymphoma and diffuse large B-cell lymphoma. As we mentioned in our recent quarterly earnings call, based on interim data from a cohort of patients dosed with our modified step-up regimen, we believe odronextamab may have the lowest rates of grade 3 or higher cytokine release syndrome for this class of bispecifics in follicular lymphoma and diffuse large B-cell lymphoma while maintaining the efficacy profile previously reported. We look forward to presenting these updated odronextamab data soon and potentially submitting a BLA for both indications in the second half of this year, pending feedback from the FDA.
We also plan to share updated data for our BCMAxCD3 bispecific in relapsed or refractory multiple myeloma by the end of the year. Pending regulatory feedback, we are planning to submit for regulatory approval in 2023. An umbrella study in multiple myeloma investigating BCMAxCD3 in combination with various standard of care products and investigational candidates is now open to enrollment while we plan to initiate an additional study in earlier lines of multiple myeloma later this year.
Next slide. As summarized on this final slide, numerous regulatory and data milestones from this year are just the beginning. In addition to upcoming hem portfolio data at ASH and PSMAxCD28 prostate cancer presentation in an upcoming medical meeting, next year, we are expecting to see initial data from several combinations in ovarian cancer, eGFR-positive solid tumors, MET-altered lung cancer, just to name a few.
In 2024 and beyond, we are expecting to see further readouts in first-line melanoma, adjuvant melanoma and additional modalities in prostate cancer. Regeneron’s oncology engine is truly firing on all cylinders. With Libtayo as the foundation and seemingly endless opportunities for rational pipeline combinations, we are looking forward to helping even more patients in the future. Concluding with a high-level summary of the most impactful ESMO and other updates we discuss today.
And with that, I’ll turn the call back over to Ryan.
Ryan Crowe
Thank you. That concludes our prepared remarks. [Operator Instructions] Catherine, could you now please poll for questions?
Question-and-Answer Session
Operator
[Operator Instructions] Our first question comes from Evan Seigerman with BMO.
Evan Seigerman
Congrats on the data presented at ESMO. Just taking a step back, aside from Libtayo, I know that’s the backbone, what do you view as the most promising project or tumor types among all of your efforts? And where do you believe investors should be most focused on as your oncology franchise continues to unfold?
David Weinreich
So thank you for the question. I think there’s 3 things that I would focus individuals on. The 2 near-term oncology assets are going to be odronextamab and fianlimab. Just in terms of timing, those are going to be the 2 next big swing points for which we already have very strong Phase II data in hand. But the third one, I think, is what Izzy led off with regarding our PSMAxCD28. For a while, this portfolio of costims has been restricted to positive animal data, but historically, we know that in oncology, positive animal studies don’t necessarily translate to clinical activity.
We now have pretty convincing data that this costimulatory platform, our animal models, are predictive of what’s going to happen in the clinic. And we have many of these CD28s. And I think the likelihood that these are going to work has gone dramatically up. And I think that is a portfolio change for an investor looking at our oncology pipeline as a whole.
Operator
We have a question from Tyler Van Buren with Cowen.
Tyler Van Buren
Congratulations on the recent high-dose EYLEA data. On fianlimab/Libtayo, the data appeared much better than Opdualag. So how quickly can you get to market? And how confident are you competing in the space versus BMS who is fairly entrenched?
Ryan Crowe
Thanks, Tyler. Izzy, why don’t you take that one?
Israel Lowy
Sure. Well, we’re ramping up a Phase III clinical trial in advanced melanoma, where, yes, we will be behind BMS since they are approved. But what we believe is that we have potentially best-in-class data. So we’ll see how that works out.
In terms of adjuvant melanoma, we’re not very far behind. And so I think we’re contemporaneous with the rest of the field. And we’re exploring other indications, in particular, in areas like lung cancer, where we already have Libtayo established and hopefully soon to be established not only as monotherapy but in combination with chemotherapy and has a nice combination in the first-line setting.
So although we’re enrolling, I’m not going to give a forward-looking statement of exactly when I expect the trial to read out. But we’re hoping by 2024, we’ll at least have some information from the early stages of the trial that support our investment in this combination.
Operator
We have a question from Salveen Richter from Goldman Sachs.
Salveen Richter
On the MET x MET program, you talked about looking to combine it with Libtayo. Just maybe help us understand the strategy there and then on the ADC program that you’re taking a look at as well.
Ryan Crowe
Izzy, do you want to take that one as well?
Israel Lowy
Sure. Thank you for that. So let me take the ADC first. What we were very pleased to see with our MET x MET naked program was single-agent activity in advanced lung cancer patients with MET alterations. As I described, we were — the response rate seems to go up with higher levels of expression. But we expect with the ADC — or we hope with the ADC that we’ll be able to effectively target patients with lower levels of elevated expression of MET receptor by virtue of the fact that the MET x MET bispecific enhances receptor internalization and will be a very efficient way to deliver the antibody-drug conjugate.
There is data suggesting that PD-L1 positive tumors can be seen in a fair number of patients with MET x MET — with MET alteration. And so this is an area we are continuing to explore. What is striking to us was also that in our MET x MET monotherapy cohorts, we saw responses in patients who had previously progressed on anti-PD-1 or PD-L1 therapy.
Operator
And we have a question from Brian Abrahams from RBC.
Brian Abrahams
Congrats as well on all the progress of the oncology portfolio. On the MUC16 ubamatamab, it looked like you saw solid responses, although you didn’t see substantial additional benefit with doses above 20 milligrams. So I guess I’m curious to the degree to which this may relate to heterogeneity in tumor T cell infiltration intrinsic to ovarian cancer, the degree to which PD-1 combos and/or CD28 elements could potentially overcome this and then, given all that, how you’re thinking about go-forward dosing.
Ryan Crowe
Izzy?
Israel Lowy
Thank you for that question. So you’re right. We do see real responses in this very advanced population of patients who are heavily pretreated. And to date, in the limited numbers of patients that we’ve treated across different dose levels, we have yet to discern any clear dose response. So in fact, the Phase II portion of our study will interrogate that question. Two very different doses, threefold difference in dosing will be tested one against the other. And the third cohort will test that lower dose in combination with cemiplimab so that we can actually address clearly whether or not there is a — what the right dose would be.
You bring up a very interesting question as to whether there’s heterogeneity in terms of what the cellular immune capabilities are of patients when they’re exposed to a CD3 bispecific. And that’s a very good question worth investigating, which is a separate issue. But what we’re really excited about is the fact that as a monotherapy of MUC16xCD3 in the solid tumor, we’re seeing real responses, and we have multiple mechanisms at our disposal to try to augment that, one with Libtayo and one with MUC16xCD28, the costim for ovarian cancer, which is already in clinical trials and where we have already begun dosing the combination of the CD28 costim with Libtayo as well as the first in the field, I believe, of a CD28 costim in combination with the CD3 bispecific.
So this is where we are bringing in our plug-and-play combinatorial flexibility to see what we can do to further enhance activity. So we need to do better on activity. Even though if we look at the IHC-selected population, we’re running at a 30% type of response rate, which is quite respectable in this advanced line. But we have I think at our — in our disposal, we have the opportunity to enhance responses even further.
Operator
We have a question from Carter Gould with Barclays.
Justin Burns
Yes. This is Justin on for Carter. Congrats on all the updates and progress over the weekend. During the fianlimab presentation, the discussion alluded to movement of the LAG3 PD-1 combos into the adjuvant setting. We’re just wondering if you’re going to have to wait for the Phase III readout in the metastatic setting before starting the adjuvant trial? Or are there things you can do to shorten the time lines there?
Ryan Crowe
Thanks, Justin. Izzy, can you answer that one, please?
Israel Lowy
We are not waiting.
Ryan Crowe
That’s right. In fact, we intend to begin enrollment later this year in our adjuvant study with the fianlimab-cemiplimab combination.
Operator
And our next question comes from Christopher Raymond with Piper Sandler.
Christopher Raymond
Just another question on ubamatamab. So I think — I know you guys have a decent set of data, the higher the MUC16 expression, sort of the better the response. But I’m not totally clear. I know these were refractory patients. What line of therapy were these responders in? I know it was the — median line of therapy was 4.5. But was there any sort of distribution that was notable?
Israel Lowy
It was across the board. It was across the board. There were some that had many lines and some that had only a couple.
Operator
We have a question from David Risinger with SVB Securities.
David Risinger
Let me add my congrats as well. So with respect to the MET x MET in non-small cell lung cancer, I believe you mentioned that there was a 34% response rate in MET-expressers and TKI-naive patients. So in light of that, could you remind us about how you’re thinking about the MET x MET opportunity in non-small cell lung cancer in both TKI-naive and TKI-experienced patients? And also, if you could frame how you plan to run a Phase III first-line study in what patient populations.
Ryan Crowe
Izzy, can you take that one, please?
Israel Lowy
Sure. So I would say it’s a little premature for me to say exactly how we’ll run our Phase III first-line study. And there are a number of possibilities for us to move this forward. As I mentioned during the talk, we could potentially combine the ADC. We could combine the setting. We saw data, actually today, people talking about adding MET tyrosine kinase inhibitors on top of eGFR tyrosine kinase inhibitors and patients who have progressed on the eGFR and who are escaping by virtue of MET receptor or MET pathway upregulation. We think the MET x MET antibody added to a TKI is likely to have a superior safety profile, although I can’t guarantee that, because based on what we’ve seen so far. So we’re still in early stages of defining exactly how we’ll move this forward. But we have several possibilities in front of us.
Operator
We have a question from Mohit Bansal with Wells Fargo.
Mohit Bansal
Congrats on the data. Maybe a question from both clinical and commercial angle. If you look at the development of PD-1/L1 inhibitors lately, they’re all going in earlier lines of treatment. Now Regeneron being the fast follower here, do you see opportunity to do trials in adjuvant and new adjuvant settings of these various cancers? And I think I want to bring in Justin as well. As you negotiate these contracts, how important it is at this point to get — to be in those earlier lines given that most of the [indiscernible] growth is actually coming from those lines now?
Ryan Crowe
Thanks, Mohit. Justin, you want to start?
Justin Holko
Thanks for the question, Mohit. We generally don’t comment on anything contracting-related. I think, more importantly, we’re just excited to be in the market today. We’re the leading non-melanoma skin cancer treatments. We’re getting a lot of good traction in lung cancer. I would just say, more broadly, we’re realizing our vision of becoming a global oncology leader. And much of that is here at the European Society for Medical Oncology. And that’s a vision that many of us saw years ago, which compelled us to come here. And I’ve spent a lot of time with customers in the field at ESMO, and they’re really beginning to take notice of Regeneron. And you can see that in terms of what Izzy presented today.
We’re attracting a strong team of commercial professionals who have deep experience in building these immuno-oncology franchises. And beyond that, in lung cancer specifically, Mohit, people recognize the strength of our clinical profile and everything we’re bringing to the table. And in fact, we’re the preferred PD-1 in some major institutions around the country. So we know it’s a competitive market. We’re competing today, and we’re hopeful for this approval here in the next several weeks to be able to launch in the broader lung cancer population.
Israel Lowy
Yes, let me just add on to that, that we just presented today neoadjuvant data in CSCC. So we’re in the neoadjuvant space. And we are doing a neoadjuvant study with I-SPY. And we’re doing an adjuvant Phase III in CSCC. That is ongoing as well. So we’re already there, but I want to actually build upon what Justin said. Often, analysts look at things quarter-by-quarter, which I understand. But we took a long-term view of building an integrated immuno-oncology portfolio when we set out to get involved in this field. And we have a long view in mind. And that long view in mind was to build an integrated combinatorial approach because that’s the way the immune system works.
You don’t work with one antibody. You don’t work with one T cell. You recognize multiple epitopes. You bring to bear multiple modalities. And that’s also the most successful treatment of cancer has been with multiple modalities. So what we believe we’re demonstrating today is execution on that vision. We started first with bringing forward a Libtayo PD-1 that gives us the flexibility and the ability to bring forward a best-in-class — or equivalent to best-in-class anti-PD-1 to serve as a foundational component. And what we’re demonstrating at this ESMO is our investment and long-term planning is showing fruit. And we expect — we’re just at the beginning, and we expect to show more.
Ryan Crowe
Catherine, we have time for 2 more.
Operator
Our next question comes from Robyn Karnauskas with Truist.
Robyn Karnauskas
Congrats on all the data. Maybe you could just expand on the patient demographics for your LAG3 combo study given the impressive responses that you’re seeing, specifically maybe the LAG3 expression and PD-1 expression. And just a follow-up to that, just could you give us any more color on to why you think what’s different about your LAG3 antibody that you think would be causing such a different effect?
Ryan Crowe
Izzy, can you take that one?
Israel Lowy
So we have — in our presentation today, we showed data around the PD-L1 and LAG3 IHC, and we were able to show efficacy across all strata of LAG3 and PD-L1 expression, whether they were — even if they were low in both, we were able to see activity, although numerically, the activity was a little lower than it was when both were high. So there is probably some continuum there, but across the board, we had a 60% — over 60% response rate. Other demographics of the patients, these were naive, obviously, to PD-1. But these were not cherry-picked patients. These were patients who had liver mets. These were patients who had elevated LDH and M1c disease. And so these were the typical patients that need in this setting.
What was the other question?
Robyn Karnauskas
Just from the biology standpoint [indiscernible].
Israel Lowy
Biology, yes. So I think it’s possible. I don’t know that why the BMS LAG3 antibody has a lower response rate or their PFS seems a little shorter. I will acknowledge that this is just a total of 80 patients versus a large Phase III. So I’m not going to swear to it. But it’s possible also that the doses at which we’re administering our LAG3 might be achieving a more effective blockade of LAG3 target than has been done in the BMS experience. And we understand actually that what we’ve heard is that BMS is, in fact, exploring higher doses.
David Weinreich
Robyn, this is David. If I can just add one other thing. If you look into the PD-1, PD-L1 landscape, there are certainly differences between these assets. So we don’t exactly understand the biological rationale. If you look at Libtayo, it’s the only — it’s only 1 of 2 PD-1 antibodies that has succeeded in both the chemo combo non-small cell lung cancer and in monotherapy. And there have been other PD-1s and PD-L1s that have either not succeeded at all or succeeded in only one or the other setting. And we don’t understand exactly why the biology is that explains that. Izzy’s right. It may be dose. It may be something else, but we do have test, retest data in 2 separate cohorts. And Izzy showed you the data in — for our LAG3 fianlimab in combination with cemiplimab in melanoma. And we’re quite confident it’s a strong combination.
Operator
Our last question comes from Yatin Suneja with Guggenheim Partners.
Yatin Suneja
Just a broader question on the bispecific safety and tolerability profile. Can you just touch on it a little bit? How do you envision that playing out as a differentiation as you add on PD-1? Obviously, you are applying some of the learnings from the CD20 CD program by using a step-up dosing paradigm. Is there any efficacy trade-off with that strategy? Would love to hear a little bit about that.
Ryan Crowe
Why don’t we have David to start with that and perhaps Izzy can add?
David Weinreich
So the short answer is, no, there does not appear to be an efficacy trade-off with our modified step-up regimen. You have to understand we were the pioneers in this space many years ago, and we introduced the step-up regimen for the CD3 bispecifics. And if you look at the toxicity from this class of agent, I’ll break it down into 2 components. One is cytokine release syndrome. And that, for the most part, all occurs very, very early, only in the first couple of weeks as you’re introducing the drug. The modified step-up regimen that we implemented in the CD20 program only as 1 extra week to get to the full dose. And just biologically speaking, it would be very unexpected for a 1-week delay to result in a marked difference in efficacy. And you’ll see that data when we present it later this year.
In terms of the addition of cemiplimab, the one thing that we learned, and we learned it quite early, was that because of the cytokine release syndrome, you don’t want to give a CD3 bispecific immediately with PD-1. You want to get through the CRS period and then talk about introducing a PD-1. And if you — and we plan on exploring that combination in the CD20 program also later this year.
Israel Lowy
Yes. I can add to that, that in our MUC16 — by the way, I want to complement all the people that were able to pronounce ubamatamab. That was very — I’m very gratified. But ubamatamab study, we’re also doing a cohort in combination with cemiplimab. And the way we do it is actually, as David outlined, from our lessons from the CD20xCD3, we get through the initial step-up dosing and apply the target dose, and then we add cemiplimab. And doing that, so far, so good, we have not had any issues with the addition of cemiplimab on top of the MUC16xCD3 bispecific.
So I think one of the other things we’ve also learned is that these things will vary from one agent to another. So David may want to comment more, but I think in the BCMAxCD3 program, it’s another hematologic CD3, but the profile of CRS and toxicity is much easier to manage than the — and requires less work than the CD20xCD3. So I think it’s individual. We learn from each program that we do how to do things wisely. And we are in a constant learning and improving kind of modality.
Ryan Crowe
Okay. Thanks, Izzy, and thanks, David. I think that concludes the call. Catherine, can you wind this down for us? Thank you.
Operator
This concludes today’s conference call. Thank you for participating. You may now disconnect. Everyone, have a great day.
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