Good day, and thank you for standing by. Welcome to the Regeneron Pharmaceuticals ESMO 2024 Investor Conference Call. My name is Kevin, and I'll be your operator for today's call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there'll be a question-and-answer session. To ask a question during the session, you'll need to press star one one on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star one one again. Please note this conference is being recorded. I would now like to turn the call over to Mark Hudson, Director of Investor Relations. You may begin.
Thank you, Kevin. Good morning, good afternoon, and good evening to everyone listening around the globe. Welcome to our ESMO 2024 Investor Call. I'd like to remind you that remarks made on this call today include forward-looking statements about 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 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. George Yancopoulos, Board Co-Chair, Co-Founder, President, and Chief Scientific Officer, Dr. Izzy Lowy, Senior Vice President, Translational and Clinical Sciences, Oncology, Dr.
Andres Sirulnik, Senior Vice President, Hematology Clinical Development, and Justin Holko, Senior Vice President, Global Oncology and Hematology Commercial. On today's call, George will provide an overview of our progress toward becoming a global oncology leader and Regeneron's differentiated discovery and development approach, which has generated a pipeline of novel targets across solid and hematologic cancers. Izzy and Andres will then provide select updates across our clinical pipeline, highlighting data presented across oncology programs in 2024 and outlining the path forward for our robust oncology pipeline. Finally, Justin will provide an update on Libtayo commercial performance and the ongoing build-out of our global commercial organization. After our prepared remarks, we'll open up the call for Q&A. I'll pass along the call now to George. George?
Thank you, Mark, and thanks to everyone joining today's call. Our overall oncology strategy is primarily focused on using the body's immune system to fight cancer. Using our deep understanding of human genetics and the immune system, together with a variety of our pioneering technology platforms, we have internally developed and clinically validated multiple independent classes of immuno-oncology agents, with each class modulating the immune system in slightly different ways, enabling combinations that could augment antitumor activity. Our checkpoint inhibitors, including our PD-L1 antibody Libtayo, or cemiplimab, and our LAG-3 antibody, fianlimab, are designed to overcome T-cell suppression, thereby empowering T-cells to kill tumors. Our CD3 bispecifics bridge T-cells to tumors, enabling the T-cells to kill the cancer cells. Regeneron has been a pioneer in this class, being the first group to treat patients with a full-length, fully human CD3 bispecific.
We now have a growing pipeline of CD3 bispecifics for solid and hematologic cancers, with our most advanced programs in the regulatory stages. Our CD20xCD3 bispecific, also known as odronextamab, was recently approved in Europe under the brand name Ordspono for follicular lymphoma and for diffuse large B-cell lymphoma, and our BCMAxCD3 bispecific, or linvoseltamab, which is currently under FDA and EMA review for multiple myeloma. Finally, our third class of clinical agents are our costimulatory bispecifics, which currently has four programs in the clinic and more soon to enter, designed to enhance antitumor activity when combined with either our checkpoint inhibitors or our CD3 bispecifics. Regeneron was also the first to introduce costimulatory bispecifics to treat patients.
Formation of Regeneron Cell Medicines, following our April twenty twenty-four acquisition of 2seventy bio's pipeline of cell therapies, complements Regeneron's pipeline of immuno-oncology antibodies, allowing us to develop potentially transformative combinations. And beyond that, we will soon start clinical investigations of additional classes of immuno, immunomodulatory therapies, including our targeted cytokines. Next slide. It's the unique flexibility of our pipeline that differentiates our oncology approach. Our immuno-oncology efforts were prospectively designed so that the various individual agents could be rationally combined with the goal of maximizing antitumor responses, resulting in a very broad and multifaceted portfolio of combinations. And these are the programs that we'll highlight today. The innovative oncology assets in clinical development at Regeneron comprise nearly half of our pipeline across over 30 solid and blood cancers.
These almost entirely homegrown assets enable us to devise rational investigational combinations, which we believe give us the opportunity to change the treatment of cancer. With that, I'll turn it over to Izzy Lowy.
Thank you, George, and greetings to everyone on the call. The rest of us are here in Barcelona at ESMO, where we've been showing our data and meeting with investigators and having a lot of excitement. I'd like to turn to our pipeline. Next slide. So Libtayo is has provided for us a best-in-class foundation for combination with other oncology assets. It was first approved by the FDA in 2018 for advanced cutaneous squamous cell carcinoma, and it is the first antibody that was approved in this indication. Following that, also in basal cell carcinoma, where we have established the leading presence in treatment of non-melanoma skin cancers. We've demonstrated a commitment to this area with an adjuvant program underway that will be reading out an interim analysis by the end of this year.
And we also presented a year ago practice-changing data in the neoadjuvant setting, where our approach to giving neoadjuvant Libtayo in patients with operable cutaneous squamous cell carcinoma has become a new standard of care. We have also developed and gotten approval for Libtayo in lung cancer, and we are one of PD-L1 or PD-1 agents that have approval in the first-line setting as both a monotherapy or in combination with chemotherapy across squamous and non-squamous histologies. At World Lung Cancer, on the next slide, just before ESMO, we were able to present our five-year long-term survival benefit from our first approval study of monotherapy of Libtayo versus chemotherapy from the EMPOWER-Lung study.
And it evaluated Libtayo as a first-line treatment for adults with either squamous or non-squamous advanced non-small cell lung cancer with elevated greater than 50% PD-L1 expression. The presentation was a late-breaking presentation that showed that at Libtayo the monotherapy nearly doubled the median overall survival and reduced the risk of death by 41% compared to chemotherapy. The median survival of 26 months, double that of 13 months, and the 5-year survival rate also doubling at 30% versus 15%. Next slide. The 5-year outcome data compares favorable in cross-trial comparisons to other PD-1 or PD-L1 antibodies and further supports our position for this to be a backbone for our oncology portfolio.
In this slide, we show that the data that we saw at our one-year analysis remained consistent at our five-year analysis, with hazard ratios being preserved and with confidence intervals contracting as our precision around the measurements increased, and the duration of our response also became as long as 24 months with a longer follow-up. In this study we also developed new important data to help doctors manage patients in the first-line setting when they're facing a choice of either giving monotherapy or monotherapy in combination with chemotherapy. We showed in a non-randomized way that patients who started with monotherapy and then subsequently progressed, could achieve a benefit by the addition of chemotherapy with preserved treatment with Libtayo, offering some confidence to providers that they are not missing out by choosing to give monotherapy upfront.
And this study was one of the few trials to evaluate this in a prospective way. In conclusion, Libtayo's maturing clinical profile across multiple cancer settings has established it as a strong agent in its own right, as well as a strong foundation for our oncology portfolio. Next slide. I'd like to now turn to our work with our LAG-3 inhibitor, fianlimab. While PD-L1, the introduction of PD-L1 has been an amazing progression in the field, obviously there's a lot of work that needs to be done to further improve efficacy, even in the tumors that respond, and certainly in the tumors that don't.
And we worked very hard to figure out what we could add to cemiplimab. And our early clinical data in metastatic melanoma suggested that LAG-3 blockade with fianlimab plus cemiplimab might be an unusual combination that would demonstrate meaningful additive benefit and without the cost of exacerbating safety. At this ESMO conference, we presented new two-year results evaluating the combination of fianlimab and Libtayo in adults with advanced melanoma, pooling three independent expansion cohorts from our first-in-human multi-cohort study. The combination is being further studied in an ongoing randomized phase III study of fianlimab and Libtayo versus pembrolizumab monotherapy in previously untreated, unresectable, locally advanced or metastatic melanoma. This pivotal study has been enrolling briskly and is expected to read out sometime next year. In addition, we are also in melanoma, studying the utility of fianlimab and cemiplimab in the adjuvant setting and in the perioperative setting.
And we have also mounted a study comparing in first-line metastatic melanoma head-to-head against the current standard of care approved PD-L1/LAG-3 combination, to demonstrate that our combination is at least as good, if not superior, to what's out there. Next slide. With longer follow-up of the initial cohorts, fianlimab and Libtayo continue to demonstrate encouraging antitumor activity in advanced melanoma patients. Now, with a median follow-up of 23 months and a median treatment duration of 35 weeks, the results show persistent and deepening tumor responses across all three independent cohorts. And you can see in the pooled analysis, the last column on the right of the table, that our objective response rate overall is 57%, and including a development of a 25% complete response rate, 24 of 98 patients.
This complete response rate has evolved and emerged over time, when in our earlier cuts it was more on the order of 12-15%. And in fact, it is this durability, as highlighted on the next slide, where you can see the spider plots. Next slide, please. Showing that the benefits, once they occur, are rock solid and persist out well beyond the treatment duration, even in patients with stable disease. And this actually has emerged as a theme that we see in our experience with this combination, that patients, once they respond, appear to develop durable responses. Robust clinical activity was observed also in subpopulations, where one might expect weaker results and there is currently no established standard of care, such as patients who were previously treated with anti-PD-L1 in the adjuvant or the neoadjuvant setting.
Here, six out of 13 patients who had previously been treated with PD-L1 in that setting responded to therapy for an ORR of 46%. Overall, anyone who had had any type of adjuvant, 11 out of 23, also close to 50%, had benefit from the combination. The safety profile on the next slide showed that the combination was generally well tolerated, consistent with the safety profile of Libtayo monotherapy and other PD-L1 agents. The one notable exception was a slightly higher rate of adrenal insufficiency, with 12% of patients, of which 5% were at grade three. What was striking was in those 12 patients who had the adrenal insufficiency, we had a 92% overall response rate, suggesting that there is something linked between that particular adverse event and efficacy.
Overall, adverse events of any grade occurred in 95% of patients. Grade three or greater or immune-mediated adverse events were in 47%, and high grade were in 13%. AEs leading to death occurred in 7 patients, two were considered treatment-related. On the next slide, we show some cross-trial comparisons, understanding the caveats of such comparisons, but as you can see, based on the preliminary proof of concept data from the three independent cohorts that we presented with long-term follow-up, we have nearly doubled the complete response rate compared to other PD-1 monotherapies. We have a median PFS of 24 months, which significantly outperforms other treatments in patients with similar baseline characteristics, and this durability and safety gives us confidence in ... for advanced melanoma and potentially other cancer indications.
Amongst the various trials that we are pursuing, we have two lung cancer trials that in phase two, that one of which should be reading out by the end of this year in combination with chemotherapy. And the next slide shows some data that we presented at ASCO, suggesting that we had an elevated response rate compared to monotherapy in head and neck squamous cell carcinoma, again, with a durable response lasting for as long as twenty months as a median. And therefore, we have also decided to initiate a trial in both HPV positive and HPV negative first-line head and neck squamous cell carcinoma in patients who are PD-L1 positive. So next slide. In conclusion, our long-term follow-up of advanced melanoma patients treated with the combination have shown encouraging and very competitive response rates and PFS across three independent cohorts.
This combination may offer a potential best-in-class treatment in first-line metastatic melanoma, which we will learn with the pending phase III results next year. We have encouraging results that we've seen in head and neck squamous cell carcinoma, and therefore, initiating a randomized phase II. Our studies in lung cancer will also read out, and we are initiating potentially pivotal phase II studies for fianlimab and Libtayo in perioperative melanoma and in perioperative lung cancer. Next steps, we results from our phase II studies in lung cancer later this year, and hopefully be able to present registration-enabling data from phase III study sometime next year in, from melanoma. Next slide. Let's turn back now to our costims.
As George mentioned, we were actually the first to initiate these types of molecules in the clinic, where on the basis of preclinical data, we realized that the CD28 pathway was a potent lever to employ to augment immune responses and essentially try to convert tumor cells into antigen-presenting cells. What you can see here is that the example of the mechanism, how we see these working, where a costimulatory bispecific bridges CD28 to a tumor-associated antigen, rather than the CD28 engaging its normal B7 ligand, which then, in combination with anti-PD-1, can augment a normal signal that the TCR recognizes.
Regeneron's first-in-class CD28 costim, which was a PSMA by CD28, demonstrated proof of concept for this mechanism, in which we saw rapid and dramatic responses in prostate cancer, with three of four patients dropping significantly with their PSA, although it was complicated by immune-mediated adverse events. Therefore, we have taken on the next steps to further augment our ability to separate the efficacy from any safety issues, and we are doing this in a number of different ways. We are testing a monotherapy cohorts with an option to add lower dose cemiplimab if there's no response. We're also investigating the combination of our prostate-specific costimulatory bispecific with a CD3 bispecific, which, based on strong preclinical data, we believe will be better tolerated and may provide a similar efficacy profile.
We are exploring additional approaches to prostate cancer use, utilizing our CD28 platform, which are being evaluated preclinically. Next slide. We have made the decision to test this costimulatory bispecific platform in multiple different settings, and currently exploring them in early clinical trials across a variety of solid and hematologic tumor settings, in combination with cemiplimab or in combination with complementary CD3 bispecifics, with more to enter the clinic soon. I'd like to next focus on our EGFR by CD28, where we presented initial dose escalation data in microsatellite stable colorectal cancer at ASCO earlier this year. That's another cancer that is typically viewed as unresponsive to PD-1 monotherapy or has failed other combinations with chemotherapy to date. Next slide.
At ASCO, we showed that in our dose escalation study, in a cohort of 15 patients who had advanced colorectal cancer, but without liver metastases, three out of 15, or 20%, had a significant response rate, and 80% showed disease control rate. Microsatellite stable colorectal cancer historically has been unresponsive to immunotherapy, and these early results, in combination with Libtayo, are encouraging, again, showing that the antitumor responses in a highly difficult to treat cancer can be obtained, and we are working now to explore the ability of this in multiple other treatment settings in different indications. As you can see from the bottom on the right, safety was assessed in 84 patients with multiple solid tumor types at a variety of doses. The combination showed an acceptable safety profile, and the maximum tolerated dose has not yet been reached.
There have been no dose-limiting toxicities to date, and notably, no reports of cytokine release and no treatment-related deaths. Of particular note, we have not observed the same type of severe immune-mediated adverse events through the dose level that we've reached so far of 900 milligrams, as has been seen with PSMA by CD28. Indicating to us that there is much to learn about this whole class of agents, and that each one may have slightly different properties, and we are working hard to learn the rules for how to optimally use these. We are now opening up additional expansion combination, including patients with lung cancer, head and neck squamous cell carcinoma, cutaneous squamous cell carcinoma, as well as more patients with colorectal cancer. Next slide.
So our conclusions on the co-stim bispecific platform, we are focused on developing a unique portfolio of oncology medicines, including checkpoint inhibitors, CD3 bispecifics, and CD28 costimulatory bispecifics. Not mentioning here the cytokine-directed therapies, potential for cellular therapies, and other combinations that we're doing, that we're developing preclinically and in collaboration with other companies. Over the past several years, we've made progress in our programs across checkpoint inhibitors and the CD3 class, and are now showing promising activity with two costimulatory bispecific antibodies in the clinic. These were designed with the goal of turning cancer cells into antigen-presenting cells, thereby converting historically immunotherapy-unresponsive tumors from cold to hot.
Early data speak to the potential of EGFR by CD28 in combination with Libtayo and add to a growing body of evidence supporting novel costimulatory bispecifics that are in clinical trials for a range of both solid and blood cancers. And turning to blood cancers, I'll turn now to Andres to carry on.
Thank you, Izzy. I will now discuss the recent progress and updates across our hematology oncology development pipeline, focusing on linvoseltamab, our BCMA by CD3 antibody for myeloma, and Ordspono, our CD20 by CD3 and which was recently approved in Europe for certain lymphomas. Next slide, please. I will start with linvoseltamab. At the recent European Hematology Association Congress, we presented 14 month median follow-up data from the ongoing LINKER-MM 1 trial in patients with relapsed refractory multiple myeloma. As a reminder, an earlier data cut at 11 months served as the basis for regulatory filings in both U.S. and Europe. This longer-term data further reinforce our confidence in linvoseltamab as a potential best-in-class BCMA bispecific, and we are continuing development in early lines of therapy.
Last month, we announced that the FDA had issued a complete response letter for the BLA in the relapsed refractory setting, related to findings from a pre-approval inspection at a third-party field finish manufacturer for another company's product candidate. We are working with all stakeholders to resolve this issue. The third-party manufacturer is awaiting reinspection by the FDA, which is expected to take place in the upcoming months. In Europe, we anticipate a regulatory decision by the first half of 2025. Now let's move to the data on the next slide. Linvoseltamab demonstrates deep and durable responses in patients with relapsed refractory multiple myeloma. As the graph depicts, we continue to see a trend of responses deepening over time. Based on the latest data cut with a median follow-up of 14 months, a 71% objective response rate was observed in patients treated at 200 milligram dose.
This was assessed by an independent review committee, also showing 50% of the patients achieving a complete response or better. These response rates and complete response rates continue to represent the highest rates across the BCMA bispecific class. Next slide, please. As we previously highlighted, responses occur early, deepen with time, and have shown durability, all critical efficacy measures for this heavily pretreated patient population. Based on the 14th-month median follow-up, the median duration of response was 29 months for all responders, while the median duration of response had not been reached for those who achieved a complete response or better. Now, turning to safety, briefly on the next slide. Linvoseltamab showed a manageable safety profile that was generally consistent with the early data cut. And it is important to emphasize that the majority of patients did not develop CRS.
CRS was reported in 46% of the patients, and most of those were grade one. There was one grade three CRS event during step-up dosing, but no other grade three or higher CRS events were observed, and these CRS events mostly occurred during the step-up dosing period and typically occur and resolve within 24 hours. Next slide, please. Based on clinical evidence to date, we believe linvoseltamab has a compelling and differentiated profile relative to other FDA-approved BCMA bispecifics. Of course, we should take into consideration that these are comparisons across different trials. But with that caveat, we can state that we have a compelling, differentiated BCMA bispecific.
While the eleven-month data cut serve as the basis for our regulatory filings, the updated data further supports a potentially best-in-class profile for linvoseltamab in frontline myeloma in terms of efficacy, safety, and patient burden. Next slide, please. We are rapidly advancing our clinical development program into early lines of therapy, including pre-malignant conditions, and given the strength of the data in late lines of therapy, including the observed level of efficacy and favorable safety profile of linvoseltamab, we are exploring monotherapy approaches in early lines of therapy, as well as novel combinations. In the context of early lines of therapy, we look to expedite our trials by incorporating MRD endpoints that could accelerate development. We are also evaluating linvoseltamab in precursor conditions such as smoldering myeloma and monoclonal gammopathy of unknown significance, or MGUS, while a study in light chain amyloidosis is also enrolling.
These indications represent potential opportunity for linvoseltamab to help even more patients in need. In summary, I believe linvoseltamab is among one of the most exciting programs we have in our clinical pipeline, and we are rapidly advancing development efforts to bring this important therapy to many more patients. Next slide, please. Moving now to odronextamab, which now has the brand name of Ordspono. This is our CD20xCD3 bispecific antibody in lymphoma. Ordspono, which was approved in Europe last month, is Regeneron's first bispecific approval. It is approved in both relapsed refractory follicular lymphoma and relapsed refractory diffuse large B-cell lymphoma. We know that per EU label, Ordspono can be administered in the outpatient setting and does not have hospitalization requirements.
As we previously highlighted, Ordspono has the highest complete response rates observed in follicular lymphoma, and for diffuse large B-cell lymphoma, is the only bispecific in the class to have a post-CAR-T cohort in its label, a high unmet need. We continue to enroll patients in phase three confirmatory trials, and we'll provide further updates later this year on progress made on the FDA regulatory front. Next slide, please. You can see that we have a comprehensive odronextamab development clinical program for Ordspono, which is progressing rapidly. We are enrolling across several phase three studies, evaluating odronextamab, both as monotherapy and with novel combinations to challenge the current treatment paradigms. We are also very excited about progressing a combination of this, CD twenty-eight costimulatory bispecific with Ordspono, where we are hopeful to increase activity in late lines of therapy and beyond.
In summary, we are excited about the prospects of odronextamab in lymphoma and the progress that we are currently making across the entire clinical development program. Next slide. To summarize, linvoseltamab demonstrate the potential best-in-class efficacy, and we believe it is highly differentiated from the competition. Ordspono continues to show durable responses and a competitive profile with a recent approval in the EU. And based on the competitive and differentiated profiles of these bispecifics, we are pursuing a large clinical development program in early lines of therapy with a goal of establishing Regeneron as a leader in hemato-oncology. With that, I will turn to Justin.
Thank you, Andres. Izzy and Andres have reviewed exciting data from across the oncology portfolio, and now I'd like to speak briefly about the ongoing build-out of our commercial oncology organization and the success we've had with Libtayo, as well as how this positions us for long-term success as the pipeline continues to mature. Next slide, please. Since the initial launch of Libtayo in cutaneous squamous cell carcinoma in two thousand and eighteen, executed commercially to establish the brand as the leader in this disease category with approximately 80% share of the PD-1 class, and we continue to make tremendous progress on growing this market, given the significant unmet medical need that is out there. With the addition of basal cell carcinoma, we have solidified Libtayo as the leading anti-PD-1 therapy in non-melanoma skin cancers, despite increasing competition in recent years.
Libtayo growth has also been fueled by the approvals in non-small cell lung cancer, where in 2022 , Libtayo- Libtayo became one of only two PD-1 antibodies to be approved in the U.S. for use in the first-line setting in combination with chemotherapy, irrespective of histology or PD-L1 expression levels. We have steadily grown Libtayo share in both monotherapy and with the chemotherapy combination, despite entrenched competition. In the first half of 2024 , Libtayo global net sales grew 43% to $561 million, putting Libtayo on track to be Regeneron's next drug to surpass $1 billion in annual net sales and with significant margin expansion over the last couple of years. Next slide, please. Our acquisition of global rights to Libtayo from Sanofi in 2022 has provided us with the opportunity to expand our international commercial presence to support the strong growth of Libtayo.
As of July, we have completely transitioned the Libtayo business from Sanofi. We have attracted an all-star team from a diverse set of backgrounds with strong oncology and hematology expertise. Our international operating model is also designed to support launches in hematology and potential future treatments. Speaking of hematology, we are pleased about the recent approval for Ordspono in Europe, and we look forward to a decision from regulators on odronextamab in the first half of 2025 . In the US, our hematology oncology commercial teams are well prepared to begin launch activities for both treatments, pending resolution of the complete response letters, which were received from the FDA. In summary, our organization has driven strong growth for Libtayo through solid commercial execution. We have expanded our global footprint across international markets, and we are well-positioned to maximize both Libtayo and future brands in oncology and hematology.
I'll now turn the call back over to George for some closing remarks.
Well, thanks, Justin. As I hope you've all heard from Izzy and Andres and Justin, that there's been a lot of exciting developments with our innovative pipeline. I think some, of course, things just to emphasize again, as Izzy said, first of all, in terms of our work with checkpoint inhibitors, he presented perhaps some of the most exciting new data since the dawn of the checkpoint inhibitor era, in terms of new combinations with new abilities to take these classes of agents to the next level, and showed incredibly striking data, particularly if you focus on things like the complete response rates and the durabilities that Izzy described.
Similarly, Andres talked about our innovative class of CD3 bispecifics, and once again, perhaps best-in-class data for the very important BCMA class of CD3 bispecifics, once again, with perhaps field-leading data in terms of, very importantly, complete responses and duration of action, for patients suffering from this very serious disease. And a recurring theme from both Izzy and Andres was the flexibility based on the many modalities we have in our pipeline of prospectively and logically designing combinations that can take activity to the next level, not only with the combinations that I just mentioned, but also, for example, with these very innovative costimulatory bispecific approaches that they talked about.
And of course, Justin finished by talking about how we're moving forward, and doing well commercially, and particularly with our first checkpoint inhibitor as a monotherapy, as he said, on its way to becoming a billion-dollar drug. But just as importantly, that's as a monotherapy, that's not talking about what the possibilities in the future can be, as it's gonna be a foundational agent for a variety of our ongoing and future combination approaches. So with that summary, I'll turn it over to Mark to take questions.
Thank you. We'll now open the call for Q&A, where George, Izzy, Andres, and Justin can address your questions. In order to address as many questions as possible, we ask each caller to limit themselves to one question, and please keep the scope of your question limited to today's subject matter. Kevin, please go ahead.
Thank you. Ladies and gentlemen, if you have a question or a comment at this time, please press star one one on your telephone. If your question has been answered and you wish to remove yourself from the queue, please press star one one again. One moment for our first question. Our first question comes from Evan Segerman with BMO Capital Markets. Your line is open.
Hi there, this is Conner Onfred, and thanks for taking our question, and congrats on all of the data. With the data from the phase II fianlimab plus Libtayo, frontline lung, study coming in the fourth quarter, can you maybe just share what you view as the bar for that readout to take it into phase III? And then maybe any read-throughs or potential points of differentiation from the Opdualag data that we saw this weekend. Thank you.
Hi, so-
Well-
Oh, go ahead.
Go ahead, Izzy. Go ahead, Izzy.
Hi, Evan. So one of the things we were pleased about to see in the Opdualag data was additional data emerging that lag three can augment the responses in lung cancer to PD1 and chemotherapy. We believe we have the opportunity to do better than that, but I think we will have to see what the data reads out as. We have, and we have a stronger PD1 chemo combination performance in first-line lung cancer than the control arm in that study of nivo plus chemo. And we have, as you know from our, what we shared in melanoma, we believe we have competitive performance of the combination of lag three and fianlimab and cemiplimab.
... I'm not going to predict the specific criteria. We have to be convinced that we are seeing a clear benefit in the first-line lung cancer setting in order for us to take it forward. Our initial data was with a limited cohort where we saw again what looked like an enhanced response rate, but more compelling to us was the durability that we saw. So that's going to be kind of the general criteria. This will be deeper responses and you know the opportunity for suggesting that they will be more durable, although we obviously won't have as much follow-up.
Yeah.
Thank you.
Thanks, Izzy. Let me just add and amplify a little bit to that. So as Izzy said, in the BMS data, they seem to show in a small data set that the LAG-3 blockade added to the activity of their PD-1 agent, nivolumab. But it's important to point out that in their study, just as in all their historical studies, nivolumab underperformed other PD-1s. Most notably in lung cancer, as we know, our PD-1 agent, Libtayo, that you just heard about, as well as Keytruda, have the class-leading data. Nivolumab has not been approved as either monotherapy or as a single agent on top of chemo because it just doesn't look as powerful an agent in lung cancer. That said, in their small study, the LAG-3 added to that.
So Izzy points out that if you would now have a more powerful PD-1 and perhaps a more powerful LAG-3 approach, which, looking at the data right now, there is a real opportunity that we would have it, that we could have profoundly more exciting data. And that's what we're hoping for. And as Izzy said, we're hoping when we see the data, that it'll be clear-cut, and it'll point to a direction that we'll wanna undertake in lung cancer.
Thank you. Kevin, let's go to the next question.
One moment. Our next question comes from Tyler Van Buren with TD Cowen. Your line is open.
Hey, guys. Thanks very much for the presentations. You guys are doing a lot of great work in oncology. So I wanted to ask about fianlimab, fianlimab again. Given the data of fianlimab and Libtayo in melanoma, I'd be shocked if the phase III next year was not successful. Perhaps we could talk about the market a bit. What % of the frontline melanoma market do you believe a LAG-3 IO combo could take, and do observations with the ongoing Opdualag launch support that so far?
Why don't we let Justin take that?
Yeah, thanks for the question, Tyler. You know, it when it comes to oncology, physicians, treating physicians really look at the data. And if we can deliver unambiguous, promotable differentiation, that's something that is going to resonate with customers. We see with the current agents on the market that there is already some pretty strong uptake. So our expectation is that if we can deliver on what we're seeing in the phase II cohort, that it could be a significant opportunity for us in first-line melanoma.
Thanks, Justin. Kevin, let's go to the next question.
One moment. Our next question comes from Salveen Richter with Goldman Sachs. Your line is open.
Hey, good morning, and thank you for taking our questions. This is Elizabeth on for Salveen. Wondering if you could help contextualize and kind of remind us of the discontinuation rate, for the fianlimab study in melanoma, for the data that was just presented at ESMO, and, kind of what are some contributing factors to the discontinuation seen? And then a second question also on fianlimab, if you could speak to the relative importance of LAG-3 expression in patients, with non-small cell lung cancer, and if there's any expression criteria for the phase II/III study, that we'll see data from later this year. Thank you.
Izzy, why don't we let you take the question? But why don't you put the slide back on that shows the spaghetti plot, that shows the durability that Izzy had highlighted. And then, Izzy, you can maybe take on the question about discontinuations first.
All right. So the overall discontinuation rate was in this that were discontinued due to treatment emergent adverse events was about 17%, 17 out of 98. If you look across different trials, the overall discontinuation rates were similar to what's been seen in other advanced, you know, cancer settings, where generally it was due to either progressive disease or it was due to actually patients deciding that they had good responses and no longer wanted to continue treatment. So I think those were basically on par. What you see here on the spider plot is the durability of responses that actually could encourage physicians and patients to say they would stop.
I'll point out that this first-in-human cohorts originally planned only a year of therapy rather than the typical two-year therapy that we have in our phase III program. So only a proportion of patients actually decided to opt for an optional second year. What we didn't show in the slides here, although it's listed in the subheading. We did look at PD-L1 or LAG-3 expression in the melanoma group. We did not see a marked difference between an activity in the high PD-L1 versus low PD-L1, or high LAG-3 and low LAG-3. It's important to note the two measurements are a little confounded. They're not independent, because it's usually patients who have higher PD-L1 expression that might be more likely to have higher LAG-3 expression.
So, we see important there's a slightly higher response rate in the high PD-L1, LAG-3 of, you know, it goes up to closer to 70%, whereas it goes in the mid-50s% if it's in the lower PD-L1. But within the context of this study, we didn't think it really differentiated. And in fact, in our phase III program, we are not requiring a specific PD-L1 or LAG-3 expression level. Similarly, in our phase II lung cancer cohorts, what we're doing is we're doing one phase 2 study for patients with PD-L1 greater than 50%, where we're testing the combination of semi versus semi and fianlimab as an IO/IO combination. And then we're also testing the combination of PD-1, cemiplimab plus fianlimab on top of chemotherapy across all PD-L1 levels.
At this point, we are not predefining a particular cutoff required for looking for activity. We want to see what we get first, and then we'll learn from that.
Thanks, Izzy. Kevin, let's go to the next question, please.
One moment. Our next question comes from Chris Schott with J.P. Morgan. Your line is open.
Great. Thanks so much. Just maybe pivoting over to the BCMA bispecific. Can you just elaborate how you're thinking about competitive dynamics here over time? It seems like some of your competitors are evolving their dosing profiles. And I'm just wondering, just your thoughts on do we end up with the various products in this market, end up with dosing and hospitalization that maybe looks more similar than different to one another? And how do you think about what that would mean competitively? Thank you.
Why don't we put up that slide that shows the various agents, and Andres, why don't you take that question?
Thank you for the question. In terms of how we see linvoseltamab, first, I want to start with the level of efficacy that we have observed, which I believe is very competitive. I want to remind you, 71% overall response rate and a 50% CR rate, which are very durable. And I think that's rather remarkable in this difficult to treat patient population that actually was included in our pivotal clinical trial. That's one aspect. I think that the other important aspects that differentiate linvoseltamab from others is, as mentioned, the dosing regimen. It has a convenient dosing regimen with minimal hospitalization. In addition to that, the fact that the schedule of administration is competitive.
This is the only in the class bispecific targeting BCMA that eventually can be and has been explored given every four weeks. Again for those patients that achieve a VGPR or better we extended the interval of administration to every four weeks initially once a week then twice a week and eventually to every four weeks. And this is the only one that has been at the moment prospectively studied in that manner. So all in all I think that the data that is emerging consolidated in our that we have a competitive BCMA bispecific.
And I, the other thing I would add to this is that when you look at the BCMA market, particularly in relapsed refractory settings, it's a very fragmented market. You think about multiple modalities. You have CAR-Ts, you've got ADCs, antibody drug conjugates, you've got bispecifics. We expect that the bispecifics class is going to grow over time, just given the convenience, given the strength of the data. You know, some of these other drugs have limited durability, some of these other classes have toxicity and other challenges. So not only, as Andres said, does our data really hold up within the class, but we expect this class is going to grow over time.
Great. Thank you. Kevin, let's go to the next question.
One moment. Our next question comes from Brian Abrahams with RBC. Your line is open.
Hi, this is Brian from RBC. Thank you for taking our question. So back to melanoma, can you talk more about the adrenal insufficiency events you saw, how they were typically managed and how transient or persistent these events were? Thank you.
Izzy, why don't you take that?
On the safety slide, which is slide 17, we pointed out that there were a 12% rate of any grade of adrenal insufficiency and 5% that were grade three or greater. I would point out that no one died because of this. Number two, that patients were able to continue treatment with replacement steroids. As I also pointed out, remarkably, that the response rate in these patients was actually 92%. You know, again, it's a small subset of the group, but it suggests that there was something interesting linking this toxicity. Also point out in cross-study comparisons with other LAG-3 antibodies, it's not that dissimilar.
So I think there's something about the LAG-3 targeting axis that has uncovered a propensity towards a higher rate of adrenal insufficiency. Still not completely clear how much of this is primary adrenal insufficiency versus secondary adrenal insufficiency coming from a pituitary source, but it's manageable. And in our studies so far, our investigators say well, compared to PD-1 and CTLA-4, this is a walk in the park.
Thanks, Izzy. Kevin, let's go to one more question, please.
One moment. Our next question comes from Terence Flynn with Morgan Stanley. Your line is open.
Great. Thanks for taking the questions. Thanks for the overview. You know, obviously, there's been a lot of excitement over the last several months on PD-1, VEGF bispecifics. I know you guys have a different type of bispecific platform, but just wondering if that's something you've looked at, at all in any of your animal models, if that's something you're considering? And then, what are the implications as you think about kind of future lung cancer market? Thank you.
Yeah, certainly-
George, do you wanna start out?
Yeah, I was gonna just make a comment. Certainly, the reported data looks very interesting. It's a completely different class of bispecific. Right now, it's not obvious why, in this case, a bispecific here would have any different sort of activity than just combining PD-1 and VEGF blockade. And, you know, there really is no good design purposes for making this type of bispecific, but it's certainly data worth keeping an eye on. Great. Thanks, George. Kevin, I think we have time for one more question.
Sure thing. One moment. Our next question comes from Mohit Bansal with Wells Fargo. Your line is open.
Great. Thank you for squeezing me in. And going back to the Opdualag data, so I just... Like, what would be your rationale behind that combination not working among less than 1% PD-1 patients? Is it down to PD-1 there? And in that regard, your combination could be better because more and more you look at the data, Libtayo seems more like Keytruda versus any other agent that is out there.
It's a little hard to hear the question. Mark-
Yeah.
Could you repeat the question, Mark, if you heard it? Well, Izzy, did you hear that? Could you repeat it, the question, please, for the rest of us who didn't hear it that well?
Sure.
Can you?
I can repeat it. So the question is, for Opdualag, what would be the like, when you look at the data, what is your internal thinking about why this drug did not work among less than 1% PD-L1 patients? Is it down to the checkpoint inhibitor or PD-1 inhibitor here? And to that point, do you think your combination may have a better shot at that particular subgroup of the patient, given that your PD-1 seems more similar to Keytruda rather than nivolumab? Thank you.
Yeah. I think that it's hard to read the tea leaves with these very small data sets right now. But I think that the big points that you're making and that Izzy and I both tried to make, which is that if you're gonna do a combination in lung cancer or in any setting with a PD-1 and with a LAG-3, you'd want to have the best possible PD-1, and you'd have the best possible LAG-3, and then you're putting them together, especially with a combo that looks like it might have best-in-class activity. So I guess that's why there's reason to have both hope and excitement about our combination, because we believe we are doing that.
We are putting a best-in-class PD-1 together with a best-in-class LAG-3 that's already has suggestive data in one setting with a rather large data set, though still limited in first-line melanoma. And then I think increases the potential and the excitement that it could also have exciting performance and exciting benefit for patients in another setting, such as lung. But the data sets right now are a little small, and hopefully we'll contribute to them, we'll contribute to the understanding, we'll contribute to the exciting potential for our combination in particular.
Great. Thanks, George. And thanks, Izzy, Andres, and Justin as well. And thanks to everyone who joined this call today. Apologies to those that we couldn't get into the queue today. We're happy to follow up after this call.
Hope everyone has a great day, and thanks again for joining us.
Ladies and gentlemen, this concludes today's presentation. You may now disconnect and have a wonderful day.