Genmab A/S (GMAB) Earnings Call Transcript & Summary

Hello, and welcome to Genmab's ASH 2025 update. As a reminder, this webcast is being recorded. During this webcast, you may be presented with forward-looking statements that include words such as believes, anticipates, plans or expects. Actual results may differ materially, for example, as a result of delayed or unsuccessful development projects. Genmab is not under any obligation to update statements regarding the future nor to confirm such statements in relation to actual results, unless it is required by law. Please also note that Genmab may hold your personal data as indicated by you as part of our Investor Relations outreach activities in order to update you on Genmab moving forward. Please refer our website for more information on Genmab and privacy policy, I would now like to hand over to your first speaker today, Jan Van de Winkel. Please go ahead.

Hello, and welcome to Genmab's 2025 R&D update and ASH data review. I'm Jan Van de Winkel, President and CEO of Genmab. I'm delighted to share with you some of the highlights for Genmab in 2025 as well as exciting EPKINLY data from this year's ASH meeting. Next slide, please. As a reminder, this presentation may contain looking statements and as such, may contain certain risks and uncertainties. So let's move to Slide 3. We will begin with a review of the focus we made this year as we advance toward our 2030 vision. Next, we will review some of the encouraging epcoritamab data presented at this year's ASH meeting. And for this, we are pleased to have Dr. Lorenzo Falchi. Then looking ahead, I will provide a brief overview of some of the key events we are anticipating for 2026. To conclude, I will open the floor for a lively Q&A session. And for this, Dr. Falchi and I will be joined by Genmab's Chief Medical Officer, Dr. Tahi Ahmadi; and our Chief Development Officer, Dr. Judith Klimovsky. But first, let's explore some of the highlights from the past year. Next slide, please. I'm pleased to say that we have successfully delivered on the commitments that we made at the beginning of the year. With the proposed acquisition of Merus and the addition of petosemtamab to our portfolio, we saw an opportunity that will position us for sustained growth and long-term value creation. And our other commitments this year support our conviction that we will be able to rapidly maximize petosemtamab's full potential. We significantly accelerated the development of Rina-S. And together with our partners, we expanded the reach of both EPKINLY and TIVDAK. These strategic investments, in addition to our high-quality recurring revenue have set us up for success in 2026 and beyond. So let's look at some of the specific progress we have made this year on the next slide. Since 2013, we have been executing a strategic shift from our royalty depending earnings to a diversified fully integrated 100% owned model. The addition of petosemtamab to our already compelling late-stage pipeline significantly accelerates the shifts. The totality of data that we have seen from petosemtamab underscores its potential as a best-in-class EGFR directed bispecific across head and neck cancer indications as well as other EGFR expressing tumors. We anticipate the transaction will close by early in the first quarter of next year, and the integration of Merus will be a key priority for us in 2026. For Rina-S, we have presented compelling data in both second line endometrial cancer. Rina-S also received breakthrough therapy designation as well as in platinum-resistant ovarian cancer or PROC. What emerges from these data sets is a highly compelling product profile across efficacy, durability, safety and through the whole spectrum of poly receptor alpha expression. And we are investing to maximize the potential we see in Rina-S with an accelerated and comprehensive development plan. We are ending this year with 3 Phase III trials and 2 Phase II potentially registrational trials. For acasunlimab, hopefully you have seen the updated data presented at ESMO IO just yesterday, showing promising overall survival and durable benefit with manageable safety. Turning to our already commercialized medicines, TIVDAK was approved in both Japan and Europe, providing us with the opportunity for the first independent product launches in Genmab's history. With these launches, we are building a foundation in the gyno community that will set us up for future success with the potential future launch of Rina-S. EPKINLY expanded with additional approvals including the approval from the FDA just last month in combination with R2 in second-line follicular lymphoma. The unprecedented Phase III data in this indication was simultaneously published in the prestigious journal, The Lancet, and highlighted during an oral presentation at ASH. One of 7 oral presentations and over 30 total accepted abstracts for EPCORE this year. Now let's review this data along with 2 other key data sets presented this year -- at this year's ASH annual meeting. Let's move to the next slide. To present this exciting data, I'm delighted to introduce to you Dr. Lorenzo Falchi of the Memorial Sloan Kettering Cancer Center in New York. Lorenzo is a medical oncologist and hematologist and an expert in the treatment of lymphoma. As an investigator, he is still intimately involved in the development of epcoritamab. Lorenzo, please go ahead.

Thank you. Thank you so much, and it's a great pleasure to be here with you and to share some of the exciting reports that Genmab has presented at this year's ASH, and I was very honored to be part of several of those. I'll begin with this slide, which is an overview of the accomplishments that have been made at this year's ASH through epcoritamab with 31 abstracts accepted and 7 of them being an oral presentation, and you see them highlighted here in 3 particular disease domains. Follicular lymphoma, diffuse large B-cell lymphoma and Richter's transformation, which is a specific complication of chronic lymphocytic leukemia and a very severe one. For follicular lymphoma, you can see 3 abstracts were presented in the frontline setting, the first EPCORE NHL-2 Arm 6/7 were presented combined in 1 oral presentation with a 3-year follow-up update of this triplet combination of epcoritamab plus rituximab and lenalidomide or R2. EPCORE NHL-2 arm 3 was also presented as a 3-year update in this particular study. Epcoritamab was combined with a chemoimmunotherapy standard bendamustine and rituximab. And then finally, in an academic study from the Dana-Farber group, epcoritamab, combined with rituximab was also tested for patients with newly diagnosed follicular lymphoma and presented as an oral talk. In the relapsed/refractory setting is where we really were happy to share for the first time the primary analysis of the randomized controlled Phase III trial named EPCORE FL-1 which tested rituximab and lenalidomide with or without epcoritamab. And I'll talk a little bit more about the study that I was honored to be presenting at this meeting. As a corollary to that study, we also presented in the form of a poster patient-reported outcomes from the same study showing how the addition of epcoritamab really preserve the patient's quality of life while improving the results, as I mentioned. In diffuse large B-cell lymphoma in the frontline setting, 3 studies were presented, 2 of them is an oral talk, the first is the Arm 1 of EPCORE NHL-2. This is the flagship study, if you will, for patients who are fit to receive full dose chemotherapy. And in the study, patients received R-CHOP plus epcoritamab. Here, we gave an updated 3-year follow-up or longer than 3-year follow-up. And we showed really encouraging results, and I'll talk about this in a subsequent slide. The Arm 8 of the same study, EPCORE NHL-2, looking at dose reduced chemotherapy for patients who are a little bit more elderly and cannot receive a full dose chemotherapy. And then EPCORE DLBCL-3, which is looking at epcoritamab monotherapy, meaning epcoritamab given alone, for patients who are really more frail or very elderly and really cannot take any chemotherapy at all, and this is really going to fill a really important unmet need in that space. In the relapsed/refractory setting, a 4-year update of the EPCORE NHL-1 study, the original trial that led to the approval of epcoritamab for recurrent large cell lymphoma. This 4-year update gives essentially the longest update for a bispecific in diffuse large B-cell lymphoma in the market. And these data were also very exciting and very confirmatory in a good way. EPCORE NHL-6 study was looking at epcoritamab in the same indication that it's approved for but including a diversity cohort in the U.S., including Puerto Rico and kind of testing epcoritamab a little bit more in the real world. And then NHL-2 Arm 5 study, also was presented as a 2-year update in this particular trial epcoritamab was combined with GemOx. Also exciting news from the Richter's transformation space, as I mentioned, both epcoritamab as monotherapy and in combination with either lenalidomide or R-CHOP were tested and reported both as oral presentations. Of note, the epcoritamab monotherapy study eventually led to the NCCN recognition and so this treatment, this drug is now included in the NCCN compendium for patients with a recurrent chronic lymphocytic leukemia. And so you see here how you have a Phase III readout, you have first reveal of data in a niche, a very important disease such as Richter's transformation. And you have a lot of long-term updates, in particular for the frontline follicular lymphoma and large cell lymphoma setting in combination, but also in the relapse setting as epcoritamab monotherapy. So a little bit more about the EPCORE FL-1 study. This has been really our pride, and certainly has been my honor and my pride to present this study on behalf of all our co-authors. This was a randomized Phase III trial comparing in a one-to-one fashion, epcoritamab plus R2 versus R2 alone. You can see a large study, 488 patients equally distributed in the 2 arms. These were patients with follicular lymphoma who have received at least 1 systemic therapy, including chemotherapy and in need of subsequent treatment. The study was designed to demonstrate the dual primary endpoints of overall response rate and progression-free survival, and it was conducted at 189 sites across the globe. We presented in this particular analysis with a median follow-up of 14.8 months. This was the second interim analysis, where we were able to analyze both primary endpoints. Here is a look at the patient's characteristics at baseline by treatment arm. Obviously, this being a randomized controlled trial, the characteristics were well balanced in general. But I invite you to look at the bottom part of the chart where you can see the treatment history of these patients. And although just over half of the patients had received 1 line of therapy only prior to entering the study, there were a large number of patients with heavily pretreated disease, but more importantly, patients with high-risk features, including POD24, which means an earlier relapse after frontline chemotherapy and also patients that were refractory to the first-line therapy, meaning they never achieved the satisfactory response or patients who are double refractory, meaning that neither rituximab or chemotherapy has succeeded, so a particularly difficult to treat patient subgroup. So here's the study first co-primary endpoint. The addition of epcoritamab to R2 led to a massive 79% risk reduction in the risk of progression or death. And this was with a hazard ratio of 0.21, which at least in my experience is unprecedented. I don't recall seeing a hazard ratio that's favorable, obviously, highly statistically significant. But it's important to emphasize also that when we did the subgroup analysis of progression-free survival. What we found is that the benefit in terms of progression-free survival was preserved across patient subsets, including the higher risk but also the lower rice patients across ages, obviously, sex, regions of the world, et cetera. So this really demonstrates that the benefits of adding epcoritamab to R2 are really maintained across a broad population of patients with recurrent follicular lymphoma. And here is the second co-primary endpoint, which is overall response rate. This is -- this was an earlier endpoint that we looked at. This was also met. The overall response rate was 95% for epcoritamab R2 and 79% for R2 alone and the complete response rate, perhaps even more compellingly, was 83% for epcoritamab R2 and 50% for R2 alone. So it's a large difference. And we know that the value of complete response is very significant in follicular lymphoma, where the complete response really translates almost one-to-one fashion into better progression-free survival and eventually better outcomes. We also looked at a number of secondary endpoints. Perhaps an important one is a duration of response. That is how long the response that is achieved can last. And here again, we saw a very large difference with a very significant improvement in the duration of response with the addition of epcoritamab to R2. Again, here, an incredibly favorable hazard ratio of 0.19, highly statistically significant, really suggesting that once that response is achieved it tends to be maintained for a long time. This was true for epcoritamab alone, and it's even more pronounced with the addition of epcoritamab and R2. We also took an early look at overall survival. Now I don't want you to overinterpret this curve because the follow-up of the study, as I mentioned, is too short, and this is, as we know, follicular lymphoma, where overall survival analysis can take a long time. But with this very early time point, we started to see a little separation in those curves with a hazard ratio of 0.38 and a significant p-value. This does not mean that epcoritamab R2 results in a longer progression overall survival than R2 but it's possible that with longer follow-up, we may be able to see that difference. This would be, I would say, unprecedented that new treatment improves overall survival over an established real second-line therapy like R2 that it's an internationally accepted standard of care. And then finally, we looked at safety because obviously, we were very happy to see the efficacy result, but we didn't want to neglect safety. And obviously, we want to make sure that this is not only an effective treatment and a superior treatment, but it's also well tolerated with adverse events that are manageable. This was indeed the case. Obviously, adding a drug that's very powerful is not going to go without any side effects. There were a little bit more adverse events in the patients treated with epcoritamab plus R2. But these were not adverse events that were unexpected. In other words, it's what we call in jargon, there was no safety signal. We didn't see anything surprising. There was no strange toxicity coming out of the combination by putting together these 2 components. So certainly nothing that we were not able to manage. CRS or cytokine release syndrome has been a major theme in terms of adverse events when talking about bispecific antibodies with the addition of rituximab with the particularly modified step-up dosing schedule during the first month of therapy, we were able to bring down not only the incidence of CRS but also the severity. There were no cases of severe CRS no patient was hospitalized for this treatment. So this treatment really is a fully outpatient therapy that can be applicable even in community settings across the country and beyond the U.S. One brief comment about infections. Obviously, epcoritamab is an immunosuppressive therapy, and it's not surprising that these patients had a little bit of an excess in infections. But I would note and most of these infections were mild respiratory infections that we were able to monitor in an outpatient setting. Sometimes patients had to be admitted for infections, but this was in part true also for the control arm of the R2. Clearly, this data point towards an attention that needs to be paid to prophylaxis and proactive management of infections. We don't want to start patients on this treatment without adequate antibiotic prophylaxis and adequate monitoring. But I think after a brief learning curve, what we've learned ourselves is that it's really easy to do that frequent monitoring and just really treating proactively this infections, ultimately, at least in our center, we didn't have to hospitalize anyone. And so here, you really have an essentially practice-changing study that shows that the addition of a highly potent bispecific antibody like epcoritamab in patients with relapsed follicular lymphoma leads to a massive reduction in the risk of progression or death has a positive trend in overall survival. It is chemotherapy-free. It is fixed duration. I should mention this. You might remember in the epcoritamab monotherapy cohort treatment was given into progression. So indefinite here, we've fixed the duration to 12 months or 12 cycles. So this was really a transformative treatment in a transformative study. This was recognized by prestigious journal like The Lancet that we were honored to be accepted in. But it also importantly was recognized by health care authorities, in particular the FDA, that, as you know, on November 18 granted approval to this combination for the treatment of patients with follicular lymphoma after at least 1 line of therapy and it also secured traditional approval for epcoritamab monotherapy in its present indication in follicular lymphoma. Other regulatory submissions are ongoing globally, and I would expect them to be positively received. Now moving on to other follicular lymphoma settings, as I mentioned, in the frontline space, things are moving. Here's 3 studies that were presented. Arm 6 of EPCORE NHL-2 study, classic frontline study, patients with high burn disease in need of therapy, 2 years of treatment with epcoritamab, rituximab and lenalidomide same combination as in EPCORE FL-1 but given for a little bit longer, very impressive overall and complete response rates, 95% and 88%, respectively, and at 33 months, a pretty impressive 90% of patients remain progression-free. These data, if confirmed, would compare favorably with what we typically see with chemotherapy. Similarly impressive a smaller study, epcoritamab combined with classic chemo immunotherapy BR same patient population. Almost every patient here had a complete response, and these were also preserved at 3 years, another very powerful combination. And I would note the study led by my good friend and colleague, Dr. Reid Merryman at Dana-Farber, this was an investigator-initiated study looking at chemo-free but also lenalidomide-free combination of epcoritamab and rituximab. Very impressive overall response rate, 97% complete response rate, 91%. It's a little bit early. The follow-up is still short but certainly very promising results. So you can see how epcoritamab-based combinations are really bringing a serious challenge to standard chemotherapy for the first-line treatment of follicular lymphoma. So moving on to diffuse large B-cell lymphoma, particularly talking about the frontline setting. There's 3 studies that I'm going to briefly cover the Arm 1 of EPCORE NHL-2, Arm 8 of the same study and then EPCORE DLBCL-3. The first study, Arm 1 of EPCORE NHL-2. It was dedicated to patients fit for full dose chemotherapy and with high-risk diffuse large B-cell lymphoma, with R-CHOP given for 6 cycles and epcoritamab extended to a 1 year. In these patients, we saw an impressive overall response rate of 98% and a complete response rate of 85% and at this 3-year follow-up update. We also observed that 83% of patients remained alive and 74% in complete response. If we think about a comparator for this, for example, the control arm of the POLARIX study, that 3-year mark has a probably lower progression-free survival, and it makes us have high hopes for this particular combination in this setting. In Arm 8, we tested lower dose of chemo immunotherapy with epcoritumab. And again, here, there was a 3-year follow-up of data that was presented. This is for patients who are not able to tolerate full dose chemotherapy. But look at the responses, again, high overall response rate, 93% and 86% complete response rate, very similar to patients who had a full dose chemoimmunotherapy. And at 2 years, which is the update presented here, 82% of the patients remained alive and 79% in response. And then finally, EPCORE DLBCL-3 looking at epcoritamab monotherapy that is epcoritamab alone in patients who are elderly or very frail and unable to tolerate any chemotherapy. These patients are really a highly unmet need because they would not be treated other than palliatively and they don't really have viable options. So having a chemo-free treatment that results in a very encouraging 73% overall response rate and 62% complete response rate with the vast majority of patients completing treatment remaining in remission is certainly is very encouraging news for these patients who will really have very few, if any, options. The collection of this data really strongly supports the versatility of epcoritamab and the ongoing Phase III registration-directed EPCORE DLBCL-2 trial comparing epcoritamab plus R-CHOP versus R-CHOP in patients with newly diagnosed diffuse large B-cell lymphoma. And the study will read out in 2026. So I'm very eager to really discover the results of that study, and I'm very hopeful to celebrate those results as well. So in summary, we dedicated a little more time to the EPCORE FL-1 study because it really is a transformative study. It really exemplifies the power of epcoritamab and how we can really reshape treatment paradigms just really displaced current treatment standards, really unprecedented progression-free survival and, more importantly, massive reduction of the risk of progression or death, almost 80%. There certainly is momentum for the drug. There is -- this is the first positive Phase III study, not for just eccritumab for any bispecific in follicular lymphoma. In fact, it's the only randomized trial published for bispecifics in follicular lymphoma. Got FDA approved, we got published in a highly resonant journal. Basically, we have the trifecta here. I couldn't be prouder of the team, and I couldn't be more grateful to be part of this project, really. But more importantly, I couldn't be happier for our patients and now have a really substantial improvement in their outcomes when treated with this combination. In large cell lymphoma, I think we continue to build momentum around epcoritamab based combinations and really support very strongly the Phase III study that's ongoing comparing or R-CHOP plus epcoritamab versus our R-CHOP alone. And I think the collection of this data, including the ones in Richter's and some others that I didn't have time to mention or they were unpresented this year, ASH, really speak collectively to really the broad versatility of epcoritamab as a combination partner and as a drug that can really make a big dent in many disease settings in B-cell and Hodgkin lymphoma because it's administered subcutaneously. It doesn't have really significant share time, doesn't have overlapping toxicity with most treatments that we commonly use for B-cell and Hodgkin lymphoma. It really has its position in the best way to really make a difference in every existing treatment paradigm for these patients. So really, all the data that I went over really support epcoritamab as almost shifting the narrative as a backbone therapy as opposed to considering chemotherapy as the backbone for patients with B-cell non-Hodgkin lymphoma. So very excited to look forward to 2026 when more data will read out and just really going to be there and watch as the data unfold and probably and hopefully at least to celebrate many of these data. I'm just really thankful to be a part of several of these efforts. It's been so rewarding to use this drug in the clinic and see really the patients' outcomes under our eyes improved so significantly. And I really -- and thank you all for your attention. I'm happy to take any questions you might have.

Thank you, Lorenzo, for that inspirational presentation. So now let's move to some of the key pipeline events that we are anticipating in 2026. Next slide. Yes. 2026 will be a year of important catalysts for Genmab. A key focus will be the rapid integration of mirrors following the close of the proposed acquisition. As a reminder, we integrated ProfoundBio in less than a year, and we are confident that we will replicate this success with Merus. As part of this integration, we will keep a laser sharp focus on our investments in order to position the company for optimal growth. This includes investments to maximize the potential of our commercialized medicines, and a promising late-stage portfolio. In 2026, we expect multiple potentially registrational data sets for EPCORE, Rina-S and petosemtamab. If successful, we envision a 2027 with 4 KYSO products on the market, half of it will be entirely Genmab owned. So in summary, in 2025, we significantly strengthened the foundation of our business. With that is through targeted M&A and strategic investments in the expansion of our key late-stage and commercial programs. In 2026, we will take the next difficult steps in our shift into a diversified, fully integrated 100% owned model, advancing our evolution into a global biotech leader and positioning us for durable growth. So let's move to the next slide. Yes. Now it's time for our Q&A session. And I'm pleased to note that in addition to Lorenzo and I, we also have members of our executive committee to answer your questions. our Chief Development Officer, Judith Klimovsky; and our Chief Medical Officer, Tahi Ahmadi. And before we begin, a quick note that, as Lorenzo is very busy with the important work of caring for patients in New York, we will not be able to join us for the entire Q&A. So please now open the line for questions.

[Operator Instructions]. Our first question comes from Jonathan Chang with Leerink Partners.

Congrats on the data. On EPKINLY, what is the strategy for increasing adoption in community settings for both FL and DLBCL?

Thanks, Jonathan, for that question. I'll hand it over to Tahi to give you a perspective.

Yes. Again, John, ,thanks for the question. Well, generally speaking, just to go back a little bit. I mean from the very beginning, we've been very clear that we thought a key component of the differentiated profile of epcoritamab was the subcu administration. Efficacy, the safety and the convenience that comes with that, and that has translated into the relatively low Grade 2 CRS data, which we have further been able to improve in follicular lymphoma with 3-step-up dosing in diffuse large B-cell with a modified steroid regimen that we have already presented to help to it. So to come to your question, I think a, the subcu administration in and of itself is an important differentiator as we enter the community, which is where a lot of these patients, particularly in follicular lymphoma are going to be are being treated today, but also in diffuse large B-cell, particularly if we get into front line. The documented safety and the ease of administration, together with clinical trials that we are conducting and have been conducting to generate data that this is actually -- the community physicians are able to administer EPKINLY alone or in combination safely and confidently, that's an added differentiator. And so also the updated label that comes with this particular study and that we also are looking forward to the B-cell, all of these components change in the label, subcu administration, safety, experience in the community that then gets communicated are components of our strategy to increase adoption in the community where most of these patients are being treated. And so we're looking forward to seeing this '26 play out.

Thanks, Tahi. Thanks, Jonathan, for the question. Let's move on to the next one.

Our next question comes from Matt Phipps with William Blair.

For Dr. Falchi, how do you think about the infection risk for EPKINLY and bispecifics? Is there any additional prophylaxis that needs to be done, particularly as these move into those community settings, making sure they're familiar with that? And if I can just ask the company on the acasunlimab update, the OS did median, OS did come down to about 12 months in the 6-week dosing regimen. How do you think about OS's success there when some docetaxel arms have shown maybe an 11- to 12-month median OS in recent Phase III studies?

Thanks, Matt, for the questions. I think I don't know whether Dr. Falchi is already on the line. Otherwise, Tahi can answer the first question and Judith can definitely handle the acasunlimab question, Matt. But let's wait for a second, Dr. Falchi is on board. Otherwise, he may join later on that, I will ask Tahi to address the first question on prophylaxis.

Well, I mean, I'm going to try to do my best to answer the question of Lorenzo. Thanks, Matt, for the question. From our point of view, and then obviously, you want to hear the external point of view. With the instructions in the protocol it and also translated into the naval instructions, which is guidance on general guidance on using G-CSF when appropriate, but not mandating it we don't think there is a OE need to include antibiotic prophylaxis. I think what's going to happen is, generally speaking, that physicians and the community will get increasingly more sophisticated in individualizing this a little bit. I would remind everybody that this is kind of like an interesting phenomenon. The more you deplete B cells, the more you end up with neutropenia, but there was really infectious neutropenia, neutropenic fever or the likes of was really not an issue on the study. You mentioned that the most -- actually all of the patients were managed really in the outpatient setting. So from my point of view, from the company's point of view, we feel like we have given the community sufficient instructions to administer EPKINLY very safely. And I'm pretty sure that as a community, they are going to continue to fine-tune this, individualize this a little bit. There might be patients where there are higher risk we may get some prophylaxis. That's just the way it's an always been handled in oncology and also chemotherapies.

Thanks, Tahi. Judith, maybe you can address the new data, the updated data, I would say, on acasunlimab.

Yes, of course. Thank you for the questions. And we were delighted to have this data in the public domain. So I want to call to your attention that the subset Phase III eligible is the one that matters for the comparison and this encompasses patients that PD-L1 positive as per central and all of them exhausted PD-1 inhibitor and chemotherapy. In that subset, which is numerically 32 patients, the median OS is 14 months. But what I want to call to your attention is that the median overall survival is not predictive as much as milestone survival analysis. And here for the ITT population, the 12 months is 51%, which is considerably higher than the docetaxel even if you go to ITT and the population of interest, which is the 32 patients that were used the subset that's Phase III eligible. The 12 months is 64%. And when you compare with docetaxel, you see that the delta is meaningful. And most importantly, this study has follow-up to really see detail. And you see the 24 months which is 30% with some sensoring. So the tail is real, and this is totally different with the curve of docetaxel. So we are pretty confident that these results support the strategy that is being implemented in ABBIL1TY 06.

Thanks, Judith. Thanks, Matt, for the questions. Let's move on to the next question.

Our next question comes from Judah Frommer with Morgan Stanley.

Maybe I'm not sure if Dr. Falchi's on, but maybe one just high level on CAR-T versus bispecific. So maybe just high-level thoughts on sequencing CAR-Ts versus bispecifics in lymphoma, where we sit after rash, certainly it was a big debate in multiple myeloma, but curious how you're thinking about sequencing in lymphoma? And then just on DLBCL, specifically, with POLIVY approved in the front line, but not seeing necessarily an OS benefit over R-CHOP, how do we think about predicting OS and the benefit there in first-line DLBCL for other assets?

Please go ahead, Lorenzo.

Yes. So in terms of the sequencing, that's a very different question in the setting of follicular lymphoma in large cell lymphoma. I think in large cell lymphoma, it's a little less straight -- a little more straightforward because at least at the moment outside of the context of a clinical trial, you don't really have a label conflict because CAR-T cell therapies are approved in the second line and EPCORE monotherapy approved in the third line. However, particularly in the United States, some of these boundaries that can be pushed through compendium indications and through just by virtue, by sheer fact that third-party payer system sometimes allows for earlier use of bispecific based therapies in the second line. What I will say is that there's data for both the bispecific to CAR sequence and the CAR to bispecific sequence. And I would say the overall take away is that in the first case, there's not a clear evidence that the performance of CAR-T cell therapy is affected by prior bispecifics. In the second case, as we know from the pivotal trial, the complete response rates remain high or higher than pretty much any other alternative for bispecifics after CAR-T cell therapy. And so I think that bispecifics do remain the go-to therapy after CAR-T. But I think that bispecifics pre-CAR-T is a more important question in 2025 because as I said, more and more people are using them. And so some of the questions are, if you use bispecific therapy as a holding therapy, meaning before CAR-T cell collection does that affect the collection. We're actually trying to answer that question here as we speak. And we presented also data as the bispecifics consortium had this ASH showing that really, the performance of CAR-T doesn't seem to be affected whether you use bispecifics as holding or bridging therapy. In follicular lymphoma, the question is a lot more nuanced because when the goal of remission versus rather than cure, it comes down a lot more to patients' preference and to the specific context where that patient is being treated. If you focus for a second on bispecific monotherapy, the clear advantage of bispecifics over CAR-T is they're off-the-shelf nature and ability to be accessed outside centers that practice CAR-T cell therapy. Let's not forget that out of 6,000 health care facilities in the United States, 5,100 are community hospitals. And out of those 6,000 facilities, only 300 offer CAR-T cell therapy. So when you scale this discourse up nationwide, you immediately see how having an off-the-shelf therapy that has excellent tolerance or tolerability and good, if not very good, long-term outcomes is a huge value. The longest lasting bispecific study in that space shows that if you have a response, you have an about 40% chance of being disease 3 or 5 years. I mean that's not something we've ever seen before this era. So I don't think that the sequencing matters too much in terms of efficacy. I also don't think the sequencing matters too much in terms of burning bridges, so to speak. The whole discussion that I had about whether CAR-T cell could be affected by prior bispecifics. I think here is a little less relevant in follicular lymphoma, where you always have more time before between one treatment and another with a few exceptions. So that ability of T cells to regain their fitness is much more likely in the setting of follicular lymphoma. But I would say now with the results of EPCORE FL-1, this whole discussion acquires a whole new different light because when you're looking at patients in the second line -- first of all, there's an additional indication that CAR-T currently doesn't have, which is second line. Secondly, when you look at that performance, which is the same in second and third line, you're looking at complete response rate in the mid -- mid-80s percent that are deep and durable when you achieve that response, a duration, we don't even know what it is yet because it wasn't reached, but I wouldn't be surprised if it's in the overall years. Progression-free survival that are very long and more impressively, the time to next lymphoma therapy being essentially 93% next lymphoma therapy free 16 months with no sign of the curve dropping, I think that's pretty impressive. Anything that makes a strong case to prefer treatment like R2 in follicular lymphoma after frontline treatment and lead CAR-T cell therapy as a third line. With regard to your DLBCL question, I think that's very important. And the short answer is we don't really have great tools to predict overall survival during chemotherapy, but I think we're starting to have great tools to predict long-term survival after induction chemotherapy. R-CHP polatuzumab is the best treatment for non-GCB large cell lymphoma. And I think not using that treatment for non-GCB large cell lymphoma patients is -- I'm not afraid to say it's an error. For GCB, large selling lymphoma, I think it's much less clear. I don't think that polatuzumab -- what it adds in non-GCB. But in either case, the measurement of minimal residual disease at the end of induction therapy, seems to currently be the most powerful predictor of cure, not just remission or progression-free survival. We know that if you have a clearance of MRD regardless of the results of PET, granted than most of those patients are PET negative, you have an almost 100% chance of being cured. So I think we're getting to a point where we're very, very precise in predicting overall survival after induction therapy. Before the induction therapy that is at baseline, we don't have that ability at the moment. And I think that we're really all very eager to await the results of studies like EPCORE DLBCL-2 that if positive, may have an advantage and may have an advantage not only in progression-free survival because the results that we had seen in the Phase II experience were just so good in patients who were otherwise higher risk. So I think to answer your question, I think that right now, there are tools to predict survival, none of which is readily applicable in clinical practice and we're waiting to see the results of these randomized trials chiefly to EPCORE DLBCL-2 to see if we can improve overall survival across the board, perhaps not even need too many tools to predict overall survival after induction is done.

Thanks, Lorenzo. So thanks, Judah, for the questions. Let's move on to the next question.

Our next question comes from Jaena Han with TD Cowen.

Yes, another question for Dr. Falchi also on kind of the first-line DLBCL opportunity. So EPCORE DLBCL-2 is versus R-CHOP and we know that's COLUMBA versus Pola-R-CHP. I was curious for you and for your colleagues, what degree of PFS benefit do you want to see with the TCO combination over R-CHOP to drive the usage of this regimen over both our job and also over Pola-R-CHP. And also if you could give us some context about kind of the current uptake of Pola-R-CHP in the real-world setting.

Yes, thank you. You couldn't have picked a more difficult question to answer, but I'll do my best. I think that -- it's important to understand there's a big distinction that's important to understand, and that speaks to both of your questions. One thing is what the FDA is asking of a clinical trial. And one thing is what the community is going to do with those results. What the FDA is asking is a progression-free survival advantage that is statistically significant per the study design. If that happens, the study is positive. Now obviously, there's a Phase 4 where you have to see what happens when the community if and when the community picks up the new standard. I think if there is even a strong suggestion of overall survival advantage, there's no question, that's going to just become the new standard across the board. If there is a progression-free survival only advantage it's not going to be at 2%, right? If it is an advantage, it's probably going to be more substantial. As you know, POLARIX had a 6%, 7% advantage in progression-free survival, that was enough to give it at whatever it is, 30%, I believe, uptake in the community. And as always happens, then you do the people do the -- well not be the investigators, they present usually subgroup analysis that have the limitations that they have, but then people interpret those subgroup analysis. And if there are subgroups that have big advantage. It's possible that colleagues in the community might be more attracted towards using the combination in one subset versus another. But I would say again, the study is designed to answer a question in patients, IPI 2 to 5 and in particular, 3 to 5, all comers. And if the study is positive, and you're empowered as a physician to use epcoritamab in association with R-CHOP for those patients. In patients with non-GCB large cell lymphoma, where R-CHP polatuzumab really is delivering very good results. It's going to come down to the always unwarranted practice of cross-trial comparison and frankly, familiarity of the specific position with one regimen or another. That's very hard to control, certainly, even harder to predict now. But I would wait and see. It's not just about the progression-free survival advantage the magnitude of it. Obviously, if you have a 10%, 12% advantage, that's plenty. And if possible, frankly, based on the EPCORE NHL-2 results. But if the advantage is a little bit thinner, then it depends on the specific estimate of progression-free survival in that particular non-GCB population.

Thanks, Lorenzo. So thanks, Jaena, for the questions. Let's move on to the next one.

The next question comes from [ Alec ] from UBS.

Great. Two, please. First, on EPKINLY and R-CHOP in first-line DLBCL. So it's nice to see sustained high PFS and OS rate at the 3-year follow-up. I'm just wondering if the duration data are similar in the GCB and ABC subtypes and if the duration curves are largely driven by one subtype. And second question on Rina-S on ovarian cancer. I was just wondering if you could share anything on the potential filing strategy there. Do you think you can file based on pivotal Phase II data? Or will you have to wait for the confirmatory Phase III trial?

Thanks, Alex, for the questions. I think Dr. Falchi can probably best address the first one and then Judith can address the second part.

Yes. Thank you. Yes, we -- I don't believe we have curves by subtype, the response rates are very similar, and the representation of those patients in the clinical trial is fairly similar to real life with about 60-40, GCB, non-GCB. It's perhaps not surprising because bispecific antibodies were never really shown to work differently in GCB, non-GCB. And so again, you might have that in high-risk patients that is IPI3 and above. With non-GCB, you may have excellent survival curves. And I always recommend caution in comparing and in doing cross-trial comparison. But what we have seen in our experience is really sustained responses at 3 years plus, which is more -- plenty of follow-up for large lymphoma in all patients that we treated.

Thanks, Lorenzo. Judith, why don't you go on, on the registration strategy for Rina. Very exciting.

Yes, super exciting. And as you know, we have R&C, which is designed as a potential pivotal arm more than 100 patients and could potentially make subpart accelerated approval requirements. And in addition, we have the 2 study actively enrolling. So the regulatory strategy is including both the potential pivotal for accelerated approval and a Phase III for full approval.

Thanks, Judith. Thanks, [ Alec ]. You should watch out for next year. Very exciting year. Let's move on to the next question.

Our next question comes from [ Sarah ] with Guggenheim Securities.

This is Sarah on for Michael. Just a really quick one for you. I was wondering if you could speak to the rationale for choosing a core plus square to move into frontline follicular over EPCORE plus bendamustine and rituximab given that now we've seen positive data for both.

I think Tahi can probably best address this, and Lorenzo can chip in there as well, but you're very actively involved Tahi.

Yes, sure. I mean thanks for the question. And so I think you have to just give a little bit back and look at the data that also Lorenzo talked about, which if you start thinking about when we start to make our decision, the ambition that we articulated for opinion was truly going to change follicular lymphoma and really challenge these paradigms that existed in follicular lymphoma where it's an incurable disease. And eventually, with every kind of relapse the duration of response to the PFS shorten. So if you just look at the second-line data in combination with R2, I think it's probably reasonable to say it's at least a reasonable or even one could make that these assumptions in the past are being challenged as we speak with the data in front of us. And they're being challenged essentially with what is a regimen of tough 2 CD20-directed antibodies, a bispecific and native antibody in the pill, which has enormous amount of convenience, but also safety implications. And so I think it's probably fair to say and Lorenzo can add his perspective as a treating physician to that. Generally speaking, the toxicity of R2 even in frontline will probably not be comparable to a region that includes any form of chemotherapy may be bendamustine or more historical cyclophosphamide combination regimens that have been used in front line follicular lymphoma. So the idea was to come up with a regimen that can challenge the current fundamentally change the outcomes for patients in frontline follicular lymphoma to meet these criteria for intensive care, which is criteria historically and provide an option that can be easily administered in the community, and that is patient-friendly and better tolerated. That's broadly speaking, the idea, the ambition of the frontline study and our general strategy in follicular lymphoma was.

Thanks, Tahi. Lorenzo, any further perspective from your side?

Yes, I echo the sentiments and articulation of the rationale. I think having been part of both trials as well as the relapse refractory trial, which -- with EPCORE is clear. I can tell you, when we first discussed the state, this is maybe late 2020. And then the Genmab team presented all the 5 arms we were discussing. And I pretty much after they went through the list, I was like, that's the one that I want to be part of. And I was the R2 EPCORE just because mechanistically and biologically makes just so much sense. You may be aware, but just to simplify lenalidomide, one of the things it does. It reinvigorates your immune response against the lymphoma. So it just kind of made so much sense to say, okay, well, on the one hand, you're reinvigorating the T cells. And then on the other, just hitting them with a drug that just literally grabs them and brings them in proximity to the target lymphoma cell. So that was just the kind of a theoretical rationale then you have to prove it. And what happened in the first few patients in Arm 2, which is the relapse setting was that everybody responded. At our side, everybody responded we just got so excited overnight. And so the hope was that it was going to go further and continue like that and lo and behold, it did. And you can find it published in blood earlier this year, over 100 patients in that arm 2 had an 88% complete response rate. Then the other arm, which is Arm 6, which is a frontline arm, which has a very similar design, has pretty much the same results. So you're seeing something that has the same very powerful effect in second line plus or first line almost doesn't matter what line of therapy you are. That's one element. The other element is let's not forget that now you have 108 patients in the second line for Arm 2. 243 additional patients in second line for ARM 2 and 40-odd patients in frontline. That's why like 400 patients treated with R2 EPCORE. The data for the efficacy and the follow-up are among the most solid in the space, I might say. For bendamustine, rituximab epcoritamab, we really have a very low number of patients. And yes, it's powerful, perhaps to no surprise. But there are several reasons to not prefer, at least from my point of view, I'm happy to discuss. But bendamustine is a very immunosuppressive drug, and it tends to kill several of your T cells, some of the ones that you need for epcoritamab to work. That's not to say that epcoritamab didn't add to bendamustine, rituximab, but it just doesn't add as much. And on the other hand, you really are compromising the immune system quite severely. We've had a number of pretty severe infections in that arm. And there really is no appetite, I think, in the community to use chemo immunotherapy as a backbone. If you take a look across the landscape, all the randomized controlled trials in frontline follicular lymphoma, are against chemo without chemo. So that's really where the field is going. Again, that's not to say that chemotherapy is not working. But we're now in a place when I think Tahi mentioned this, where bispecific antibodies, we're flipping the paradigm. It's not that there's a backbone and then you add bispecific antibodies to them. There's bispecific antibodies, which you really can do without and then you choose the treatment to add on. So I think of R2, for example, as an add-on to EPCORE, not the other way around. If you look at PCRF2, the difference between the curve is so huge, and that's all core that you can't help but think, okay, well, that's core that's driving everything are square is decorating it, but it's really -- the core therapy is really the bispecific. So if that's true, then in my physician researcher mind, like why would I add chemotherapy to that? I think you do more harm than good to the EPCORE. So to me, it's really the chemo-free rationally conceived therapy that's going to have the better hand. And that's why I think EPCORE FL-2 is designed the way that it is.

Thank you, Lorenzo. So I think, Sarah, that's an answer. You can go backward to Michael. So really clear.

Our next question comes from Qize Ding from Rothschild & Co Redburn.

One question from me on EPKINLY. So I remember, I remember you previously talked about the potential indication expansion for EPKINLY in COL. So after seeing the latest data presentation at ASH this year, can you just talk about your latest thoughts on this potential indication expansion opportunity?

I definitely can, but I have a much better colleague to answer that question, that's Tahi.

Yes. Thank you for the question. Lorenzo touched on this in the beginning. The data we presented is in a specific complication of chronic lymphocytic leukemia, essentially a transformation that has been named Richter's transformation, so MYC transformed large cell lymphoma. That's why we presented the data. It's something that we've had conversations with the health authorities in the past and continue to think about what our strategy is in that particular subset. Equally in CLL, I mean this has been a topic where we are continuously thinking. I think it's probably fair to say that the CLL field is fluid right now with multiple changes. And so I think there's a little bit of work to be done on our end to establish the most perfect place for cane to be positioned in that space and we'll continue doing that.

Thank you, Qize, for the question. Let's move on to with the next one.

Our last question comes from Asthika Goonewardene from Truist.

It's on -- so maybe something quick to Dr. Falchi apologies if something similar been asked already. But in the context -- so there are multiple studies in frontline DLBCL. But besides T-cell engages that also include BTKs, we saw so much with [indiscernible], et cetera. All these do have some pretty high CR rates. So maybe to Dr. Falchi here in the context of having all these options in the future, how would you pick the right therapy? And what do you want to see a T cell engager plus R-CHOP show to rationalize using this over the other modalities? And maybe related to that, can T cell engagers be given in the community as easily as CLAs and BTKs to treat frontline DLBCL?

Yes. Because the topic would be too huge to address here, but there's something like 7 or 8 randomized controlled trials going on now. And when we presented the EPCORE R-CHOP data, I think it was last year at ASH, that session was stellar. Like everybody has 100% CR rate. So clearly, CR is an early good surrogate, but you need a time to event analysis. And that's what we presented this year with job at 3 years with very reassuring and encouraging PFS curves in patients who -- let's not forget, have high-risk disease, many of whom have double or triple hit lymphoma. You -- obviously, you may have a situation where 1 or 2 trials largely stand out from the crowd with progression-free survival advantages that are more sizable in more subgroups. It's going to be a slicing and dicing of data. But there's a few factors that are going to help navigate and the landscape, right? One is very simply, who reads out first, right? Because if you read out early, usually, that's a good sign. But you also have more time to penetrate the market and the community. And we know that familiarity with a certain drug or a certain regimen is key. I'm very good at using Ascot, for example, or EPCORE R-CHOP, my neighbor that's never used, they may be less familiar. So that's one other factor. But if you do see a delta that's large enough, frankly, I hope so, from bispecific R-CHOP or polatuzumab, then I think if there is a bispecific that's easy to combine with chemoimmunotherapy, that top core and there's multiple reasons for that. One is that it's subcutaneous. Let's not forget, logistics are very important. Some of the other intravenous bispecific, you can't give them the same day. as R-CHOP or polazutumab, that means patients have to come another day. Secondly, because your peak of CRS incidence is in cycle 1, day 15 you have given R-CHOP 2 weeks prior, you have debulking enough to dampen some of the CRS. The CRS rates in EPCORE NHL-2 were quite good. But even more importantly than that, perhaps, the idea that you have a subcutaneously administered bispecific that is "gentler" or it gets eased a little bit more smoothly into the patient allows you to start that bispecific in cycle 1, day 1, and that's critical for me. Because most of the resistance that you see, even in patients who end up having a complete response is born in cycle 1 in second one. And so having the ability to potentially rescue those patients who are destined to fail later starting from cycle 1 may be a structural advantage of EPCORE-based platforms as opposed to others. Again, you're going to have to see the data. You're going to have to compare to the best of your ability to data. But at least in principle, as of now, the reason that I'm more excited about following those developments with EPCORE DLBCL-2 because of these very plausible advantages that it has over the landscape.

One quick one to you here. The [indiscernible] data at ASH looked really interesting in the unfit frail population. I was just wondering if that is encouraging Genmab to also consider something like that with an ADC with a chemo preoption and if you could tell us a little bit more about your thinking.

Thanks, Asthika. That's probably question for Tahi.

Yes. I mean thanks, Asthika. Generally speaking, I would say this in our strategy on the elderly frail has been to essentially establish an anchor and plan. And hopefully, the study will read out in the anchor registration, which would be frontline R-CHOP and then provide additional data that informs factors within that anchor in R-CHOP, where you basically just can dose-reduce anthracycline or even in monotherapy where you can basically just drop the chemotherapy if the patient is really not tolerant. That's kind of like how we're starting to think about this and I would say there's a lot of -- there was a lot of debate at ASH actually to who is really fair and how far has been defined on these trials. And so there's a little bit of a discussion on each of these trials. So rather failed patients are something to think about. So we don't really -- actually at this point, concretely have any plans to combine with [indiscernible]. It is probably for Medicare first point, an interesting strategy. It's not necessarily clear to me why we would engage in that end. But anyway, we'll see. More to come on that end. We feel very happy with where we are with the data that we're generating in elderly, in fair, and we're really enthusiastically expecting the readout of our front line for the next year.

Thank you Tahi. I think that's a good closing remark. So thank you, Asthika, and thank you all for the very good questions and sight for questions today. Next slide, please. Thank you all for joining us today, and a special note of thanks goes to Dr. Lorenzo Falchi for his contribution to this year's event. We're very thankful for that. And from all of us at Genmab, we wish you all happy holidays and the healthy, happy and truly wonderful '26. Looking forward to speak with you next year. Thank you.