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

Hello, and welcome to Genmab's 2024 R&D update and ASH data review. I'm Jan VAN de Winkel, President and CEO of Genmab, and I'm delighted to share with you some of the highlights for Genmab in 2024 as well as data from this year's ASH meeting. As always, we have a busy agenda, so let's jump right in. Next slide, please. As a reminder, this presentation may contain forward-looking statements and, as such, may contain certain risks and uncertainties. Let's move to Slide 3. Genmab is a science anchored and innovation -- has a science-anchored and innovation-focused culture. Collaborations and partnerships have always been part of our DNA. During today's presentation, we will reference some of the products being developed under the strategic collaborations, and this slide acknowledges those relationships. Let's move to our agenda on Slide 4. We will begin with a review of the progress we made this year as we advance toward our 2030 vision. Central to our achievements are the significant advancements for EPKINLY and Rina-S. To provide a comprehensive understanding of these developments, our Chief Medical Officer, Tahi Ahmadi, will deliver an overview of both the EPKINLY and Rina-S programs, highlighting key milestones and near-term plans. Following Tahi's presentation, we are excited to share a pre-recorded presentation by Dr. Elizabeth Lee. She will discuss the latest Rina-S data that was showcased at the European Society for Medical Oncology Congress in September. And next, we will review some of the pivotal epcoritamab data presented at this year's ASH meeting. And for this, we are very pleased to have a presentation with Dr. Martin Hutchings. Looking ahead, we will provide a brief overview of some of the key events we are anticipating for 2025. To conclude, we will open the floor for a lively Q&A session. But first, let's explore some of the highlights from the past year that have set the foundation for our continued success. Next slide, please. This has been a landmark year for Genmab, marked by significant milestones that advance our mission to bring innovative medicines to patients. We and our partners successfully submitted and obtained multiple regulatory approvals for both EPKINLY and TIVDAK. These approvals are pivotal in making these therapies accessible to a wider number of patients. And with its strong performance in markets like the U.S. and Japan, we are confident in our ability to grow the footprint for EPKINLY to reach even more patients. We will also accomplish 2 additional -- this 2 additional indications. And I'm pleased to note that there are currently 5 Phase III trials ongoing for epcoritamab, including frontline trials in both diffuse large B-cell lymphoma and in follicular lymphoma. While EPKINLY was our primary focus at the beginning of 2024, we have now expanded our late-stage development pipeline to include Rina-S and acasunlimab. All 3 of these programs, EPKINLY, Rina-S and acasunlimab have the potential to drive significant future growth. Rina-S was a key factor in our acquisition of ProfoundBio, the first major acquisition in our 25-year history. This acquisition enhances our pipeline and positions us for long-term success. All partnerships continue to validate our innovation and technology. And notably, both DARZALEX and [indiscernible] received multiple additional regulatory approvals this year. Of particular note is the relatively recent submission by J&J for regulatory approval of subcutaneous daratumumab in both the U.S. and Europe for high-risk [indiscernible] multiple myeloma. And if approved, this would be the first treatment option for these patients, providing a novel approach to treat people at risk before the onset of active disease. So let's move to the next slide to explore the impact of these milestones. The acquisition of ProfoundBio has been a significant milestone, enhancing our capabilities with next-generation ADC platforms. This strategic addition, combined with our diverse existing next-generation antibody technologies, positions us to accelerate the development of world-class therapies. With 2 50-50 partnered medicines successfully on the market, we are building the necessary infrastructure and expertise to bring medicines directly to patients ourselves. And now these capabilities can be leveraged with our wholly owned programs, Rina-S and acasunlimab. These product candidates, along with EPKINLY, exemplify our focus on developing best-in-class therapies. And we will continue to develop our novel clinical stage assets, while also making strategic decisions to prioritize high-potential programs, ensuring our pipeline remains focused and impactful. Before we move to today's data presentations for Rina-S and EPKINLY, I would like to introduce our Chief Medical Officer, Tahi Ahmadi. Tahi will walk you through where we are with both programs, including a look at our development plans for Rina-S. Tahi, the floor is yours. Next slide, please.

Well, thank you, Jan, for this kind introduction. And if we just move on immediately to the next slide. Well, let's start with EPKINLY. We just come out of an exciting ASH, where we had a significant presence with more than 20 abstracts, 4 oral presentations, really highlighting the quality of data across a spectrum of data that we've been generating, focusing on efficacy and the durability of the efficacy, the safety profile as well as the versatility and the ability to combine with a variety of backbones, which to us is a key component of the development strategy for EPKINLY as we move it along the lines. As note, EPKINLY is the first and only bispecific approved for both indications, diffuse large B-cell and for follicular lymphoma and third line. On this slide, you have the 5 Phase IIIs that Jan highlighted, this is a very robust program this early in the development stage for any product in lymphoma. They're very part of our achievements with our colleagues at AbbVie. I should note that the frontline diffuse large B-cell study in combination with [indiscernible] versus [indiscernible] is already fully accrued way ahead of the initial projections, a testament to the excitement of both patients and investigators. The same is true for the second-line follicular lymphoma study in combination with R2. We have a Phase III in combination with lenalidomide in the second-line diffuse large B-cell that is now actively ongoing. And the frontline follicular lymphoma study is also moving very rapidly. So very excited about these Phase IIIs and expecting readouts on these Phase IIIs, particularly on the ones that are fully accrued in the foreseeable future. As we transition to the next slide, the expansion of our plan to the acquisition of ProfoundBio, Jan highlighted the key component of that is Rina-S. Again here, moving very rapidly into expanding our development program. We have an ongoing Phase I study that has multiple cohorts. It has expansion cohorts both in endometrial as well as in ovarian, but also combination data that's being generated with [ cabo ] with PD-1 and really intended similarly to what we have done on EPCO. To very early generate data in combination to then allow us to move into earlier combination settings in earlier lines. The Phase III, as we already discussed on the Q3 call in receptor alpha, all-comer population product is open and is ready. So [indiscernible]. And so we're excited about the acceleration of our registration-enabling program here in this program as well. And with that, I hand it over back to Jan.

Thank you, Tahi, for that excellent overview. It's now my pleasure to introduce a video by Dr. Elizabeth Lee. Dr. Lee is a faculty member within the Department of Medical Oncology and Division of Gynecologic Oncology at the Dana-Farber Cancer Institute in Boston. In September, she presented the promising Rina-S data at ESMO, and we are grateful to see Dr. Lee -- to have Dr. Lee provide us with a review of the data again today. Please play the video. Move to the next slide, please, and then the video.

On behalf of my co-authors, it is my pleasure to present data from the Phase I/II study evaluating [indiscernible] or Rina-S in patients with advanced ovarian or endometrial cancer. These are my declarations. There continues to be a significant unmet need for the treatment of patients with ovarian or endometrial cancer. Fully receptor alpha or FR alpha is a validated therapeutic target that is overexpressed in multiple solid tumors, including in ovarian and endometrial cancer. Rina-S is an investigational antibody drug conjugate, or ADC, that is directed at [ ever ] alpha with a novel hydrophilic [ cleavable linker ] and carrying a [indiscernible] payload. Additionally, Rina-S features a high homogeneous direct to antibody ratio of 8. We conducted a study evaluating single agent Rina-S administered once every 3 weeks for the treatment of advanced solid tumors, regardless of fully receptor alpha expression, which was only tested retrospectively. From Part A dose escalation, we evaluated patients with heavily pretreated ovarian and endometrial cancer, treated with Rina-S 100 or 120 milligrams per meter squared. Cohort B1 of dose expansion involved 42 patients with heavily pretreated ovarian cancer who are randomized 1:1 to receive either Rina-S 100 milligrams per meter squared or Rina-S 120 milligrams per meter squared. These patients received a median of 3 prior lines of therapy, and almost all [ hapatinum-resistant ] ovarian cancer and had received prior bevacizumab. Additionally, 20% of patients received prior [ mirvetuximab soravtansine ], or MIRV, for short. In dose escalation, Rina-S showed encouraging antitumor activity in patients with ovarian and endometrial cancer with a confirmed objective response rate of 30.8% and a disease control rate of 88.5%. As shown on the waterfall plot on the right, treatment with Rina-S led to meaningful reductions in target lesion size for both ovarian and endometrial cancer patients. The median duration of response was 35 weeks, as was the median on study follow-up. At the time of data cutoff, 3 patients had ongoing responses. In patients with ovarian cancer from dose expansion, treatment with Rina-S 120 milligrams per meter squared led to an encouraging confirmed and objective response rate of 50%, including one complete response. Treatment with Rina-S 100 milligrams per meter squared led to an objective response rate of 18.2%. In addition to a superior response rate, treatment with Rina-S 120 milligrams per meter squared led to deeper and more meaningful tumor size reductions, as seen in the waterfall plots on the right. At the time of data cutoff, the median duration of response was not yet reached. As shown on the [indiscernible] plot, responses with Rina-S 120 milligrams per meter squared were observed as early as 6 weeks. At the time of data cutoff, all confirmed responses with 120 milligrams per meter squared were ongoing, and most patients with stable disease had not yet progressed. Of note, responses were also observed in patients who have received prior [ mirvetuximab soravtansine ]. Responses with Rina-S were observed in tumors with [indiscernible] expression of [ PS2+ ] at both cutoffs of greater than or equal to 75% and less than 75%. An exploratory analyses, we also observed clinical activity with Rina-S and ever alpha expression of [ PS1+ ] at a cutoff of less than 25%. In cohort B1 of dose expansion, the safety profile was similar between the 2 dose levels. The most common treatment-emergent AEs were cytopenias and Grade 1 or Grade 2 gastrointestinal events. Grade 3 or Grade 4 neutropenia occurred in approximately 45% of patients. Treatment-emergent AEs leading to dose reduction or treatment discontinuation were similarly low. Prophylactic GCSF was used in 32% and 50% of patients treated at the 100 and 120 milligrams per meter squared dose levels, respectively. There were no signals of ocular toxicities, interstitial lung disease or neuropathy observed in this reported patient cohort. In conclusion, single age Rina-S given once over 3 weeks showed encouraging antitumor activity in patients with ovarian and endometrial cancer. In dose expansion, treatment with Rina-S at 120 milligrams per meter squared resulted in a confirmed objective response rate of 50%, including a complete response in patients with heavily pretreated ovarian cancer. All responses were ongoing at data cutoff. Responses were observed regardless of FRL expression levels as well as in patients with prior [ mirvetuximab ] exposure. Rina-S was both tolerated with manageable treatment-emergent AEs. Based on these findings, further evaluation of Rina-S is ongoing as a single agent and in combination with other agents. On behalf of the authors, we'd like to thank the patients, study investigators and site personnel for their participation.

Let's move to the next slide. Next slide, please. Turning now to the upgrade and update at ASH, I would like to introduce Dr. Martin Hutchings. Dr. Hutchings is a hemato-oncologist at Rigshospitalet in Copenhagen, Denmark. He's a world-class expert in the treatment of malignant lymphoma and a key investigator on the first Phase I/II study of epcoritamab. We very much appreciate Dr. Hutchings being with us once again to review some of the algorithm update presented at this year's ASH. Martin, please go ahead.

Thank you very much for the introduction. And I think you just need to tell me whether I share my slides or whether I can ask to the next slide.

Yes. Next slide, please. We can see your slides. Yes.

So thank you very much for the opportunity to give a fresh brush up of a truly exciting ASH, which finished just yesterday. So I completely agree with Tahi that there was a lot of action also on epcoritamab, really exciting and clinically useful data. And I will try to give you a brief update of the most important points that have been made over those last 3, 4 days. So next slide, please. We have technical issues here. Are you just playing my slides? Here we are. So we'll begin with the pivotal NHL 1 trial, and this trial was -- or is a trial of looking at single agent epcoritamab therapy in the treatment of relapsed and refractory large B-cell lymphomas with 2 or more prior lines of treatment. And this is a situation for which until, just a few years ago, there was actually no standard of care and outcomes of conventional therapy were generally very poor. So since then, we've had the introduction of CAR-Ts in third-line therapy, much improving outcomes for those patients with access to such treatment. And then more recently, approval of the bispecific antibodies, including epcoritamab. So this is an update of the pivotal study that led to the approval of epcoritamab in this very indication. So this is an overview of the study design. You can see that the patients who were led into the study had what we call large B-cell lymphomas. There are several subgroups of those with different characteristics and risk profiles. They needed to have a reasonable performance status, so general status and organ function, and they needed measurable disease. Epcoritamab was given in the step-up fashion. So with a small initial dose, a slightly higher intermediate dose after 1 week and then from cycle 1, day 15, so that's 2 weeks into treatment, the full dose of 48 milligrams of epcoritamab given weekly for the first 3 cycles, that's 12 weeks, then biweekly for the next 6 months and then every 4 weeks and until progression or an acceptable toxicity. The primary endpoint of this study was overall response rate with key secondary endpoints included, complete response rate and, of course, the survival analysis, particularly duration of responses and progression-free survival. So what was presented here at ASH? And fortunately, just in a poster with quite mature follow-up results at a -- mature follow-up of almost 3 years, including not only the efficacy parameters, but also a long-term look at safety. Next slide, please. So to cut a long story short, the overall safety profile consistent with what has been reported and also published recently. So of course, the primary acute toxicity of the bispecific antibody is cytokine release syndrome long over with in all of these patients and already reported and really quite manageable and generally of low grade in the majority of patients. So at this point, more interesting is perhaps to look at the more long-term side effects, which are dominated by the slightly increased risk of infections, which is brought about by the long-term B-cell depletion. So it's encouraging to see that almost 3 out of 4 patients who were on treatment for more than 2 years. And these are perhaps the worry because of the long-term suppression of B-cells, 3 out of 4 of those, 73% did not experience a serious infection as defined by Grade 3 or higher. We do see cytopenia, so drops in blood counts among patients, mainly seen to a high degree in -- during the first couple of months of treatment. And then later on, these reduced rates of both platelets and particularly white blood counts go back to normal. Except, of course, for the B cells that I mentioned, they keep being low and depressed as long as we treat the patients because it goes with the territory of B-cell depletion. Next slide, please. So looking at the long-term efficacy outcomes, the overall response rate for the overall population remains stable, let's see, at 59%, with 41% of complete responses. So 41% with a complete disappearance of the signs of disease on the PET scan, which is the used method, preferred method for response assessment in this disease. Now for patients who were on treatment for a long time -- prolonged time, over 12 and 24 months, we see that very few of those patients actually lose their response. So patients come off treatment during the first year, a few due to toxicity, more due to progressive disease. But for those patients who are on prolonged treatment beyond 1 and particularly 2 years, we see very rare cases of loss of response, which is really encouraging, and to some extent, supportive of the treatment until progression at least in some patients. Next, please. So this is the take on the durability of the complete responses. 41% of the patients responded completely, and they are really the meaningful responses. And I think this chart is really a testament to that clinical meaningfulness. You can see that for the overall group, the median duration of a complete response was 36 months. That is 3 years. So 3 years of maintained complete responses in disease situation where, like I said, until 5, 6 years ago, there was no real meaningful treatment. And this durability is more or less the same regardless of which of the subgroups of large B-cell lymphomas that we are looking at. At the bottom, you can see a statement saying that this suggests a curative potential that was criticized and discussed a little bit during the ASH meeting because how can you say that something is curative if you keep giving the drug. But I think the suggestion is strong enough. But of course, it's clear that clinicians and colitians need guidance on how long to treat patients and if treatment until progression is really relevant, at least in a subgroup of patients. Next slide, please. Looking at the overall survival. Again, a testament to the clinical meaningfulness of this great therapy. You can see that at 3 years of follow-up, 75% of the complete responders have not initiated a new antilymphoma therapy, and that is because they were still alive and progression free at the time of the most recent follow-up. You will see that for the overall group of large B-cell lymphoma patients at 3 years, the overall survival, 63%. Next slide, please. So in conclusion, the long-term safety consistent with previous reports and no new important safety findings, which is really encouraging because it's a concern when you keep B-cell depleting your patients for several years, but really no serious long-term signals. About efficacy, the complete response rate is maintained. That's not a big surprise, but the durability, that was really the big news from this year's ASH with a median duration of complete response of 36 months, 3 years, median progression-free survival, more or less the same, 37 months. And the median overall survival, as I just showed you, is not reached. So long-term remission support, to some extent, treatment until progression, at least for subgroups of patients in this heavily pretreated patients with at least 2 prior lines of treatment and in the eyes of the beholder, suggesting a curative potential, at least for some of these patients. Next slide, please, which is where we move on to another important study also presented in this time as an oral session. This was the Phase II study of fixed duration epcoritamab plus R-CHOP in previously untreated patients with diffuse large B-cell lymphoma, and this was one of many cohorts of the important EPCO-NHL2 trial, which had a lot of different cohorts where epcoritamab was combined with several different standard therapies in various indications and various treatment lines. But here, we're looking at the combination of epcoritamab and R-CHOP in first-line treatment. Next, please. So the background for this is that we have a very well-established standard of care in first-line treatment, unlike third-line treatment. R-CHOP has been used for 20, 25 years and has not very often been successfully challenged by new regimens. But that doesn't mean that there isn't an unmet need because with R-CHOP, we actually only cure approximately 2/3 of patients. And also, there are many patients who cannot tolerate R-CHOP. We have initial data showing safety when looking at the combinability of epcoritamab and R-CHOP. And here, we present long-term outcomes with more than 2 years of follow-up for this combination in the first-line treatment of large B-cell lymphomas. Next, please. So this is the study overview. Patients could be included if they had large B-cell lymphomas newly diagnosed. And they need it and this is important, an IPI score of 3 to 5. What does that mean? That means that they need to be among the approximately 50% of worst prognosis patient in order to be included in this study. R-CHOP was given in the usual 3 weekly doses, time 6. Epcoritamab added weekly for the first 4 of those doses, then every 3 weeks, so once together with each of the 2 last of the R-CHOP doses. And then in this study, every 4 weeks after the completion of chemotherapy until up to 1 year of total epcoritamab treatment. The primary objective of the study was the antitumor activity as assessed by the overall and complete responses and also with MRD negativity as an important secondary endpoint using the [ Avino Cap Seq ctDNA ] essay. The median follow-up for this analysis, importantly, just over 2 years, 27 months. Next, please. So here, you see a rough overview over the safety profile, actually very similar to what has been presented previously. And I would say that the safety profile of the combination really is in keeping with the contributions of the individual elements. So looking at R-CHOP on one side and then epcoritamab. And it's important to look at the cytokine release syndrome which is the bar #3. That is brought about, of course, by the epcoritamab, mainly during Cycle 1 and early in Cycle 2 of this treatment, and we see that both frequency and severity in keeping with epcoritamab monotherapy, very rarely, CRS of Grade 3 or higher. Next, please. So this is a very active combination. We're not surprised to see high responses because we see high response rates to R-CHOP as well, but it's still quite encouraging to see 100% response rate in the efficacy-evaluable population of 46 patients. That's actually all patients except one that made it to the first response assessment and could be included in the efficacy evaluable population. So 100% response rates. And as you can see -- and this is just as important -- very high complete response rate in the range of 80% to 90%, depending on the subgroup studied. Next, please. And these responses are really quite durable. These swimmer charts are a little bit busy to look at. But what you will see is that for the patients who end their treatment finish -- complete their treatment, not only the chemotherapy, but also the epcoritamab maintenance up to 1 year, you will see that all these patients at some point, most of them very early during treatment, some of them later during treatment, reach complete responses. And in the vast majority of patients who are still being followed, these complete responses are maintained. That is actually the effect for all patients finishing treatment and complete response, except 3. So really durable responses and promising a high cure rate in these difficult-to-treat patients with high-risk features. Next, please. And that is, of course, reflected by the both survival curves and, in this case, the curve showing the durability of complete responses. Time is here counted from the time of the first complete response observed in the patients. And you can see that, for those patients who read to complete response at some point, the durability of that complete response is very, very high. The median, of course, far from being met, 83% at 21 months, which is the median follow-up for that part of the population. Next, please. And that is, of course, reflected in equally impressive progression-free survival. I just told you before that for the overall group of patients with large B-cell lymphoma, the cure rates are among -- just around 60%, 65%. Of course, this is not cure rate. We're looking at progression-free survival, but still, it's encouraging to see 82%, 83% progression-free survival rates at almost 2 years, considering that we are thinking about a high-risk group of pensions. Next, please. And overall survival increasing and in -- just equally encouraging at 87% for the overall population and 83% for the high-risk group of patients with double or triple hit lymphomas, those that we also call hybrid lymphomas. Next, please. So the conclusion from this important update was the fixed duration epcoritamab with the standard R-CHOP chemotherapy induced remissions in the vast majority of patients and in the majority of these patients with responses, also highly durable remissions, as we can see with this long-term update. No safety signals observed. And this is really quite important, particularly because these patients are, of course, all -- the majority of them will be cured. So long-term safety signals are particularly important here. And we believe that these findings compare favorably with R-CHOP alone. Of course, that is a historical comparison so far. But as Tahi Ahmadi already told you, the Phase III study of R-CHOP, plus or minus epcoritamab in the first-line treatment of large B-cell lymphoma has been ongoing, accrued very quickly and has, as I understand it, completed accrual earlier this year. Next slide, please. So then we move on to another abstract, which also made it to the oral sessions. It was the single-arm study of epcoritamab monotherapy in elderly and/or frail patients over the age of 75 years with previously untreated large B-cell lymphoma patients, excellently presented by my colleague, [ Frank Morschhauser ], a couple of days ago. Next slide, please. So this is a completely different population because, generally, the cornerstone of curative treatment or curative chemotherapy for large B-cell lymphoma is the [ anthracyclines ], usually doxorubicin. But this is not an easy drug to tolerate, particularly for NMV patients. So the majority of patients over 75 or 80 years, they cannot tolerate the full course of R-CHOP. Sometimes we reduce the doses of the chemotherapy, then we call it R-MINI-CHOP, but many patients cannot even tolerate reduced doses of these quite intensive chemotherapies. So about 10% of newly diagnosed patients are ineligible for anthracycline treatment, low or full doses. And of course, as you can imagine, they are highly concentrated among patients who are elderly, both because the general frailty and particularly because of cardiac or other comorbidity. So this trial looked at patients who were old or elderly, older than 75 years and for many -- in many cases, had relevant comorbidities, preventing them from accepting or tolerating anthracycline-based curative intent chemotherapy. Next slide, please. And this is really a population of patients that we struggle with in the clinic. They are not easy. And as the median age at onset of large B-cell lymphoma is around 65 years, you can imagine that this is actually a relatively high group -- prevalent group of patients that we see every day. Patients could be included if they had newly diagnosed large B-cell lymphomas, a reasonable performance status of 0 to 2. And then, like I said, ineligibility for anthracycline-based cytotoxic therapy defined as either an age over 80 on its own or an age over 75 with a well predefined comorbid condition, and that could be cardiac comorbidity, but also other co-morbidities. And patients should have measurable disease. So this was, in fact, a randomized study, but no randomization results were presented in this analysis. So you can regard the data that I show you here as a kind of single-arm study of single-agent epcoritamab because no data have yet been presented regarding the other side of the randomization, which is the combination of epcoritamab and lenalidomide in the same patient group. Next, please. So this -- just a quick overview to give you a taste or a feel for the comorbidity status of these patients. And this is actually a slide that really called attention because you can see there was a lot of comorbidity. 78% of patients included hypertension. 71% had elevated cardiac enzymes. That means there is some kind of strain on the heart, not necessarily symptomatic, but still a clear signal that these are patients where you should be very careful with anthracyclines or probably not give them at all. And then you can see a long list of other comorbidities with relevance, particularly for the vasculature of the patient. Next slide, please. So despite these patients being previously untreated, which means that they have a relatively intact immune system, they actually tolerated treatment quite well with less cytokine release syndrome than some of us had perhaps feared or anticipated. You will see that frequencies of cytokine release symptom are a little bit higher than, for example, in the groups of patients treated for relapsed or refractory disease. CRS was seen there in approximately just under half of the patients. And here, you can see that cytokine release syndrome is seen in just over 70% of patients, not a surprise because this is a single agent given to patients who have not had their immune system suppressed by previous chemotherapy. But the good news is that the majority -- the vast majority, in fact, of patients experiencing cytokine release syndrome did so at low grade. So 39% with Grade 1, that is just fever, and 27% Grade 2 fever accompanied by either hypoxia and/or hypotension, manageable in a standard hospital setting and generally of relatively short duration and easily manageable in a regular hospital clinic. So 8 patients experienced serious infections. We call that Grade 3 to 4 infections or a serious adverse event infections. And this was, to some extent, dominated by COVID-19 because many of these patients were treated during the height of the COVID pandemic. Neutropenia was relatively rare. We do see neutropenia in the context of epcoritamab treatment, but usually quite transient and rarely, very deep. So that's probably the explanation why none of these neutropenias led to febrile neutropenia. So 5 patients had fatal treatment-emergent adverse events. And mainly of infectious character, 2 caused by COVID-19, 1 by CMV virus reactivation, 1 tumor hemorrhage and 1 case of tumor lysis syndrome early during therapy. ICANS were reported in 7 patients ICANS is a complex of central nervous system phenomena that was seen in association with cytokine release syndrome and immune effector cell therapies. I would cast doubt on whether these were, in fact, real ICANS. We are talking about elderly patients who develop a high fever in a hospital environment. So confusion and related phenomena are actually expected in patients even if they are treated just with chemotherapy or without any immune therapy. But this is conservatively reported and still quite encouraging. Next slide, please. Another take on the cytokine release syndrome. Like I said, just over 70% of patients experienced cytokine release syndrome. At some point, the vast majority of those are low-grade, fortunately. And you can see on the right that the pattern of first occurrence of CRS is just like we've seen it with monotherapy in a later light setting, which is that most of the cases of cytokine release syndrome occur after the first full dose of epcoritamab, which is 2 weeks into treatment. And quite predictably, the majority of cases of CRS occur within the first 24 hours of that first full dose. And in the vast majority of cases, quite easily manageable and resolving within typically 2 to 3 days. Next slide, please. So a quick look at efficacy. For the full analysis set, which is 45 patients, all of the -- including patients who were not response evaluable. The overall response rate was 69%. And if we look only at patients who made it to their first response evaluation, the overall response rate was 78%. And among those, the vast majority reached complete responses. In the efficacy evaluable set, that's 70% of all patients, which is regarded as relatively good in such a difficult-to-treat population. Remember, these are patients who are not candidates for real effective chemotherapy. So they would be candidates otherwise for what we would consider more or less palliative chemotherapy. You can see in the subgroup analyses, which are, of course, hampered by the relatively low number of patients, there are no real clear signals as to which patients benefit less or more than others. But it's actually comforting to see, if you look at the age that patients included over 80 years of age, which was the majority of patients actually had the same good response rates as the overall population and perhaps looking at the main numbers a little bit higher, even. Next slide, please. And here, we look at the swimmer plot showing the individual patient's fate in order to give us a little bit of a taste of the durability of these responses. And you can see that many of the patients reaching complete responses, and that was again the vast majority of patients, they remain in remission with a complete response at the most recent data cut, so suggesting not only effective antitumor activity at the time of treatment and early thereafter, but in fact, suggesting high cure rates in these patients, even though, of course, that should be said with caution because this follow-up is relatively short. Next slide, please. So here again, you have another take on the durability of the responses. 82% for the overall population of at least 6 months of response, and you will agree with me that the follow-up is really short, but it's still nice to see that patients stay in response well beyond the completion of their treatment. Next slide, please. And here, we have the progression-free and overall survival. And you will probably notice that this is -- looks not quite as good as in the previous demonstration of the efficacy of R-CHOP plus epcoritamab. And this is what we are used to seeing in the elderly patients, first of all, they more frequently die of other things than lymphoma. They are more frequently subject to fatal adverse events that are not lymphoma-related, but still seeing progression-free and overall survival not reaching 50% within the first year of observation is actually quite encouraging. The median follow-up here is too short to really make firm conclusions, 8.1 months for the analysis of PFS and 9.5 months for the analysis of overall survival is, of course, only very preliminary data. Next slide, please. So this actually caught quite a lot of attention. And the audience generally seem to be agreeing with the conclusion that epcoritamab, which in this case was given up to 1 year. So not until progression, what seems to have a role in this difficult to treat and how to reach population of elderly and/or comorbid patients ineligible for anthracycline-based first-line chemotherapy. CR rates in the evaluable population of 70%, and 89% of the complete response is ongoing at the most recent data cut, which admittedly is quite soon after completion of treatment with a very short follow-up. Also something that I didn't stress, MRD negativity as we have observed often is reached in the younger population, is also seen in this elderly population, and it's another surrogate for the benefit of the treatment and a surrogate for later cure, at least in some patients. Safety, quite encouraging. The -- perhaps feared a high-grade severity of cytokine release syndrome in immune naive and previously untreated group of patients was not confirmed, even though CRS was seen more frequently than in cohorts of patients with heavily pretreated disease. Again, the vast majority of cases of CRS were Grade 1 or 2. So this is really regarded as quite promising, and there was a line of debate after this presentation. So next slide, please. Perhaps the most talked about at least of the oral abstracts that I attended involving epcoritamab was this one. Another set of results coming out of the NHL 2 study with the many different cohorts. And in this cohort, it was patients with newly diagnosed follicular lymphoma treated with the combination of epcoritamab and bendamustine rituximab. Next slide, please. So this is a group of patients where we have had many standard treatments for many years. And the most commonly used standard nowadays is the combination of rituximab and bendamustine chemotherapy. And that leads to a response in the vast majority of patients. This CR rate of 30% is from historical data before the introduction of PET CT. So you should take that with a very big pinch of salt, but still, the point is that we induce responses even with standard chemotherapy in the vast majority of patients. The problem is that all these patients eventually will relapse and have a need for new treatment. And the whole idea behind first-line treatment of follicular lymphoma is to make that relapse-free period as long as possible. So that's the background for the combination of bendamustine rituximab with epcoritamab in this very treatment setting. Next, please. So patients could be included into the study if they had a newly diagnosed follicular lymphoma with a treatment need according to the [indiscernible] criteria and a good general status and organ function. So they were treated with the classical schema of rituximab bendamustine, which is a 64 weekly cycles. And for the first 3 of those cycles, epcoritamab was given weekly for the next 3 -- every 2 weeks and then every 2 weeks for another 3 cycles of epcoritamab. And then every 4 weeks from cycle 10, day 1 and onwards and until up to 2 years after beginning of treatment, with overall response rate as the primary endpoint and again, secondary endpoints such as CR, complete response rate and durability of complete responses, progression-free and overall survival as important secondary endpoints. Next slide, please. So again, here safety is important because we are talking about newly diagnosed patients with a very good treatment already available. So it's important that in order to perhaps increase efficacy antitumor activity a little bit, we should not compromise safety. Fortunately, again, that was not apparently the case because what we saw of side effects or toxicity signals were really in keeping with the individual contribution of bendamustine on one side and epcoritamab on the other side. In this case, cytokine release syndrome was not the most commonly reported adverse event that was seen in the majority of patients, but exclusively of Grade 1 to 2. But due to the timing of this study, the most frequently occurring adverse event was really COVID-19, which, as you can see, was recorded in the vast majority of patients. Fortunately, not of the fatal character in the majority of these patients. One patient had a Grade 5 COVID-19 event. Next slide, please. So cytokine release syndrome, we look at that again, focused here. You can see, like I said, no cases of Grade 3 or 4 CRS occurred and the majority of the cases of cytokine release syndrome once again occurring after the first full dose of that drug, which is 2 weeks into the first cycle of treatment. Again, occurring quite predictably within 2 days of the first full administration of glofitamab and usually quite transient resolution within a median of 2 days, although there were some cases of more prolonged cytokine release in a few patients. Next slide, please. Overall responses, 96%. And all of those 96% of responding patients, which is all but 1 of 25 evaluable patients, had complete responses. And of course, you can't really compare that with historical data because, back in history, PET CT scans were not used, so the comparator is a little bit tricky. But still, this is really encouraging. And I wouldn't say that in the clinic, we expect 96% of patients with newly diagnosed follicular lymphoma to reach a complete response. So the median follow-up for this patient group is 2.5 years, 13 months. You can say that looks like a long time, no. In follicular lymphoma, indeed 2.5 years is a short time. Follicular lymphoma is a disease where benefit is measured more rather in decades than in years. So these are just really preliminary data, but I must say they are very encouraging. And as you can see that the durability of the responses on the right looks very, very promising indeed. Next slide, please. This is another take on the durability of responses and the clinical benefit for the patients. All the green dot means that patients at their regular assessments are in complete response. Many of them make it to the end of the 2 years of treatment. That is the blue diamonds, a complete treatment. And you can see that the complete responses extend beyond the complete completion of this fixed duration treatment. Next slide, please. And that leads to a progression-free survival, which is at 2.5 years, estimated at 83%. And, of course, the median very, very far from reached, and you can discuss whether, in fact the median progression-free survival will be reached because I know that we generally look at follicular lymphoma as an incurable disease, but perhaps the introduction of the T cell engagers will change that dogma. Next slide, please. Overall survival, a testament to the high efficacy of the treatment, but also the natural history of the disease itself, 96% at 2.5 years. Next slide, please. So generally accepted conclusions, they were not really debated during the presentation is that the combination of bendamustine rituximab plus epcoritamab leads to very, very deep in durable responses, even though the follow-up is still relatively short in the context of newly diagnosed follicular lymphoma. Safety profile, manageable, consistent with previous reports from the study and also consistent with the individual components of the combination. And you can discuss whether the comparison with historical CR rate of 30% is meaningful, but I think this data just can stand for themselves. CR rate of 96% is really, really high even in this setting. Next slide, please. So another study in follicular lymphoma has been presented several times before is another cohort from the EPCO NHL 2 multi-arm study. And in this case, it's the combination of epcoritamab and R2. That's the same as rituximab, lenalidomide, which in this part of the study was given for patients with relapsed or refractory follicular lymphoma. This has been presented several times before, but still an important and interesting update of the efficacy and safety from this cohort. Next slide, please. So R2, as I call it, rituximab-lenalidomide, has been used in many years, and it is a standard of care for patients with follicular lymphoma, sometimes used in first line, sometimes in second or in later lines of treatment. So that is based on the data from the AUGMENT study in relapsed refractory follicular lymphoma, where the overall response rate was 78%. And CR much lower, but again, based on CT-based determination of responses. So this is the standard that this study would look to improve by combining R2 with epcoritamab. And in the case of this study, next slide, please. The treatment is given, again, in a fixed duration, so with lenalidomide up to 1 year of treatment and with epcoritamab for up to 2 years of treatment and rituximab only in the beginning of the lenalidomide induction. So patients could be included if they had follicular lymphoma with a treatment need and relapsed disease and at least one prior line of treatment. Next slide, please. So again, looking at the safety profile first, very consistent with what we have seen so far, and this is important because both lenalidomide and epcoritamab lead to some immune suppression. So the long-term safety is really important to follow in these cohorts. Again, we see cytopenias. That is mainly the contribution of lenalidomide, and we see other constitutional symptoms that are very commonly seen with lenalidomide: diarrhea, fatigue, constipation. But the contribution of epcoritamab is mainly seen with cytokine release syndrome in approximately half of the patients and in the vast majority of Grade 1, which is very encouraging. Next slide, please. So responses have already been reported previously, a staggering overall response rate in this relapsed/refractory setting of 96%, including 87% with complete responses. And I never cease to enjoy looking at these response rates because it's really quite high even in comparison with effective existing therapies, such as R2. On the right, you can see that these very high response rates are consistent across various subgroups, including the high-risk populations of primary refractory patients and those with progression of disease within 24 months of completion of first-line treatment, those that we call POD24. Next slide, please. So you can look at the durability of these responses, really quite high. So for the overall group of patients, 96 patients, we see the durability of complete response rate, with 86% having durable complete responses at 21 months. Why 21 months when that was the median follow-up. And there was some debate whether it's fair to show a durability curve like this with so many patients still at risk at the far end of the survival curves. And perhaps that is a tip for future demonstration of these impressive data that it's actually fair to even show longer follow-up even if the patients that are way beyond the median follow-up. So next slide, please. That's the progression-free survival. And you can see that because of the durability driven by the complete responders, which is the vast majority of patients, we saw for the overall group of patients progression-free survival at the point of the median follow-up for 24 months of 80%. So really, really impressive and durable benefit of this combination treatment. Next slide, please. And this is really the important curve when you assess the benefit of a treatment for follicular lymphoma. It's the time to the next treatment. Because you can have a slow relapse of follicular lymphoma and perhaps not even need your treatment yet. The really important determinant for the benefit of the treatment is the time to the next treatment. And you can see that at 24 months, and this is looking at all patients responders, as well as nonresponders, 85% of patients had not made it to their next initiation of the next treatment, which is really encouraging for this combination treatment. Next slide, please. And that, of course, leads to an excellent overall survival for the overall population of 90%. Not a surprise to any of you that such high response rates, of course, leads to a very high overall survival, albeit overall survival is a tricky endpoint in follicular lymphoma, which, like I said, is a disease where benefit is measured over decades rather than years. Next slide, please. So we see confirmed safety findings and efficacy findings from this study. Overall survival maintained at 96%, CR rate maintained at 87%. MRD negativity rate, so that's the clearance of MRD as measured by the -- [ ctDNA ] assay in 88% of patients, so that's either during or after completion of therapy, and this correlates very well with progression-free survival, as you would expect. Next slide, please. No, former slide, sorry. Because it's important to note that these are the -- next slide, please. So just direct your attention to the last bullet point on this slide, which is that, of course, such impressive results need to be followed. And I direct your attention to the ongoing and I believe recently completed Phase III trial of this very combination in comparison with the standard R2 in patients with relapsed follicular lymphoma, highly interesting study, and we are eagerly awaiting the readout from that randomized study. Next slide, please. Which is the last one for me. So already now, I have to thank you for your patience. This is the important study of epcoritamab as a single agent therapy in patients with relapsed/refractory CLL. This was presented by [ Aleksei Danilov ] from California. He was on his own home turf when he presented this excellent study report. Next slide, please. So now we are shifting to a completely different disease, patients with refractory CLL. They are not so easy to treat. They have been exposed to chemotherapy, usually, and also in order to be included in this study because these are standard treatments, they should be exposed to both a bruising tyrosine kinase inhibitor, BTK inhibitor and a Bcl-2 inhibitor, usually venetoclax. These are great treatments. They keep the patients alive for many years in many cases. The problem is when they relapse and the majority eventually do, they are very difficult to treat. And at that point, they have a poor prognosis and usually a relatively limited time span. So we need desperately new treatments for these patients, and we have already seen encouraging results from this study of epcoritamab as a single agent in this patient population. So what we saw was both of the safety and particularly the efficacy from this treatment. Next, please. So this is the design of the study, and it's important to note that the first patients, what we call the expansion part of this study, were treated with the usual epcoritamab step-up dosing, but there was an optimization cohort of a slightly lower number of patients, 17, where an extra step-up dose was introduced. So between the intermediate and full dose, there was another dose of 3 milligrams of epcoritamab in order to harness cytokine release syndrome, which, as I will show you in a second, was done quite successfully. Patients could be included into the study if they had relapsed refractory CLL, but they also needed at least 2 lines of systemic therapy, which in the vast majority of cases included both a BTK inhibitor and venetoclax or another BCL-2 inhibitor. Next slide, please. So here, you can see the safety findings, more frequent toxicities than in the lymphoma population, which is not a surprise. It has to do with the nature of the disease, the prior treatments and also the way that epcoritamab reacts in a patient with a systemic block borne disease rather than a solid lymphoma. You can see that the vast majority of patients had cytokine release syndrome, 96%, but fortunately, the vast majority of those with low grades of CRS and reasonably manageable CRS as well. Very commonly did we see cytopenias, which is -- goes with the territory of CLL treatment. And then also the other constitutional symptoms, which are very commonly seen in studies of this disease. Next slide, please. So this is important. You can see that cytokine release syndrome was particularly commonly observed in patients treated at the normal schedule of epcoritamab. This is what I just showed you before. But shifting to the optimized delivery of epcoritamab, where another step-up dose was introduced after 2 weeks. This really dramatically changed. So first of all, the overall frequency of CRS went from 96% down to 82%. But perhaps more importantly, all the relatively commonly occurring cases of CRS and Grade 3 completely disappeared. So with the optimized dosing schedule, all cases of CRS, albeit still quite frequent, were of Grade 1 and 2 and thus quite manageable. Next slide, please. Responses were really encouraging in this study. 61% of patients responded, and 39% of those had complete responses, which is actually a relatively rarely occurring outcome phenomenon in relapsed/refractory CLL. So very encouraging efficacy results, that's the depth of the responses occurring usually quite early during treatment. The challenge, of course, is to maintain these responses. Next slide. And as you can see, there are in this swimmer plot, which, of course, is a relatively short follow-up, quite a lot of patients who either discontinued treatment because of adverse events, but particularly because of loss of the response. Next slide, please. And that leads you to progression-free survival curves, which are perhaps not what I made you used to see when we talked about the lymphomas. These patients do both died, and they also have loss of response of the epcoritamab treatment, but still a highly, highly active drug in this very tricky to treat space. Next slide, please. So that's the conclusions. Just to reiterate that the single agent subcutaneous epcoritamab led to very deep responses, more than 60%, and 39% complete response rate and the undetectable MRD ratio in 75% of evaluable patients with a response. So that's really a testament of at least long-term durability in some of these patients. And very importantly, with the optimized delivery schedule of epcoritamab, cytokine release syndrome, which in the beginning of this study was a problem has really been harnessed, lower overall frequencies and most importantly, lower grades of CRS after a slightly extended step-up dosing. So with this, I ask for the next slide, and thank you very much for your attention. I hope I stayed within my allotted time, but I'm not entirely sure about that.

Absolutely. I state -- you definitely stayed in your time, and this was fascinating. Thank you very much, Dr. Hutchings. Let's move to the next slides. Next slides. And thank you also to all the other inspirational speakers for a really excellent presentation. So let's now move to some of the key pipeline events we are anticipating for next year. Next slide, please. Genmab has an established track record of being able to select and develop innovative and differentiated therapies. We're able to do this because we are completely rooted in science. And we follow the data derived from our clinical programs. And here, you can see some of the key pipeline events we are anticipating as part of our continued development. Let's start with HexaBody-CD38. Here, I will reiterate what I said already during our third quarter results call. We are well on track to submit a data package to J&J by the end of this month. The optimum period of 60 days is expected to start in the beginning of January, which means that we anticipate a decision from J&J no later than the first quarter of 2025. We will inform the market via press release when J&J has made their decision, and this release will include relevant clinical data. To support the integrity of J&J's review process, we will not disclose this information before the official release. Looking beyond this event, next year, we are anticipating additional regulatory decisions for both EPKINLY and TIVDAK, as well as additional data for both acasunlimab and Rina-S. For Rina-S specifically, the expansion data in endometrial cancer will also inform next steps for that indication. And then finally, for GEN1042, we look forward to providing you with an update on our next steps other program in frontline head and neck cancer. In 2024, Genmab made significant strides by investing in our pipeline and technologies with a strong focus on prioritizing late-stage development and expansion for EPKINLY, Rina-S and acasunlimab. As we prioritize investments in these key programs, 2025 will serve as a key stepping stone on our path towards our 2030 vision of fundamentally transforming the lives of people with cancer and other serious diseases. Our strategic focus ensures that our pipeline remains robust, impactful and aligned with our long-term goals. Let's move to the next slide, please. So now it's time for a Q&A session, and I am pleased to note that 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, who you already heard speak; in addition to Martin Hutchings, who will also contribute to the Q&A. So we will begin by taking questions from those of you participating in the teleconference. And to ask a question over the webcast, simply ask the -- click the Ask a Question button, type in your question and then click submit. Let's move into the Q&A.

[Operator Instructions] Thank you. We'll take our first question from Jonathan Chang.

Great. First, maybe just to clarify, is Dr. Lee available for the Q&A session?

No. Dr. Lee is not here for the Q&A.

Got it. So then maybe for the Genmab team, how are you thinking about potential opportunities for EPCO beyond DLBCL and follicular lymphoma? What do you need to see before advancing EPCO for CLL in later stage development? And also, what are the considerations for potential autoimmune disease applications?

Thanks, Jonathan. Excellent questions, and I will hand them over to Tahi. Tahi can definitely give us our thinking on, for sure, expanding epcoritamab into other indications. Tahi?

Yes. Thank you for the question. So yes, follicular lymphoma, just to remind everybody, there's a Phase III combination with R2, and Martin alluded to. I mentioned this also in my presentation in second line or relapsed refractory for the component that's already fully accrued. So we're waiting for that data to read out. There is a frontline study that is very well actively enrolling already, comparing a chemo regimen versus a combination with R2 as well. So from a registration point of view, these are our big committed studies. There is a broad data generation package beyond that, also interrogating monotherapy in frontline. I think EPCO, generally speaking, is a very active drug mechanism, it's a very active mechanism in follicular lymphoma. In CLL, Martin, I think, also shared a little bit of enthusiasm. The data that was generated in this patient population has to be understood in this patient population, I think, is significant and has a potential for really transforming CLL because, for the first time, you're getting actually deep CRs, not only CRs, but also deep MRD negativity in patients who rarely even achieve a CR. And so we are actively working with our partner, and there will be indeed significant next steps on the development of epcoritamab in CLL coming up in '25, more to come on that end. On the immune disease, without a doubt, is an increased awareness of the potential of deep B-cell depletion in certain autoimmune diseases, and we are fully aware of this, and these are also things that we are getting with EPCO or outside of EPCO.

Thank you very much,. Thanks, Jonathan, for the questions. Let's move to the next question, operator?

Our next question comes from Yaron Werber.

Great. I have a couple of questions. First of all, when -- the CLL data is really intriguing. We did a KOL event at ASH, and they're definitely highlighting that as one of the highlights in CLL. When you're looking at the [ OP T1 ], you're reducing the CRS nicely, so you don't have Grade 3 anymore. The CR rate was lower, though. It was 10%. Is that just a function of an early follow-up in that specific cohort or anything we should be thinking about? And then maybe just secondly, when we looked at the data in -- it was a data for the first-line follicular, the data is really compelling, but there was a lot of dropouts in that cohort. I think 9 patients dropped because of [indiscernible], because of COVID. Did that sort of happen later on? Or how should we think about tolerability?

Thank you for the question. So I'll ask Tahi to start, and then maybe Martin can also step in because I think you can also add further perspective. Tahi?

Totally agree with your enthusiasm with CLL. I think there's a number of commentary out of the community that highlights credit opportunity that now exists with the ability to redirect T cells. I think it was important as we think about the development for EPCO and CLL to figure out the COS because in the initial standard approach, this is monotherapy CIS what was uncomfortably higher, to be very frank. And so it is now -- and Martin showed the data, converted to basically 70% of the patients having Grade 1, which is fewer, completely different safety profile, with safety -- with completely different safety risk. So the CR is truly a follow-up issue. So there's some conversion.That happens a little bit later. More importantly, I would also say that now we're actually starting to generate combination data and the CIS issues actually almost nonexisting once you go in combination. You have another mechanism that helps address the CLL burden in particular, the circulating component of that burden. The combination CRS rates are you're going to have the ability to share that data next year. I'm sure this is already in a very low rate. So that is why we are now actually able to make decisions moving forward on CLL. I believe your question on follicular lymphoma and frontline also related to the bendamustin rituximab cohort. I don't want to sound defensive, but there was a period of time around Omicron where, generally speaking, the conduct of clinical trials was difficult, and Martin can also speak maybe from his perspective on that. And a lot of this was really in the midst -- it just so happened that this particular cohort was opened right in the midst of this massive wave. It's not something that we've seen, for example, with the R2 EPCO cohort in frontline. And so that was somewhat a unique situation for that particular data set.

Thanks, Tahi. And, Martin, maybe you can jump in and then give a further perspective, if you want to.

Yes. So on the CLL, it's a good observation with the CR rates in the optimized station cohort. It's a low number of patients, and I didn't even mention the CR rate, and it's not because I was trying to hide anything. It's a really, really short follow-up to that particular cohort. So I think it's probably not really fair to assess or compare indirectly efficacy. So I think for me, the important thing here is really to look at the dynamics of cytokine release syndrome, which really was a successful optimization. So at least we've not seen -- we can try to extrapolate from other experiences with the bispecifics. And delaying by 1 week the arrival at the first full dose has not in any other examples led to less efficacy in patients. I would be very surprised if it had any negative impact on the efficacy in this particular setting.

Thanks, Martin. And we move to the...

And about the bendamustine combination. I mean the fact that it was -- that it was possible to carry these studies through during the height of the COVID pandemic, not only the bendamustine, which is perhaps particularly tricky, but generally, all these studies, is just only possible due to a higher level of confidence from patients and their relatives and a great collaboration between sponsor and investigators because this has really been tricky, and I can only dream about how results would have been if we had done this 5 years earlier when we wouldn't have had all these COVID-related events.

Thanks, Martin. That's really helpful. Let's move to the next question.

Next question comes from Paul Jeng.

This is Paul on for Michael Schmidt, Guggenheim. For Dr. Hutchings, would be great to get your view on the recent data for [ talquetamab ] plus R2 and second line follicular, which showed, I think, around 20 months PFS. How does that sort of data impact the bar for EPCO and R2? And how do you and your peers plan to sequence -- assume both regimens might be approved in the setting?

Martin?

Yes. So that's a good question. The question refers to the data presented in the late-breaking abstract session of yesterday at ASH combination of R2 and [ talquetamab ]. So yes, it looks like an active treatment, and it's a novel concept in early-line treatment of follicular lymphoma to combine 2 different B cell targets. I think it looks quite attractive, and the safety profile that we got presented, as you would perhaps expect looks quite encouraging. So it's definitely going to be one standard that we need to talk about. The durability is still something that we need to see, of course. That's always the case with the first presentation of data. And now I'm just giving you my personal subjective impression. I alluded earlier to a transformation, at least a mental one, of follicular lymphoma from something which we have regarded as incurable and chronic. I do not believe the [ talquetamab ] combination is transformative in that respect. I have confident that the CAR-Ts and the bispecifics well. This is objective. So it's only my personal view, but that is my strong conviction.

Thanks, Martin. Operator, let's move to the next question.

The next question comes from [ Eric Young ].

This is Eric on for Matt Phipps from William Blair. Just 2 questions. First, on Rina-S, where you saw activity in fully receptor alpha high and low expressors at that 75% cutoff, so I was just wondering, was there activity in FR alpha of patients such as the FR alpha-negative patients, such as those with weak or no fully receptor expression that supported the no FR-alpha requirements in Phase III? And then on the second question, just on the long-term follow-up of the EPCO NHL 1 trial. In patients who did relapse, have you looked more into the cause of relapse? Could it potentially be a loss of CD20 expression or some sort of T cell inhibitor exhaustion mechanism?

Thanks, Eric, for the questions. So the first question, I think be handled by Judith, Judith Klimovsky. And then the second question, Tahi and Martin can definitely give a perspective on that one. Judith?

Yes. So thank you for the question. For Rina-S, as Dr. Lee showed in the presentation, we saw responses in the cut that we did based on the approved companion diagnostic, which is above 75 and below 75, and responses were consistent. We did an exploratory analysis, which was mentioned in the presentation as well in patients even below 25%. And we saw activity across the board in the very low. And this is why in the Phase III, we are enrolling patients regardless of folate receptor expression. And it's not a new phenomenon for ADCs when they have a potent payload and a good linker that ensures a lot of intratumoral payload. So we -- as said, we are enrolling regardless of folate receptor, and we saw activity in very, very low folate receptor expression patients. Of course, data is being gathered as we speak.

Great. Sure. Thanks a lot. And I'll move to Tahi for the relapses and with the EPCO studies.

Thank you, Jan. And maybe if I just would like to add one more comment on what Judith said. I think I mentioned this, I think, in our Q3 call, to some degree, the concept of negativity is a function of the [indiscernible] of the essay, how capable of the essay actually is accurately to determine whether there is folate receptor. And there is these IHC essays are not completely 100% accurate. So there is a space there where patients are very low forward receptor alpha expression. And that's the explanation why we also see the activity as Judith was saying. And that's why we designed the study as we designed it. On the question of why patients are relapsing in CR to CD20 therapies. Of course, like everybody else, we have been looking into this. It's a little bit of a hodgepodge in our hands, in our data. We do have cases where CD20 loss has been observed, although I would say the loss of CD20 is not a phenomenon similar to the loss of CD19. So it might just very well be easier to drop CD19 or CD22 and CD20 is a little bit more relevant. There are increased mutations in the [ P53 ] pathway that also rendered the tumor cells irresponsive to T cell-mediated killing. They certainly play a role. Some T-cell exhaustion at times. It's really like all over the place. It's not necessarily one phenomenon. It's also a relatively rare phenomenon if you look at the numbers. So once patient actually are exceeding the CRs for a period of time, you don't have that many patients, Martin showed that in the curve. And sometimes actually what ends up an event as a curve is not even progression. It's actually the death of the patient to some other cause. Life in the end is finite. So there is actually not that much data right now for a conclusive statement of like how to mitigate that, just the main reason for us to look into this to understand how to then potentially mitigate the occurrence of late relapse in these patients, but it does occur.

Thanks, Tahi. Maybe Martin, some further perspective on the -- on what can happen with relapsed patients under pressure of T-cell engagements?

Yes. So I completely agree with Tahi, that -- here, we're talking about patients who lose their response relatively late. And they are rare and far between. And furthermore, when the patients come to clinic and they have gotten used to a benefit and then they suddenly lose it, they are usually not happy about that, which is totally understandable. And top of their mind is not to deliver a new fresh biopsy unless they have get something out of the -- themselves. We do, at our side, biopsy all our patients at every relapse, if at all possible. And I must say that in probably a small majority of the patients who lose their deep response to EPCO, we see either complete CD20 negativity or a very reduced expression of CD20 in these patients. But again, it's a small number of patients. And I'm not even suggesting that loss of CD20 is a mechanism of resistance. Maybe it's just something that goes along and is driven by an underlying mechanism. We actually presented some data from our group on [ NOTCH1 ] mutations to be a potential driver of resistance. And that's just one little contribution to a field which is really ongoing. I think in a few years, we'll learn a lot more about mechanisms driving response and resistance. But I think, overall, it should be said that targeting one antigen is, of course, weaker than going broader.

Thanks, Martin, for that perspective. And that should give you some food for thought, Eric, in that. Let's move to the next question.

Our next question comes from Yifeng Liu.

I've got 2 for acasunlimab. In 2025, there have been a data update for Phase II. Could you maybe share some color on what to expect in that update? And secondly, on its upcoming Phase III study? And I just wonder if there's any plans to test progression-free survival in the interim?

Thanks for the questions. So Judith, why don't you start with the questions, and then Tahi can add to that if needed. Judith?

Yes. Yes. So the update on 2025 is the update on the time to event's end points, which is the most relevant in this setting and disease. So basically, the data we presented at ASCO in this year will be updated with more follow-up. And with regard to the Phase III, it's from the regulatory point of view, the endpoint for second, third line on small cell lung cancer is overall survival. So there is no benefit on another endpoint. So we are following the registrational intent to starting with pivotal survival as the primary endpoint.

Thanks, Judith. I don't know whether you want to add anything, Tahi?

I think this is exactly how it is.

Exactly, exactly. All right. Let's move to the next question then.

There are no further questions at this time. This concludes the Q&A section of the call. I would now like to turn the call back to Jan van de Winkel for closing remarks.

So thank you all for the questions and for the lively interactions. Let's move to the next slide. Thank you all for joining us today. And a special word of thanks, of course, to the exceptional speakers who have joined us here in person and virtually. From all of us at Genmab, we wish you happy holidays and a healthy, happy and truly wonderful 2025.