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

[Audio Gap] for the safety and convenience of both you our audience and our speakers, we have once again gone virtual for this year's R&D update and ASH data review. And as always, we have a busy agenda, so let's begin. Please move to Slide 2. 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 has a science focus and innovation-based culture and collaborations and partnerships have always been part of our DNA. During today's presentation, we will reference some of the products being developed under these strategic collaborations and this slide acknowledges those relationships. Let's move to Slide 4. We will kick off this year's event with a review of some of the exciting events of the past year, both within our own portfolio and the ways in which our innovation has been applied to programs of pharma companies. You will then see an excellent presentation from Janine Schuurman, Genmab's Senior Vice President and Head of Antibody Research and Technology. Many of you may already be familiar with Janine as she has significant expertise in the antibody field and is a key inventor of our DuoBody and HexaBody technologies. Janine will provide you with an overview of our proprietary next-generation antibody technology platforms which are fueling both our own robust pipeline as well as the pipelines of our partners. And of course, one of the promising product candidates created with the DuoBody technology epcoritamab was featured in multiple presentations at ASH. We are pleased to be able to provide you with a prerecorded summary presentation of this data by Martin Hutchings, who unfortunately was not able to join us in person for today's event, as he is currently in a plane moving back to Denmark from the conference. We will have a lively Q&A, however, because we are fortunate to have with us today Dr. Kim Linton from the University of Manchester. And Dr. Linton is a specialist in the clinical management of lymphoma. And yesterday, she presented the preliminary results from the Phase I/II study of epcoritamab in relapsed or refractory follicular lymphoma. And after this energizing Q&A, we will conclude the event with a discussion of our key priorities for 2022 and provide you with an additional opportunity for Q&A. I'm also happy to share that we have both Judith Klimovsky, our Chief Development Officer; and Tahamtan Ahmadi, our Chief Medical Officer available for today's Q&A. So as a brief housekeeping note, regarding today's Q&A, I'm sure that you're all very familiar with Zoom by this time. But if you would like to ask a question please let us know by posting in the chat and a member of our IR team will then let you know when you can unmute to ask your question. If you would rather submit a written question please do so and also through the chats. These questions will then be read out by one of our team members and answered by the fabulous experts we have with us today. So now let's begin with a reminder of some of what Genmab has achieved during this past year and how it positions for us perfectly for continued successful growth. So please move on to the next slide. As I stated during our Q3 results call recently, Genmab has never been in a better position to achieve our ambitious vision of transforming cancer treatments. We have a consistent and solid track record of success with now 5 medicines on the market that were created using Genmab's innovation. We have a world-class team of experienced and dedicated employees, driven to make a real difference for cancer patients. One of the results of that drive is our innovative proprietary technologies which as I said, are fueling our first-in-class and our best-in-class pipeline. Excitingly, now also including our first approved medicine. Our expertise also makes us a partner of choice as we have a large variety of partnerships with industry leaders across the innovation ecosystem. Importantly, our work is supported by extremely strong financials which gives us the ability to invest in both our pipeline and our capabilities. Taken together, the solid foundation we have built has allowed us to evolve into a fully integrated biotech innovation powerhouse. The events of the past year moved solidly forward in this evolution. One of the most exciting developments of 2021 was the FDA accelerated approval for TIVDAK. As the first and only antibody drug conjugate approved in this indication, TIVDAK may provide a much-needed new treatment option for patients with metastatic cervical cancer. And for the first time in history we in collaboration with our partner on TIVDAK, Seagen are able to bring our own medicine to patients with commercial and field teams ready for launch even with an approval 3 weeks before the PDUFA date. Our commercialization efforts are just one aspect of our recent growth as we aim to remain at the forefront of innovation in all areas of our business. We will continue to strategically build our capabilities with the eventual goal of bringing our own medicines to patients on our own. We are currently fortunate to partner with industry leaders who share our goal of bringing innovative medicines to patients. This includes broad development plans for both tisotumab vedotin with Seagen and epcoritamab with AbbVie, both of which entered into Phase III trials this year. Our bispecifics in development BioNTech, GEN1046 and GEN1042 progressed in development this year with a new Phase II study and expansion cohorts added to the existing Phase I/II study, respectively. New product candidates also entered the clinic with the first in-human studies of HexaBody-CD38 or GEN3014. And very soon, we anticipate the first patient dosed with DuoBody-CD3B784 or GEN1047. In addition to progress in the clinic, we have multiple data presentations at prestigious conferences, including, of course, ASH as well as ASCO, EHA, ESMO, AACR and SITC. As far as publications, including dose escalation data on the EPCORE NHL-1 study of epcoritamab in the Lancet. Looking to the future, we entered into an oncology research and development agreement that Bolt Biotherapeutics with the goal of discovering and developing next-generation immune stimulatory antibody-based conjugate therapeutics for the treatment of cancer. Next slide, please. I would now like to focus on 2 of our early stage product candidates. HexaBody-CD38 or GEN3014 and DuoHexaBody-CD37 or GEN3009. This is in development with AbbVie. Both are currently in dose escalation. And so far, we are very pleased with the data we have seen. There are early signs of activity for both products with no safety signals. I'm excited about the potential of both products and look forward to providing you with further updates as well as the first clinical data at a future medical conference in 2022. Next slide, please. As I noted earlier, our innovations are not limited to our own pipeline, starting with progress for previously approved therapies. Once again, DARZALEX moved from strength to strength with additional approvals, including becoming the first and only therapy approved for newly diagnosed AL amyloidosis. Kesimpta also received additional approvals in Europe and Japan. Throughout 2021, a variety of data was presented and new studies were announced for clinical stage programs that either incorporate our expertise or that leverage our technology. This includes the first Phase III studies of inclacumab originally created under an agreement with Roche and now under development with Global Blood Therapeutics. The first Phase II study of Lu AF82422, which was invented by Lundbeck in collaboration with Genmab and the announcement of clinicaltrials.gov of the intention of Novo Nordisk to start a Phase III study of Mim8, a molecule created using our DuoBody technology. Of key significance was this approval in the U.S., in Europe and in the U.K. of Janssen's RYBREVANT, the first medicine created using our DuoBody platform to receive regulatory approval. Another of the bispecific products under development with Janssen, teclistamab received breakthrough therapy designation from the U.S. FDA and recently moved into Phase III, exciting data from teclistamab as well as Janssen's talquetamab was just presented at ASH, including in combination with daratumumab. We are very encouraged to see the progress over the past year with so many products that incorporate Genmab's innovation and expertise. Next slide, please. It's now my distinct pleasure to hand over to Janine Schuurman, our Senior Vice President and Head of Antibody Research and Technology, who will tell you all about DuoBody and the other exciting innovative technologies developed by our world-class R&D team. Janine, the floor is yours.

Thank you very much, Jan, for this nice introduction, and I'm very excited to be here today and take you through our innovative antibody technology platform technologies. At Genmab, we are truly fascinated by antibody molecules. And we are inspired by understanding the basic immunological principles underneath the antibodies down to its smallest molecular details. We translate this knowledge into innovative technologies, which we use to create differentiated Knock-Your-Socks-Off antibody products, products which can have a real impact on the lives of patients with cancer and their families. Here you see rotating in this slide, our therapeutic modality of choice, the antibody molecule and consider the intrinsic attributes of this molecule. It's high specificity for the target and the antigen binding domains of the antibody are indicated in blue and also the possibilities which gives this molecule with the Fc domain to steer its interaction with immune cells and other components. And this Fc domain also gives this molecule it's favorable in vivo half-life. Next slide, please. Before we go to our proprietary platform technology suites, the technologies itself and maybe it's nice to click also to have the right side also. I feel it's essential to put some emphasis on our product ideation and discovery philosophy which is in one word set biologically outcome focused. The disease biology, its underlying mechanisms and targets combined with the antibody format are all seen as critical components for a transformative products. Our product IDs have very different molecular requirements depending on their application or the biology of the targets or the target combination. So having a suite of technologies available is instrumental to our discovery, is instrumental to reach our mission of having a [ cancer ] pipeline of products, products which can have a real impact on the lives of patients with cancer. Next slide. So what do we have in our platform technology suite. First of all, our DuoBody platform, the platform being used for epcoritamab and other products in the Genmab product pipeline as well as in the pipelines of others. This is our bispecific antibody platform. We can use that, for instance, for the recruitment of cells like T cells, effector cells or can be used to combat tumor heterogeneity. Secondly, we have our HexaBody platform, which is being used, for instance, for HexaBody CD38. This platform can enhance the potency of a molecule, enhance the potency with respect to complement-dependent cytotoxicity, but also with respect to bringing targets together on the cell surface and forcing outside-in signaling for instance, enforcing apoptosis. Thirdly, we have our DuoHexaBody platform, which combines the DuoBody, the bispecific platform with our HexaBody platform and creating, therefore, bispecific molecules with an enhanced potency. This technology is being used for DuoHexaBody-CD37 program. And lastly, our newest kid on the block, which is being explored in our discovery processes at the moment, it's HexElect, and it's not the topic of today. But with this platform, you make this hexamerization process codependent on 2 antibodies. And by making it codependent, we can unlock the potency, making it more selective to cells, which express to targets. This may open a new target space, which has been previously inaccessible. Next slide. But let me first focus on the DuoBody platform. As you are all aware, bispecific antibodies were conceived decades ago but faced many challenges, limiting their application as therapeutics. And you may wonder why DuoBody technology results in such a high product hit rate or low attrition rate -- low attrition in the clinical development. And I'd like to take a moment to explain more about the principle behind this technology because this principle explains why this technology is a game changer. Before we go there, what has been the problem. From a protein engineers point of view, the antibody molecule is quite a complex molecule. It consists of 4 chains, 2 heavy and 2 light chains, which are covalently paired. Due to the structure of this antibody molecule, it was very complex to produce bispecific regular IgG molecules. It needed heavy engineering and/or other tricks to make these materials to generate bispecific molecules. Sometimes or most of the technologies also relied on the identification of an identical light chain. And of course, that impacts discovery and subsequent development and manufacturing processes. The DuoBody principle solves these issues, I mentioned. For the DuoBody bispecific molecules, we first produce 2 parental IgG molecules, each carrying a single point mutation. We mix these parental molecules under controlled Fab-arm exchange conditions reducing conditions that allow the exchange of these half molecules into the bispecific molecule. And after reoxadation, we have these molecules recovered and without any further purification effort 90% efficiency at least. This minimal engineering preserves regular IgG structure, stability and the functional properties as well as the long half-life of the pharmacokinetics, and it also minimizes the risks of immunogenicity. This controlled Fab-arm exchange process lifts those previously identified complexities from the protein engineers point of view, which benefits discovery and development processes. Next slide. From the product discovery point of view, this principle of controlled Fab-Arm exchange offers great advantages. First of all, it gives us the opportunity that any previously identified or discovered IgG antibody sequence can be used in a DuoBody molecule. Original heavy light chain pairing is preserved by this process, and that enables product lead discovery processes in an unbiased search in its final format, selecting the lead clinical candidate in an unbiased and data-driven, so fully rational manner. You could now say why is that important? Why is it important to do that in an unbiased and empirical screening. Simply said, we as humans are excelling in taking assumptions, which is counterproductive from a bispecific product discovery point of view. Let's have a look at the left part of this slide, which shows a standard bispecific antibody discovery processes. The antibody with the best characteristics as a monoclonal antibody is then picked and reformatted for the generation of a bispecific lead, which might often not be the most optimal candidate because we then ignore all kind of attributes, which do change in the reformatting process and which might have a huge impact on the biological outcome. The DuoBody platform, which you can see on the right part of this slide enables the generation of large libraries of bispecific molecules. And these large libraries can then be screened in an unbiased and empirical approach in the final format, in a regular architectured IgG molecule. This enables the selection of the best bispecific lead candidate based on functional criteria. We managed to minimize the discovery time lines and are able to maximize the throughput of the candidate screens in this process by a fully automated process that converts panels of parental antibodies into DuoBody libraries and then we can screen to find this final lead, the winner, you could say. At least we maximize the likelihood of success by not acting at assumption-driven, but by selecting the lead by a biological outcome. Next slide. A sum up of the advantages from the product discovery point of view is indicated in the left box on this slide. Just to sum up a few, the DuoBody platform is compatible with any previously discovered antibody sequence, any RTG subclass and it also is compatible with other Fc engineering platforms. It enables the discovery of bispecific lead molecules in an unbiased approach and is apparent from a product pipeline, we have identified a CD3 arm, which is being used in T-cell redirection and an inert backbone which you can use for T-cell redirection but also for instance, agonistic applications. On the right part of this slide, you see the perspectives from the development point of view. Over 10 clinical programs are active and the DuoBody manufacturing process is compatible with the standard unit operations as being used in the industry for IgG1. The exchange process is robust and fully scalable and has been established at multiple contract manufacturing facilities and collaboration partners. Next slide. So let's move on to our HexaBody technology, which is a platform for the discovery and development of potentiated IgG antibodies. The HexaBody technology is based upon a natural principle on how effective polyclonal antibody responses act in nature. Effective polyclonal antibody responses act as a team, they form after binding to its target hexamers. We'll leverage that principle to our HexaBody technology, again, by minimal protein engineering and I have to put emphasis on that only after binding to the cellular surface, these HexaBody molecules are more susceptible to assemble into organized teams of 6 in hexamers. These hexamers can then force target clustering, bringing targets together on the cellular membrane and so induce outside-in signaling or engage C1 and trigger the complement activation routes. HexaBody platform preserves IgG-1 like properties are acting as monomers in solution, PK stability and developability are all similar to regular IgG1. And by now, we have gathered clinical and manufacturing experience during the development of our investigational HexaBody products, and I'd like to again mention HexaBody CD38. Next slide, please. Depending on our product design criteria, we could also turn to our dual HexaBody technology, which is a combination of the DuoBody and the HexaBody technology. So bispecific molecules with potentiated properties. DuoHexaBody enables us to combine these effects and then engage target clustering or complement activation. And these molecules also again preserve IgG1-like properties like pharmacokinetic profile and stability. Our DuoHexaBody-CD37 development program provides us with the clinical and manufacturing experience. Next slide. To conclude, Genmab today focuses strongly on antibody product discovery around product ideation, which is biologically focused, so mechanistically focused. The disease biology, its underlying mechanisms and targets combined with the antibody format are all seen as critical components for transformative products. Targets and target combinations impose different specific molecular requirements. So our antibody products may have very different molecular needs depending on the application and the biology of the target or of the target combination. So it's great to have this playground with this platform technology suite within Genmab. Our proprietary platform technologies because that enables us the discovery and the development of transformative products for patients. I'd like to thank you for your attention.

Thank you, Janine, for the truly inspirational presentation, well done. So turning now to epcoritamab at ASH. I would like to introduce a video of Dr. Martin Hutchings. Martin is a hemato-oncologist at Rigshospitalet in Copenhagen, Denmark. He's an expert in the treatment of malignant lymphoma and a key investigator on the first Phase I/II study of epcoritamab. Relapsed or refractory B-cell non-Hodgkin lymphoma continues to be an area of unmet medical need for patients. And we appreciate Martin being with us once again, now via video to review this important epcoritamab data. Please start the video.

Hello. My name is Martin Hutchings, I'm a senior consultant with the Department of Hematology in the Phase I unit at Rigshospitalet in Copenhagen, Denmark. And I wish I could be with you in person but I have to leave back home to take care of my clinic. So I'm leaving ASH early, and I've been allowed to record this presentation for you. About the data which have been presented here at ASH in Atlanta on -- from different studies of the epcoritamab program. So as you know, epcoritamab is a bispecific antibody targeting CD3, which attracts T cells and CD20 on the malignant B cells. So it is a drug which has been designed for the treatment of CD20-positive B-cell malignancies, including lymphoma and chronic lymphocytic leukemia. So by binding to CD20 on the tumor cells and CD3 on the B cells, you -- we get a close interaction between the cytotoxic T cells and the tumor cells, meaning that we have activation of the T cells leading to cytokine mediated cell kill and also proliferation of T cells in the immediate microenvironment of the tumors. So we've already presented data from the dose escalation study of single-agent epcoritamab in heavily pretreated patients with both aggressive and indolent B-cell non-Hodgkin lymphoma and recently, data from that Phase I dose escalation and expansion study have been presented in the Lancet. So what were the conclusions from that study so far, well, we've only seen data from the escalation part of that study, but we've certainly seen very promising efficacy data, particularly in aggressive lymphomas, but also in the smaller group of patients with indolent lymphomas. And the safety profile so far has been very encouraging, with no cytokine release syndrome higher than Grade II, and no serious neurological adverse events. So, so far, the data coming out of this program has been really promising. So what has been presented here at ASH, Well, I'll focus on these 3 studies, which have all been presented as posters. Two of the abstracts came from the same study, which is a multi-arm study called the EPCORE NHL-2 study. It's a multi-arm study where each of the different arms or cohorts combines epcoritamab with different standard treatments in different settings of -- treatment settings of different kinds of groups of B-cell non-Hodgkin lymphomas. And the 2 abstracts presented at this meeting have been from Arm 1 and Arm 2. Arm 1 is a study where epcoritamab is being combined with R-CHOP chemotherapy in newly diagnosed diffuse large B-cell lymphoma patients and Arm 2 is a study where epcoritamab is being combined with rituximab and lenalidomide also called R-Squared for the treatment of relapsed refractory follicular lymphoma. The third abstract also presented as a poster is from the EPCORE CLL-1 study, and that is sort of a companion study to the Phase I single-agent study in B-cell non-Hodgkin lymphoma, where single epcoritamab is given for the treatment of relapsed/refractory chronic lymphocytic leukemia. But we'll start with the first of the 3 abstract -- That is the EPCORE NHL Arm 1 study. So again, this was a combination of R-CHOP with epcoritamab. The idea of combining these is that you have a standard treatment for newly diagnosed diffuse large B-cell lymphoma, which cures the majority of patients, but unfortunately, it's a small majority of patients and high-risk subgroups of DLBCL. There is still much room for improvement. We have way too many failures, early refractory patients and patients who later relapse. So the rationale for combining R-CHOP with epcoritamab R2, first of all, the toxicity profile of epcoritamab, which, as I already said, is very favorable is also highly combinable. So the dominant side effect of epcoritamab as well as the other bispecifics is cytokine release syndrome. And this is a phenomenon which primarily occurs during the first 3 to 4 weeks of treatment. Unlike toxicities of standard chemotherapy in most other anti-lymphoma agents, which appear all the way during treatment and in many cases, also in a cumulative fashion so occurring more and more frequently and with more and more severity, the longer the patient has been treated. And another rationale for combining these drugs is the preclinical demonstration that epcoritamab is active in the presence of what we call naked anti-CD20 antibodies, including rituximab unlike most of the other CD3, CD20 bispecifics, which are not potent or they don't have enough affinity to compete with rituximab for the CD20 antigens on the tumor cells. So this study, the Arm 1 study of the EPCORE NHL-2 study included newly diagnosed diffuse large B-cell lymphoma patients with high-risk features, and this was defined as the International Prognostic Index of 3 to 5, which means pretty sick patients. So the most easy-to-treat patients were not included in this study. This is a layout of the study design inclusion criteria, like I said, newly diagnosed diffuse large B-cell lymphoma, including the subgroups of high-grade B-cell lymphoma, double or triple-hit DLBCL and also follicular lymphoma Grade IIIB, which is treated and has more or less the same prognosis as normal DLBCL. Patients needed to have reasonable organ function and a performance status of 0 to 2, so relatively frail patients could be enrolled in this study. Patients were first treated in a short escalation part of the study beginning with a full dose of epcoritamab 24 milligrams and quickly after the enrollment of 4 patients with no particular safety signals moving on to the second and final dose level of a full dose of 48 milligrams. Patients were treated with 6 cycles of R-CHOP, which is standard, chemotherapy with rituximab every 3 weeks for 6 cycles. And for the first 4 cycles, so for the first 12 weeks, epcoritamab was given weekly. Then for the next 2 cycles or the final 2 cycles of R-CHOP every 3 weeks, so along with the chemotherapy and from the end of chemotherapy and onwards onto a full year of treatment every 4 weeks. In the expansion part of the study, all patients were treated with the recommended Phase II dose of epcoritamab, 48 milligrams according to the schedule that I just described. So at the data cutoff in mid-September for this presentation, 11 patients have been enrolled into the dose escalation part and 13 patients being enrolled into the expansion part with another 7 patients in the expansion part of the study planned. Here, you're looking at the baseline demographics and characteristics of the patient. Median age 65, which is typical for diffuse large B-cell lymphoma newly diagnosed. And you can see that it was really quite a sick patient population with 3 out of 4 patients having performance status 1 or 2, so very few patients in an excellent general condition and 75% of patients also in stage IV disease. The majority of patients were of general SCLC-P subtype, which is what you expect, roughly 2 out of 3 patients have the GCB subtype. We do not have data on the -- from FISH on double or triple hit characteristics in this presentation. So now we're moving on to the key safety data, which is really the primary end point objective of this study to look at safety. And to cut it short, we see side effects of R-CHOP. We see side effects of epcoritamab. There doesn't seem to be any added or synergistic effect when it comes to safety. So there is all the side effects from R-CHOP that you would expect and there is cytokine release syndrome. Looking at cytokine release syndrome, this was observed in 38% of patients, which is less than you would perhaps expect if the drug had been given as a single agent, particularly because these patients are newly diagnosed. So they have not been treated with several prior lines of treatment. Patients who have been exposed to a lot of chemotherapy previously, perhaps have some T cells that are not quite so fresh as newly diagnosed patients. So if you give epcoritamab to newly diagnosed patients alone, then you would expect to see more cytokine release syndrome. In this case, we see perhaps less than expected, 38% with 33% of the 38% being of Grade I to II. And that is probably because the disease is well controlled with R-CHOP chemotherapy. So already with the combination of R-CHOP, we see killing of many tumor cells and also rituximab occupies the CD20 antigen, giving a good extra mitigation of serious cytokine release syndrome. Now we're looking at the swimmer plots on the efficacy data. There were 24 patients, all in all treated before the cut for this presentation. But you can see that while the safety population was 24 patients, only 11 patients had reached the first point of assessment. So the -- only 11 patients were really evaluable for efficacy for this presentation. So these are very preliminary data. And of course, efficacy is not the primary endpoint of this study. Still it's quite encouraging to see that all patients responded. You will expect the majority of newly diagnosed DLBCL patients to respond to R-CHOP alone, maybe not 100%. But of course, this does not necessarily show that epcoritamab added anything to the efficacy, but it's certainly encouraging in this respect. And it's also encouraging to see that the majority of responses were complete responses, 73% out of the 100%. And it's also encouraging to see, which is depicted in the swimmer plot that the majority of the complete responses, all except 1 occurred already at the first assessment of efficacy, which is after 6 weeks or 2 cycles of treatment. So in conclusion. For this study, which is really preliminary data, the combination of R-CHOP with epcoritamab showed no added or synergistic toxicity, no dose-limiting toxicity for epcoritamab. Generally, safety was manageable. There was no observed events of immune cell associated neurotoxicity syndrome called ICANS something which is particularly feared and quite commonly seen with many T cell-engaging immunotherapies and only 1 case of tumor lysis syndrome which is hardly something we can attribute to epcoritamab because it's something that we do see occasionally with R-CHOP chemotherapy alone. Like I said, encouraging responses in 100% of patients doesn't mean they are all cured, but it's very encouraging, 73% of the responses were complete, the majority of which occurred already at the first assessment of response after 6 weeks. So I think it's very modest to say that the data support the further exploration of this interesting combination. Now we're moving on to the second poster, the Arm 2 from the NHL-2 study. That is a combination of epcoritamab this time with we call R-Squared so rituximab and lenalidomide. That is already a standard treatment. It's approved and it's being used in follicular lymphoma and also in mantle cell lymphoma, where it's highly active. So the idea behind this comparison also is just like with the combination with R-CHOP that the toxicity profiles are virtually nonoverlapping but also there are data to suggest that lenalidomide probably can enhance the T cell mediated killing, which is sparked by epcoritamab. So this is the general layout of the study. Again, we have a standard R-Squared treatment, which consists of rituximab every 4 weeks and lenalidomide for 21 days out of 28 days. So 4-week cycles and that goes on for a full year, after which the patients can continue with epcoritamab maintenance for another year, so a total of 2 years of treatment. Again, a dose escalation part of the study with all together 6 patients enrolled starting on 24 milligrams as the full dose of epcoritamab, moving up to 48 milligrams, the recommended Phase II dose and that is where the expansion part of the study also -- that's how the expansion part of the study also was dosed. In the expansion study, the first 23 patients are treated according to the same schedule as in the escalation part. So that's 3 cycles of weekly epcoritamab, then 6 cycles of biweekly epcoritamab and then moving over to 4 weeks. So in the planned 80 patients in cohort 2B, which is an added expansion cohort patients will only receive epcoritamab weekly for 2 cycles and then already from cycle 3 and onwards, move on to treatment every 4 cycles. And this is respecting that many patients will already at that point be in a complete remission. So probably or hopefully, without the need for very dense epcoritamab treatment for such a long time. Now we're looking at the baseline characteristics and demographics. Here we can see that the median age, 67 years, very characteristic for a relapsed refractory follicular lymphoma population. And you can also see that this is completely different from patients with newly diagnosed diffuse large B-cell lymphoma, even though these patients were not particularly heavily pretreated, actually, the median number of prior lines of treatment was just 1. You can see that the median time from diagnosis to the first dose was 92 months. So this is a disease with a completely different natural history and much longer remissions expected. Moving on to the safety. Just like with the combination with R-CHOP, there are side effects to epcoritamab. There are side effects to rituximab and lenalidomide but to cut another long story short, there is nothing to suggest any synergistic safety signals. So we do see cytokine release syndrome. We do see side effects of lenalidomide, but they don't seem to add anything to each other. It's comforting to see less than 50% of patients overall with cytokine release syndrome, 48% out of the total 29 patients in the safety evaluable cohort and even more encouraging to see that the vast majority of these had cytokine release syndrome, which was grade 1 or 2. Efficacy data are again preliminary. You can see that the patients have generally not been treated for so long. But the swimmer plots will tell you that the vast majority of patients are responding, actually 100%. And most of these patients are still in remission and on treatment at the time of the data cut for this presentation. So overall responses in 100%, including 81% with complete responses. Now some of you might wonder how would you expect R-Squared to perform in this setting. You would expect R-Squared to perform relatively well, maybe response rates of 60% to 70%, at best 75%. No one would expect 100% overall response. And of course, this is my subjective view, but I have no doubt in my mind that this is primarily owed to the presence of epcoritamab. So in conclusion, again, this combination is promising. It's apparently safe, no added toxicity, no dose-limiting toxicity for epcoritamab, no ICANS, no tumor lysis syndrome, which is something that we sometimes see in the treatment of these lymphomas and like I just said, response in 100% of patients, including 81% with complete responses, the majority of which were achieved already at the first assessment after just 6 cycles -- sorry, 6 weeks of treatment. So now I'm moving on to the third poster, which was presented here at ASH, which was from the EPCORE CLL-1 study. As the title says a study including patients with chronic lymphocytic leukemia. So this is a single-agent study. Epcoritamab was first introduced into NHL and second into CLL. And the reason for this is an expected higher rate of toxicity because CLL is a blood-borne disease present in the bone marrow, present in peripheral blood. So these are features which mean that you will expect higher rates of cytokine release syndrome. I'll keep you waiting for that, but I can assure you that it's not as bad as some of us perhaps had feared. This is the study to sign a more simple one than the ones I've just showed you before. Patients had to have relapsed refractory CLL with at least 2 prior lines of treatment, including treatment with or intolerance to BTK inhibition. Most of the patients had received ibrutinib which is an approved BTK inhibitor for CLL in most countries. They also needed measurable disease, either nodal disease or blood borne disease and acceptable organ function and general condition with an ECOG performance status of 0 to 2. So again, there was a small escalation part of this study, moving from 24 milligrams was the full dose to 48 milligrams and then an ongoing expansion part of the study where patients are treated at 48 milligrams, again, the recommended Phase II dose. Look here at the demographics and characteristics of the patients. You can see a median age of 63 years. CLL is a disease of the elderly. So this is actually a relatively young CLL population. And it's a population which where probably age is the only favorable prognostic factor because if you look to the right, you can see that the majority of patients had mutations of TP53, deletion 17p, both of which are adverse prognostic factors and only 18% had mutated IGHV, which is a favorable prognostic factor. So these are really quite adverse factors. You can see, again, all patients, 100% have been exposed to BTK inhibition and 2 out of 3 patients exposed to and failed venetoclax. Looking at safety. Some of us had feared high -- not only high frequencies, but also high grades of CRS due to the nature of the disease. And I've been comforted here, because there are 73% of patients experiencing cytokine release syndrome, but all of which stay within grades 1 and 2. And this is indeed something which is very encouraging that no severe grades of cytokine release syndrome have been observed. Also, no cases of tumor lysis syndrome, which is also a positive surprise. Some of the drugs that have been introduced into the treatment of CLL have had problems with tumor lysis syndrome, which makes it quite laborious to start patients on this treatment, but this has not been the case in this study of epcoritamab. And also, we've seen no cases of ICANS, none of the serious neurological adverse events, which is sometimes seen in the context of the T cell engagers. Now very few patients have been treated far enough to be evaluable for response, only 9 of those. And you can see that with these very preliminary observations, there are signals of activity, 4 responders so far, 1 of whom is a complete responder, 1 of my patients and 3 partial responders so far. And then a number of patients progressing disease and also 1 patient discontinuing treatment without progression but in a stable disease based on physician decision. So in conclusion, just like with the EPCORE NHL-2 studies that I presented before, we've not seen any dose-limiting toxicity to epcoritamab. Generally, again, the toxicity profile has been manageable, nothing really unexpected except for perhaps in my subjective view that the grades of CRS have again been restricted to Grade 1 and 2, just like we saw in the single-agent study of epcoritamab in non-Hodgkin lymphomas. And this is really, really important because many had expected higher grades of CRS in the context of CLL. So it's a little bit early to say anything about efficacy, but we do see responses in so far in 4 out of 9 evaluable patients. And I think we can all agree that this sparks and encourages further evaluation of this drug not only alone but probably also in combination with other drugs in the setting of relapsed refractory or perhaps with time even newly diagnosed CLL. So with that, I thank you for your attention. I hope I kept to my time, and I hope you all have a good trip back from ASH or wherever you are in front of the screen. So thank you very much.

So we now have 20 minutes for Q&A. As a reminder, please indicate in the chat if you would like to ask a question and then a member of our IR team, I think Andrew will let you know when you can unmute your line. You can also type in your question in the chat and then we will actually read it out loud, and then one of the experts will answer. So let's start with the questions. Who wants to ask a question. Please indicate it in the chart.

Thank you, Jan. I think we have Kennen MacKay from RBC Capital.

This is Sudan Loganathan, one of Kennen's associates from RBC. Thanks again for the presentation and really great, really great presentation on epcoritamab. So my question is basically on epcoritamab; the CRS levels versus the efficacy. So when physicians are looking at choosing epcoritamab, what is the sweet spot in efficacy versus CRS levels that needs to be achieved? Or are there physicians that are more willing to take on a lower efficacy level for -- to ensure that they have a better safety outcome? Or what are you hearing on that aspect?

Thanks for the question. I think I will ask Kim Linton, Dr. Linton to start first, and then maybe Tahi can give an extra perspective, Kim. I hand it over to you.

Thanks very much for the question. I think the first thing to say is we don't really have a sense that there's a correlation between the degree of CRS and the efficacy signal that we're seeing with epcoritamab and indeed with the other bispecifics that are being developed. And one thing that's very clear with the bispecific drugs and epcoritamab is particularly good in this regard is that the rates of cytokine release syndrome are really very low. It's a mild toxicity and it's very much limited to the first cycle of treatment is the first few weeks of treatment in the epcoritamab, predominantly when you get the first full dose. So because it is so mild and very easy to manage, I mean most of these patients just get fever. They don't even require any oxygen support or any tocilizumab or any vasopressors. It's so manageable that we don't really take that into consideration when we're thinking about using a drug like epcoritamab. So the only thing I think that potentially comes into consideration is the need for a brief need for hospitalization in these patients. But again, as we're gaining more and more experience with these drugs, we're recognizing that we don't necessarily need to admit these patients as we did before. And already, as we've developed epcoritamab, we've now reduced the requirement for admissions to the first full dose, which is cycle 1 day 15. So I hope that addresses your question. It's really not a major consideration.

Yes. And really quick one, to squeeze one in. So the RP2D at 48 milligrams is that a dose that will be the go-forward dose for epcoritamab? Or is there any -- due to the lower CRS rates and getting good efficacy readout, is there a chance for evaluating higher doses?

Kim, do you want to take that? Or should I hand it over to Tahi.

I think Tahi might want to take that one.

Exactly. Exactly. I see him already smiling. So thanks again for very good answer, Tahi, floor is yours.

My pleasure taking the question. Yes. So we actually will, in due time, publish this, we did a very extensive PK/PD modeling to come up with the appropriate dose of epcoritamab which is really a function of what we call trimer formation, the dose at which you get the optimal engagement of T cells, the optimal binding to B cells. And this is really where we landed with 48 milligram, certainly for lymphomas, I would say. As we look into CLL, I think in a different disease setting with a completely different kinetics of B-cell tumor there is a possibility. We will look at the PK there, whether there are other opportunities to optimize. But right now, all we have is what we know and what we know is that the dose is the optimal dose for all the tumors that we have treated so far.

Thanks, Tahi. Let's move on to the next question, Andrew, let's see what are other questions.

The next question is from Jonathan Chang from Leerink.

Congrats on the ASH data. First question, which epcoritamab combination strategies are you most excited about? And second question, actually, on your partnered programs, how does GPRC5D compared to BCMA as a target for multiple myeloma? And what are the implications on how talquetamab compares to teclistamab as a development candidate in multiple myeloma?

Thanks, Jonathan, for the question. So the first one I will definitely hand over to Tahi. The second one, I think, is really a question for J&J because they are really developing talquetamab and teclistamab, and I don't think it's appropriate for us to -- Jonathan, to go into too much detail. They both are fine. I mean you've seen the data. They are working fantastic and they both worked even better when you combine it with daratumumab in multiple myeloma. But I probably want to park that question, Jonathan. And you can ask Peter Lebowitz, one of the other colleagues from J&J, and they will be delighted, I think, to get back to you. But Tahi, maybe you can handle the first question. What are you most excited about? Are you excited about everything we do with epco?

Indeed, indeed. And so I would say this, we view epco and the mechanism of T cell reaction as a fundamental cornerstone of future treatment of B cell malignancies, both in diffuse large B cell lymphoma as well in indolent. The combinations that we are moving are in relation to the treatment paradigms in these different settings. So in indolent lymphoma, lenalidomide in combination with rituximab has shown remarkable efficacies. There are biological rationales I believe the lenalidomide can enhance the activity of Rituximab in combination with epco. The data is remarkable for the small numbers, 100% response rate nearly everyone in CR. So we're very excited about that. But equally, we believe that if you introduce epco into a frontline diffuse large B cell regimen, focus on the patients with high features, highest features such as IPI 3 and above that this drug and this mechanism can be really transformational and can increase cure rate for patients with diffuse large B-cell lymphoma. So I'm greatly excited about both of the opportunities, really looking forward to the start of the Phase III in the near future.

And then, Jonathan, we haven't even spoken with you about new combinations with other drugs, and we are preclinically testing whole combinations. We found some really, very good ones, and I'm sure that the team will speak about it in the upcoming year. And then that some of these combinations will definitely go into the clinic as well to be tested in patients. So we can hardly sit still, Jonathan. We're very excited. So maybe we can move to the next question, Andrew.

Yes. The next question is from Asthika from Truist.

Can you hear me now?

Yes, we can hear you. Please go ahead.

First off, I just want to think about maybe the data flow that we'll be getting for 2022. I like that we'll be seeing a couple of new assets potentially there. But I wanted to check in on 1042 and 1046 and maybe get an idea as to what we can expect and when.

All right, Asthika. I think I will hand over this question to Tahi again. And I will, in the next slide, actually, Asthika after the Q&A, we will say a bit more about what we expect for next year. But maybe, Tahi can more specifically talk about 1042 and 1046. They're both really important in the new year. We are very excited about both but maybe you can see what you're willing to give here to Asthika, Tahi. I'm interested to hear that also.

Not much, Asthika. But I would say the last time you and I spoke a lot of these things were not in the public domain. In the meantime, they are actually in the public domain. We have executed, as we said on our strategy. We now have combinations for 1042 and pembro, both alone or also in combination with chemotherapy, where we're evaluating the safety and then going to expansion cohorts. And similarly, with 1046 in combination with pembro, also exploring a dosing regimen that interrogates the ideal 4-1BB activation subsequent checkpoint inhibition we call [indiscernible]. And these things are ongoing. And certainly, there will be data somewhere in '22. I'm sure we'll share some of it, but I cannot give you any view right now of when we have the data. But we are really excited about generating it right now and so more to come.

Thanks, Tahi. Andrew, let's see whether there are more questions for now.

We have the next question from Xian Deng from Berenberg.

Could you hear me, all right?

Perfect. Absolutely perfect, and welcome to the team. Thank you for covering us now.

So I have a question because this year's ASH, we see, for example, POLARIX and also CAR-T potentially moving into second line. So we see sort of potentially paradigm-changing new regimens. I was just wondering how do you think especially. POLARIX, how do you think -- how should we think about that? Do you think that could potentially impact your future trial designs? And do you think, for example, CAR-T, in the second line could reduce your patient input to your third line for epco?

And they are very good questions. I just looked at the POLARIX data which was presented today, I think at ASH. But perhaps the best thing is to first ask Tahi and then maybe Kim go for the perspective of how these data could actually impact the further development of epco. And I think Tahi, why don't you start, and then let's see whether Kim can add to that.

Two questions. One is, I suspect, the CAR-T data set that was presented in the second line transplant eligible. I think the jury is still out there, and I will leave Dr. Kim Linton to comment on to what degree this data with the limitations and some of the challenges on the population is going to convince the community to adopt CAR therapy and replacement of organ transplant. My personal view is somewhat subdued, but this is my personal view. And the other question was on POLARIX. So I think congratulations that this is the first Phase III in a long period of trials that has had the positive results. And again, the jury will be out there and to what degree this will lead to an adoption. From our point of view, we don't really see either of these 2 data sets, changing our strategy. So we have a very clear strategy what we want to do with epco. We have already generated some safety data with R-CHOP. We have not really shared yet what we are going to do in a transplant eligible setting, although we have already generated data there as well. So we have a very clear plan, and we're going to execute on that plan. Neither of these data sets has changed our perception of what our strategy is going to be.

Kim, do you want to add anything to this?

You should be able to hear me now.

Yes. Yes. Perfect. Perfect. Do you want to add anything to what, Tahi, already said on POLARIX or CAR-T or it can impact the development of epco, in your opinion?

Yes, absolutely. I mean the POLARIX study was interesting. I mean it was obviously a very large study done in over 800 patients with mostly high-risk diffuse large B-cell lymphoma, a similar population, if you like, to the R-CHOP epco first-line indication and actually produced quite similar, complete metabolic response rates. But that study didn't show any progression-free survival advantage for POLARIX in combination with R-CHOP compared to R-CHOP alone. So I think that being the case with a modest PFS advantage but no overall survival advantage. It seems unlikely that POLARIX is going to take the place of R-CHOP in the first-line setting in my view. I mean I think it might be interesting to see whether the survival data matures in time. And this is telling us a story that we're quite familiar with in first-line diffuse large B-cell lymphoma, which is that there's very little that can actually improve upon R-CHOP. So I think with regards to the epcoritamab first-line combination program, I don't think there's any need for POLARIX to change that trajectory of development, in my view. But I think it is important, obviously, in due course for epcoritamab R-CHOP to be compared with R-CHOP. And if that can show both the progression-free survival and an overall survival advantage as well as demonstrating the ongoing excellent safety signals that we are already seeing, I think there's a potential chance that epcoritamab R-CHOP could have some legs on it. But for the time being, as I say, it doesn't change what we do. With regards to the CAR-T data, we saw 2 interesting presentations or at least 2 interesting presentations at ASH, one presenting ZUMA-7 data and one presenting the BELINDA trial results, both giving completely different outcomes, suggesting that in the ZUMA-7 that actually sounds better than standard of care, whereas with the tisagen that there was no difference. And the populations are so very, very different there. And the use of bridging therapy in the 1 study, but not in the other would have definitely influenced the selection of those patients. So right now, I'm not sure we've got much evidence that's going to definitively change practice in the second-line setting. I think we do need more data on how to better select patients for CAR-T therapy. So I don't think that, that is going to impact on the development of certainly the bispecifics in that space.

Thank you very much, Kim. I hope that, that answers your questions, and then let's move on to the next question, and then we'll go on with the program. Thanks, Kim. Any further questions, Andrew?

We have a question from Michael Schmidt from Guggenheim.

I just had 1 for Jan. I thought I heard you mention in the beginning that you're pleased with the data emerging from the CD37 and CD38 programs. Could you just give us a bit more context what that means and how we should think about public disclosures from those trials next year, presumably?

Yes, absolutely, Michael. And I will need to be very brief because Tahi and Judith are watching me very, very closely now. I can tell you that I said, well, basically, we see no safety signals. So we are very far advance in the dose escalation for both multiple myeloma and the other one in B-cell cancers. And we see some very clear signs of activity that are both active. And we're very, very excited about what we see there, Michael. What I already said before is that we will -- we plan to show you the data of the complete dose escalation at a conference of both of these molecules, and we're already going to test out combinations also combination therapies preclinically and next year, hopefully, also clinically. So more to come next year. Hopefully, we can move one or both of these programs to the next stage in development. And everything we see is pleasing us and that's where I probably should leave at that at this time, Michael. So let's take 1 more question, Andrew, and then we'll move to the last part of the presentation. And then we have another Q&A so that you can all think about other questions. And before we close off today's meeting, Andrew, maybe the next question and then move to...

From Michael Novod from Nordea.

Thanks a lot, Andrew. Thanks a lot, Jan. Good to see you. So just one follow-up question to epco. In CLL, what is the best sequencing strategy? Is it to move ahead with epco and CLL, where you first debulk with venetoclax and then use epcoritamab? Or is it maybe to use BTK inhibitor instead and then use epcoritamab?

And they are definitely 2 difficult for me. So I will first move it to Tahi and then ask Kim. Kim, you have a perspective on what you could do in CLL knowing that we have a safe and effective molecule essentially from very early preliminary data. Tahi, how can you address this question from Michael, it's a good one, I think.

So I would say this. So in CLL, we are in a different stage right now than we are already with the B cell malignancies with follicular lymphoma B-cells. So the first and Martin really nicely alluded that. The first question that we had to ask was with this regimen of priming intermediate and full dose, can we give this drug to CLL patients, which have a very different distribution of the disease within the periphery as well as in the marrow and with a higher concern around cytokine release because of that in a safe manner. I think we're getting confidence around that. The second question was always from the beginning, whether T-cell redirection is actually a mechanism of action in CLL. CAR-Ts, which are now having generated quite substantial amounts of data in diffuse large B-cell and follicular lymphoma, now in mantle cell lymphoma, actually despite the initial [indiscernible] paper, being 3 patients with CLL never really had a foot in NCL partially because there is an interplay between the disease and the T cell function. So most T cells in the refractory setting are actually somewhat dysfunctional. And the answer to that question is preliminary indicating it appears we are. We're getting responses. We're getting PRs and getting CRs. And like in all the other indications, what we have previously shown to say we can combine epco with a variety of other modalities. So obviously, the next step not far-fetched is to combine with other modalities, and we are in a partnership and in a fortunate situation with our colleagues at AbbVie that AbbVie has 2 exciting and very established drugs in the CLL space, and you mentioned both of them ibrutinib and venetoclax. And so I don't think it is unreasonable to imagine that we will explore the combination with either of these 2 mechanisms, which are, by the way, very different and also use very different dynamic and from there, take the next steps in our development strategy.

Thanks, Tahi. And of course, Michael, there is some very good poster data and NIH collaborative study in CLL with very, very good synergies we see already pre-clinically. So I think that's about what we can say at this time. Let me switch to Kim and see, Kim, whether you want to add a perspective for CLL development for epco.

Yes. I really think it's too early to say about the sequencing of epcoritamab with the other 2 agents that are well established and are treated pathways and very active in CLL. Clearly, most patients that have entered this study or the numbers are very small, have already had a BTK inhibitor, possibly a BCL2 inhibitor as well. So I think other studies could potentially look at changing the order of things. But I think it would be difficult to rival the BTK inhibitor with epcoritamab first until we've got more data coming through.

Thanks, Kim, for that perspective. Thanks, Michael, for the question. Let's move to the next slide. Thank you all for these questions. So let me move to key priorities for 2022. And you will see that we have a lot to look forward to in the coming year. Next slide, please. 2021 was an exceptional year for Genmab as we have envisioned since 2013. We now have our own product on the market and a pipeline of knock-your-socks-off antibodies. As we continue to focus on our core purpose of fundamentally improving the lives of patients, we are preparing for an equally momentous year in 2022. Starting with epcoritamab, you will remember, we are developing with AbbVie. And we are very much looking forward to expanding development with multiple additional Phase III studies and excitingly, the potential for a submission of a BLA subjective, of course, to supported feedback from the FDA. And if epcoritamab should be approved in the future that would join TIVDAK as the second Genmab-owned product on the market. And in 2022, we plan to work with our partner, Seagen to continue to broaden the clinical development program for TIVDAK and establish it as a clear choice for patients with metastatic cervical cancer with disease progression on or after chemotherapy. So turning to our product candidates in earlier stage development, and Tahi has already spoken about them, we very much look forward to data from the clinical expansion cohorts and progress to next step for both of the candidates in development with BioNTech, DuoBody-PD-L1x4-1BB or 1046 and DuoBody CD40x4-1BB or 1042. And we anticipate expanding and advancing our other early-stage programs we have already spoken about a number of them during today's presentation, including the potential for additional INDs or CTAs in the coming year. Finally, we intend to continue to scale our organization based on our planned portfolio developments and use our solid financial base to support this growth. So taken together, we have a lot to look forward to in the next 12 months. Let's move to the next slide. Thank you for your attention today. And I now can move to a second Q&A session here.

Let's see, Andrew, whether there are any questions. And we also have, of course, Judith on board our Chief Development Officer in addition to Tahi and Janine. Let's see whether there are any further questions from any 1 of you.

Yes, we have a couple of questions on the chat. Most of them are centered around epco. So a question about why we still believe that we have the best-in-class molecule with epco and whether or not we're confident we can file via accelerated approval? And when can we, of course, see the data that we're going to base our filing upon?

Thank you, Andrew, for these questions. So why don't I hand over the question to Judith because I haven't heard Judith today. Judith, maybe you can start with why we are still convinced or believe that we have potentially a best-in-class molecule there with Epco. Maybe you can speak a bit to that and then Tahi can step in and Kim to really see how we can convince the chat person about our belief in this wonderful molecule.

I think that there are beliefs and there's the data and the magic happens when the data confirms the beliefs. And I think that this is where we are. I think that this molecule was developed as potential best-in-class based on solid preclinical data. We developed a subcutaneous to improve convenience for patients and for physicians. So as we see the combinability data emerge with these 2 data set, it further confirms the whole package, convenience, efficacy, combinability and safety makes potentially a best-in-class and we expect to share with the medical community and all of you more data sets to keep on building to the set of evidence. So I'm still super encouraged by the data and looking forward for the next steps next months.

Thanks, Judith. Maybe Tahi, you can speak a bit about our belief and the potential accelerated approval, of course, based on the positive reception by the FDA of the data. How confident are we that we can potentially move towards that in 2022?

I mean we have always said that we're not going to preempt conversation that we have -- going to have with the health authorities, but we have also been very consistent that we anticipate that if the agencies agree with the fileability of such data that we intend to file in '22 and nothing has changed in our time line. So we are on track for everything. And in due time, we will share the data that will form the basis for the submission.

I think that's probably where we should leave that, Tahi, I agree here. Maybe, Andrew, we can move to the next question in the chat or live from one of the participants.

Yes. We have a question with regarding to news flow for 2022? What should we expect? And especially when can we expect T-cell data in solid tumors?

I mean, T-cell data in solid tumors. I can probably take that one. I would say in the first half of next year. I think we've submitted some abstracts to conferences, and we are pretty confident that we will be able to show the data. We're also confident that we will actually move into the further development of T cell in one or more solid cancers in 2022. So that's probably what I can say about news flow. We will in time probably around the February time frame when we give guidance for 2022, we will give you some feedback -- guidance on when to expect data for potentially the HexaBody-CD38 program, the DuoHexaBody-CD37 program, the 2 BioNTech partner bispecific programs and potentially other studies bit of our molecules in 2022. It's a bit on the early side, but we will certainly give you full color and openness on when we expect to see the data in the New Year, but it will be a very, very data-rich year, not only for the Genmab proprietary molecules, but also with some of the partnered molecules. I'm pretty sure that there will be a lot of data -- more data again and probably more teclistamab and talquetamab data, probably also Mim8 data. This is going to be impactful, we believe, potentially from Novo Nordisk. So 2022 will be a very exciting year. And I think we should probably leave it with that under at this stage.

Excellent. And we have James Quigley on the line.

I've got 2 on frontline DLBCL setting. So maybe one for Dr. Linton picking up in your comments. It could take a long time for a trial like for POLARIX or for eculizumab in the first line to show an overall survival benefit. So what would you need to see in terms of PFS to sort of start to use a therapy over our top in the first line and bearing in mind there's a 27% PFS benefit for POLARIX. And then maybe for Tahi, again, on the same sort of line of questioning, how -- with that in mind in terms of needing to show survival benefit or at least the change in tumor patterns how do you design a first-line trial taken in that consideration? Are there anything or is there anything clever you can do with endpoints with biomarkers, is MID potentially going to be used or potentially used in this setting as well? Just your thoughts on that.

Maybe I can hand it over to Kim Linton to maybe think a bit about diffuse large B-cell lymphoma.

Yes. So in terms of readout for trials, I think, obviously, progression-free survival is helpful. I think in terms of when you might get an indication that you're improving cure rates, I think if you sustain plateau in your progression-free survival curve at the sort of 2-year and beyond point, you start beginning to think that you're likely to translate into an overall survival benefit for patients with diffuse large B-cell lymphoma. So I don't think we have to wait as long as you think necessarily to demonstrate that. And you can see an overall survival benefit from sort of 2 to 3 years onwards. So I think some mature follow-up on POLARIX is going to be quite important. But now the follow-up is just a little bit too short. In terms of what we might look for, for surrogate endpoints, I think the PET data and metabolic tumor volume are obviously extremely interesting and looking at your complete metabolic response rates as a surrogate for overall survival, which we know is a validated surrogate in diffuse large B cell lymphoma. Now we don't have a lot of those data currently for most of the frontline studies in diffuse large B-cell lymphoma. So I think that is something that we can look at a little bit more. I think did you mention MRDx? It's not particularly well developed in diffuse large B cell lymphoma, so less reliable there. And I think probably your PET and your circulating tumor DNA, ctDNA mutational analyses are probably going to be quite helpful in looking at some endpoints there. So those are the kinds of things I would probably envisage building into further frontline clinical studies to show that there's a benefit.

Thanks, Kim. And maybe, Tahi, you can step in here. Are you going to say a bit about front line strategies and combinations or are we going to keep that for ourselves here?

No, no. I think what I'm just thinking in principal, I think Dr. Linton mentioned all the key thought process. I would say regulatory endpoints are different than endpoints that clinicians might use to get some confidence in understanding the impact. So from a regulatory point of view, in diffuse large B-cell, PFS and OS are key critical endpoints. And I don't see a path in the near future where this would change. That doesn't mean that we cannot work on introducing other surrogate data sets to support, but I would say in the foreseeable future, PFS and OS will be the main endpoints for frontline diffuse large B-cell trial. Dr. Linton has said is actually, I don't think you need to wait that long because of the kinetics of how the behavior of relapse is in diffuse large B-cell where most of the events happen within the first 2 years. So I think what it actually is focusing the population such that you have the population that has the highest unmet medical need might help. But I think if you look at IPI 2, I'm not so sure that, that was helpful in the POLARIX study. And then it's a function of the behavior of the drug. And there are 2 questions. One immediately answerable the increase in CR rate. And then the second question, not immediately answerable, but relevant to the OS question is the durability of the CRS. And that's why we have to run these trials.

Thanks, Tahi and Dr. Linton. I think we should keep up with this, James, and thank you for very good questions here. Let's see, Andrew, whether this maybe 1 or 2 final questions, and then we'll close off the session also with respect of all of your time. Andrew?

There are some questions regarding to daratumumab. So the questions are centered around when we can expect data readout on the [indiscernible] study. And there's also a question with regards to CASSIOPEIA. I think we'll just keep it with the -- when we expect data readout for the [indiscernible] data for now.

Yes. I think I can take that one. I think it's a Janssen question. Janssen needs to respond to that. What I'm willing to say is that it's likely going to come in '22 to our knowledge. But I think Janssen needs to, I think, answer the question more precisely, Andrew, because it's basically their development program.

Excellent. Then there are no further questions, Jan. And if anyone feels that we miss their questions, please feel free to reach out to me or the team and send your questions via e-mail, and we will get back to you. Back to you, Jan.

Thanks, Andrew. So thank you all for the interesting questions and for joining us for this virtual event here. And a special word of thanks. And that's really well I meant by the -- to the truly exceptional speakers who have joined us here today for the presentations and for the Q&A. So from all of us at Genmab, we wish you happy holidays and a healthy, happy and beautiful 2022, hope to speaking with all of you in the new year. Thank you all.

Thank you.

Thank you, Dr. Linton. This was great. Absolutely great. I'm looking forward to keeping contact, and this is really very highly appreciated.

My pleasure. Epcoritamab is a fantastic drug.

Thank you. And we are super excited also about novel combinations. So we really would like to work with you and all our colleagues to really position it to really give us new treatment options for patients because that's in the end what drives us very strongly, and I'm sure you too. But really nice to meet you, and thank you so much for an excellent contribution here.

Likewise, thank you very much.

Take care. Tahi, you were great. And thank you, we'll speak sooner. Thank you all.