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

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

Hello, and welcome to a brief review of some of the energizing data presented at this year's ASCO meeting. Before we begin, as a reminder, this presentation contains forward-looking statements, and as such, may contain certain risks and uncertainties. Now on to our agenda for today's call. We are encouraged by all of the new and updated results that were presented at this year's ASCO annual meeting. This highly anticipated data highlights the progress we have made and the development of our mid- to late-stage pipeline, and we look forward to both reviewing this data with you and answering your questions. Our Chief Development Officer, Judith Klimovsky, will begin with a review of the promising data for tisotumab vedotin and head and neck cancer that was presented in a rapid oral just this morning. Our Chief Medical Officer, Tahi Ahmadi, will then provide you with a look at the new epcoritamab data in follicular lymphoma that was featured yesterday during 2 rapid oral presentations, Finally, you will hear from Tahi again with an overview of the exciting initial results from the Phase II trial of acasunlimab in second-line non-small cell lung cancer. I will conclude today's call with a reminder of next steps for these programs and what I am sure will be an engaging and lively Q&A. I would like to get right into the data, so Judith, the floor is yours.

Yes. Thank you, Jan, and good morning, everybody, from sunny Chicago. So I will update you on the data just presented by Dr. Sun and ASCO on innovaTV 207 Part C, which is exploring TIVDAK, tisotumab vedotin, in head and neck cancer. So there is a compelling need for patients with head and neck cancer after failing current standard of care, which is checkpoint inhibitor plus chemotherapy concurrently or sequentially. TIVDAK preliminary data on this patient population was presented last year at AACR. And this year at ASCO just now, we presented the full data encompassing 40 patients treated at 1.7 milligram per kilo every other week. Next slide, we have patient characteristics. Some median age, 61 years and some important points. 37% of patients were exposed to 3 lines of therapy. All the patients were exposed to checkpoint inhibitors. All patients except one who are exposed to platinum. 67% of patients who are exposed to cetuximab and palcetuximab, and 57% of patients received prior taxane. So as you see a heavily pretreated population encompassing prior 1 to 3 prior lines. In the next slide, we see the main efficacy. And for the purpose of efficacy as patients with a third line are usually not included in clinical trials because the nature of the advanced disease. We presented data on the full data set, which is 40 patients and in the patients pretreated with 1 or 2 lines, which encompass 25 patients. And as we see, the ORR for the full population is 32.5%, whether the ORR for the 1 to 2 prior lines is 40%. Interestingly, duration of response is 5.6 for the 2 subsets, which is considered pretty durable in this very setting. In the next slide, we see the waterfall plot, which again illustrates that almost many patients had too much shrinkage, and very importantly, that the assessment, that the response was not influenced by prior taxane or nonprior taxane, which was a relevant question given the nature of the payload at MMA. In the next slide, we see the main safety findings. So as a conclusion, it's aligned with the safety profile of -- we know for tisotumab vedotin where the most common treatment-emergent adverse events were neuropathy, constipation, conjunctivitis, and fatigue. So the next one is the conclusion is we see the efficacy as very encouraging. No new findings in terms of safety. And very importantly, we are recruiting patients in the first line in combination with pembro or pembro-chemo, and there is another arm ongoing, which is arm E, recruiting only patients in second and third line. So with that, I pass back to Jan -- to Tahi.

No, I'll take a step -- I'll step in there, Judith. So thank you for that excellent overview. We're also enthusiastic about the new epcoritamab data presented at ASCO this year. So now I hand over to Tahi for a summary of the follicular lymphoma data presented during the rapid oral sessions. And immediately following this, Tahi will provide you with a review of the highly anticipated and exciting acasunlimab data that was presented at ASCO on Saturday. So Tahi, go ahead, please.

Thank you, Jan. Let's go to the next slide and then the next one. So the first part of this kind of review of the data disclosed at ASCO will be focusing on the optimization, just to level set with everybody, in the initial pivotal Phase II expansion of the original first-in-human trial. The step-up dosing was modeled primarily on diffuse large B-cell patients and was 0.16 milligram for the first dose, 0.8 milligram for a second intermediate dose, and then 48-milligram with the full dose that was also then used for follicular lymphoma. This was the data that had already been presented. It has been noted not only by us but by all [ C3C 20 ] that the CRS rate in follicular lymphoma is slightly differentiated from the one diffuse large B-cell, generally speaking, higher. So there was a desire to further optimize on this particular dosing schedule, and this is what we're presenting here. So after further modeling, became modeling more data follicular lymphoma, we settled on a second step-up dosing, so introduced another step-up of 3-milligram before the full dose exposure with 48-milligram. So if we go to the next slide, patient characteristics. This is mainly to emphasize the point that there is really no relevant difference between the original pivotal study as well as the optimization cohort of 86 patients. Patients were, broadly speaking, heavily pretreated and refractory and present a population of unmet medical need in this relapse/refractory follicular lymphoma setting. If you go to the next slide, you'll see a graphic presentation of the most common treatment-emergent AEs with a cover of 25%. Most importantly, of course, for this presentation, this discussion is to focus on CRS. We will have a little bit more detailed look on the next slide. And the objective, of course, for this was a reduction of CRS Grades 2 or higher. As you can see, with the second step-up dosing, we were able to reduce significant and clinically meaningful the CRS rate of Grade 2 from 25% to 9%, and we didn't have a case of Grade 3. Further also to supporting this data, there was less utilization of tocilizumab emphasizing the point that this step-up dosing led to a significant clinically meaningful reduction of CRS. Also part of this protocol was that there was no mandatory hospitalization required, and this also nicely dovetails with additional data that was presented as part of the outpatient study and provides a profile for epcoritamab and follicular lymphoma that based on the convenience of the subcu administration and the safety now with this particular step-up dosing in follicular lymphoma with the reduction in CRS allows for a treatment in treatment paradigms and settings outside of large institutions. Of course, a separate question is whether you impact efficacy with this step-up dosing. To reset everybody, there was a delay of 1 week to the full dose. And what you can see here that in this particular setting with follicular lymphoma, even though these patients were highly refractory, this did not impact efficacy. Indeed, there is actually a slight trend to a higher efficacy, presumably by a higher adherence to the dosing without interruptions for CRS. If you go to the last slide, this is the conclusion of what I talked. So no Grade 3 CRS, significant reduction in Grade 2. No mandatory hospitalization and this data is part of the package that was submitted to the FDA, and we are expecting a decision of the target date of June 28 this year. We go on to the next presentation. This was the presentation of epcoritamab in combination with rituximab-lenalidomide in previously untreated patients with follicular lymphoma, as well as a separate arm out of the 02 study that was looking at the question of maintenance. If we go to the next slide, you'll see the 2 designs for these separate arms. I don't want to spend too much time on this. If we go to the next slide, baseline characteristics for the frontline patients. A good mix of patients predominantly Grade 3 and 4 as well as a significant portion with a FLIPI of 3 and 5. The median follow-up is 22 months. And you can see that there's a relatively long ongoing treatment duration for this patient in this Phase II expansion cohort. If we go to the next slide, this is the efficacy that was presented. A very high overall response rate and a significant complete response rate, which is the most important efficacy readout for these patients with 85%. And you can also see on the right the durability with a very, very long durability. We are very excited about this data, and this data has also informed the start of a Phase III that is ongoing in this particular setting. The last slide is just emphasizing, again, the progression-free survival, overall survival on this Phase II dataset. Safety. As expected, mainly CRS and Grade 2. The rest, as has been previously reported, no new change to the safety profile with more follow-up. If we go to the next slide and we have the maintenance portion. Arm 7 of the study here. The question was really two. One was the feasibility and safety of every 2 months or every 8-week dosing schedule in the maintenance setting, follicular lymphoma. Subquestion was the ability to convert patients who did not achieve CR after the initial therapy to potentially convert into CRs. So you can see there were 8 patients who had actually PR as a response to the prior CD20-containing chemo regimen before being enrolled on the study. CRS, as expected, in line. If we go to the next slide, we see the maintenance And excitingly here is the conversion of the PRS to CRS. So the conclusion here is maintenance with epcoritamab at a 8-week schedule is feasible. SAFE can be performed after patients had received additional induction therapy and thus leads to conversion of PRs into CRs. There will be additional data in the future presented also in MRD negativity. So as we conclude the presentation of epcoritamab, we wanted to make a significant shift and we go to acasunlimab. This was the poster presentation at this year's ASCO. I'm sure there will be a lot of questions, so I will take my time as we go through the design. So let's level set in the beginning. The original Phase I study interrogated acasunlimab as a single agent. And in a quite elaborate PD/PK modeling, we ended up on a dose of 100 milligrams Q3 weeks. Important to understand here is that there are essentially 2 hooks that we have to deal with. One is a known bell-shaped curve for agonists. The second one is the phenomenon of bispecifics that in and of itself have a bell-shaped curve. And the dose was chosen to get a full [ 4-1BB ] engagement over the entire period of 3 weeks. What we had observed back then was, particularly in non-small lung cancer, not only but particularly in non-small lung cancer, evidence of single-agent activity in the sense that in this patient population, which is very comparable to the population that we're going to talk now, patients who had a PD-1 and chemotherapy, either sequential or in combination. There was an observation of efficacy but this efficacy was very short in duration. In the follow-up, as we looked more into the biological data and the translational data, what we learned was an almost immediate exhaustion of T cells. This led to the strategy of combining with a PD-1 because at the dose of 100-milligram, the PD-1/PD-L1 access is insufficiently inhibited. This was the rationale for the design as it is laid out in front of you, where there were essentially 3 distinct questions. Question 1 for the monotherapy arm was whether through a play on the dose, where you increase from 100-milligram to 500-milligram and then shift from a full engagement of 4-1BB to a sufficient blockade of the PD-1/PD-L1 access. So in essence, a sequential 4-1BB activation followed by a PD-L1 blockade, you could address the issue of durability vis-à-vis 2 combination approaches: one, where 4-1BB is continuously activated over a period of 3 weeks. This is the acasunlimab 100-milligram plus pembro 200-milligram Q3-week schedule, or based on the PK modeling where you have a 3-week off period, so 3-week 4-1BB activation, 3-week holiday of 4-1BB activation. And we used 400-milligram Q6 because this is the approved dosing regimen for pembro, where America has done a fantastic job on PK modeling showing that this is the equivalent PK with the same exposure with the same translational data, the same efficacy data. That was the rationale for this study, and these were the questions that we were asking. If you go to the next slide, what you see is that, broadly speaking, the patient characteristics are comparable. The main takeaway is that the study enrolled patients who are PD-L1-positive and by PD-L1 positive, we mean 1-plus positive. The reason that is, is the drug is a PD-L1 4-1BB antibody, it requires PD-L1 as an anchor in order to conditionally activate 4-1BB. Patients enrolled were either primary refractory or secondary refractory. As I said, patients could have pembro and chemotherapy either sequentially or combination, although I would note that 70% of the patient received the combination therapy. Patients had squamous and nonsquamous. The only patient were excluded were patients with active genetic mutations. I would also note that prognostic markers that have been found to be relevant in the frontline setting are, broadly speaking, irrelevant in this particular setting where the overall survival is relatively short with 9 to 10 months based on what study you look at with the standard of care of docetaxel regardless of all these subgroups. If you go to the next slide, this gives you a disposition. There are obviously differences in the numbers here. The reason for that is relatively quickly in the -- well, not that quickly, but relatively quickly, in the randomization, we realized that the acasunlimab monotherapy arm would not address the question that we were trying to address. And it would not lead to an increased durability of the responses. Similar to what we had seen in the monotherapy in the Phase I expansion cohort, responses did occur but were extremely short lived with 1 to 2 months. So this arm was first stopped. Later on, we also, as we evaluate the Q3 week and Q6 week schedule, preferentially expand the Q6 week schedule, which is going to be the focus of the rest of the presentation. You can see that there is a significantly larger number of patients still ongoing on the Q6 week schedule, which is part of many, many pieces of the puzzle that explain the end results, which I will get to. As we look at the efficacy, as I said, there were unconfirmed responses in all 3 arms. However, the confirmed responses are significantly different in the sense that the monotherapy has only 12% confirmed response rates. The 2 combo arms are comparable. I should note that on Q6 week scheduled, there were 2 patients who had an unconfirmed response who had to be taken off because of initial protocol specified, also discontinuation for LFT elevation grade 3. This protocol-specific language is not active anymore and will not be part of the Phase III because in the meantime, we have learned how to manage grade 3 LFT elevations that have experienced a proper management mitigation. Patients can be safely reexposed without experiencing these LFT elevations. There's also 2 responders who are still on treatment and have the opportunity to confirm. And we'll hopefully be able to update you on -- update of the data set in the near future. The other part to pay attention, of course, is the median duration of response. As you can see from monotherapy, the median duration of response, as I already alluded to, was extremely short in 2 months. With Q3 week schedule, the median duration of response was significantly longer but still short at 5 months. In the Q6 week schedule, the median duration has not been reached. Again, this is a second part of the puzzle that can explain the observation of data. This, together with stabilization of disease leads to a 6-month PFS rate, which was not 0 at the monotherapy, 14% with the Q3 week and 34% with Q6 weeks. It's important that the median PFS is usually driven by [indiscernible], but the tail of the PFS curve is driven by the patients would benefit. This activity is independent of whether patients were high or low PD-L1, where primary or secondary refractory was squamous and nonsquamous. As we now go to the most important slide, you'll see that in this randomized setting and the aspect of randomization is important, so this is not a patient bias where there's 3 distinct biological question. You see a complete separation with an overlap of the overall survival growth for Arm A and B but a distinct separation for Arm C with a 69% 12 months OS. To explain the drop at the back end, what happened was we had a safety run-in initially before the Phase III was for the safety of Q6, 3 patients were enrolled in that arm. Then this was followed by a safety run-in aimed for the Q3 weeks in which we actually had a DLT, that led to an expansion of that particular safety cohort to 6 patients. And these patients are included in the overall data set, of course, because they have exposed are not relevant. And this explains a period of roughly 5 months between the first patients dosed with Q6 weeks schedule for 3 patients and the initiation of the randomization. The main part for us here is that in a scientifically-driven question around how to most optimally engage 4-1BB, the answer that is apparent to us both on efficacy, durability, PFS and OS is that T cells require a period of a vacation in order to prevent exhaustion and maintain long-term functionality. The preclinical data that will further highlight this will be presented at the World Lung Conference and will further show that this is not coincidence, but indeed, science. As we go to the next slide, you'll see the safety. This is a little bit a complicated slide with different colors. The main takeaway is that not only is the Q6 week schedule more efficacious in the way that it allows T cell reconstitution and maintenance of T cell function, which then translates to efficacy, it also has a more tolerable safety profile, presumably because you also have dislocation from 4-1BB activation, which is the flip side of the coin. So lower incidence of Grade 3 treatment-related AEs consistent, including lower treatment-related liver events. I should further note that halfway through the study, there was an implementation of a very elaborate mitigation plan that allowed us to further reduce the liver-related events and that particular data set will also be presented at World Lung. So in conclusion, we are extremely excited about this data because we believe this is an unprecedented OS survival. We are very confident that this schedule of acasunlimab plus pembro is a safe and effective way that has a potential for meaningful impact for these patients for whom the standard of care is docetaxel. And we are excited to look forward to the Phase III, which will start dosing its first patients before the end of the year.

Thank you, Tahi. We hope that you find the data we reviewed today as energizing as we do. Now for a reminder of our next steps for these programs, let's start with TIVDAK. Following the recent full U.S. approval in recurrent or metastatic cervical cancer, we continue to look to expansion in head and neck cancer, and we are encouraged by the data that was presented at ASCO. We are actively engaging with health authorities and working to generate additional data in this indication. We also believe that the EPKINLY data in both frontline and relapsed or refractory follicular lymphoma is extremely promising and supports the potential for to be best-in-class in follicular lymphoma. As we noted during last month's Q1 earnings call, we and our partner, AbbVie, have now initiated one of the new Phase III trials planned for this year in frontline follicular lymphoma. And we continue to look forward to the potential approval later this month of EPKINLY as a treatment for relapsed or refractory follicular lymphoma following at least 2 prior lines of therapy. Finally, for acasunlimab, though the data presented at ASCO was for a small number of patients, the overall survival of 17 months is unprecedented. This efficacy combined with manageable safety profile very clearly passes a high bar for late-stage development. And as we have stated, we and our partner BioNTech, by aiming to start a Phase III trial in post-IO non-small cell lung cancer by the end of the year. So now we would be pleased to take any questions you have. So operator, please open the call for questions.

[Operator Instructions] We will now take the first question coming from the line of Asthika Goonewardene.

Want to offer congratulations on the data, particularly the acasun data, which we on Saturday. Want to dig into that a little bit more and ask, what is acasun able to drive a response in patients who were primary progressives or immediately refractory to prior PD-1? I know that in the baseline factors since you've looked at prior duration of PD-1 therapy, there was about 1/3 of a patient who had it for less than 6 months. Were those patients also seeing a benefit from the acasun Q6W regimen? And also were those patients out there in the latter end in the OS curve? Secondly, you've learned a lot about 4-1BB biology here in non-small cell lung cancer and gotten some very interesting clinical validation. Does this translate to other tumor types? Or will we need to rerun a similar Phase II experiment, Q3W or other versions of these regimens and other tumor types to answer those questions independently?

Thanks, Asthika, for the questions. I think, Tahi, you can dive in here on both.

Sorry, I jumped. Thanks, Asthika. Good questions. First one, yes, I said it and will now repeat this again. There was no difference in terms of efficacy as well as PFS and OS for primary and secondary refractory PD-L1, low and high, squamous, non-squamous. And the second question was the question of what are we going to do with this asset? Obviously, I think it's fair to say that we have learned a lot about 4-1BB. It has been a complicated journey, to be honest, because the 4-1BB biology is complicated. And then we take a decent amount of pride in the fact that we are feeling that we have unraveled this and are able now to explore 4-1BB as a mechanism in solid oncology. And of course, we will now start looking at other opportunities, and we ask questions that in the past maybe with a different approach were not as successful. So more to come.

We will now take the next question from the line of James Gordon.

James Gordon, JPMorgan. So for GEN1046, strong overall survival? Hello, can you hear me?

Yes, we can hear you, James. Go ahead. Yes, we can hear you.

Great. So a few questions on GEN1046. So strong OS data for the 6 weekly arm but still quite a wide [indiscernible] The question was on confidence in the OS data for the 6-weekly arm. Are you going to be enrolling more patients into the arm to increase the robustness of the data and/or following the patients for any longer before you definitely kick off a Phase III with this regimen? I noted there's still quite a wide confidence interval, and it looks like 2 patients are driving quite a lot of the need in OS. And the other question, if you can still hear me, was just on liver tox. Still 12% of patients getting Grade 3 or above. So assuming the product came to market, what sort of requirements do you think that would come with in terms of monitoring? And is there any possibility that even less frequent with good to improve the liver profile further and/or maintain or improve the efficacy?

So that's 3 questions. Jan?

Jump in, Tahi.

I'll just take the 3 questions. So first question. As the enrollment is ongoing but I would say we are actually quite confident, and I would disagree with this is driven by only 2 patients If you look at the plateau at the 12 months where the 69% point estimate comes from, I think there are 9 patients so it's a little bit more than that. It's probably a larger data set than any of the other data sets that were used to justify start-up Phase IIIs in the setting in the past. So given this and the fact that there is a strong biological hypothesis and a long biological supporting data set, what I usually say is when these 3 things line up, we start to believe that. So we feel quite comfortable that what we're seeing is really a function of 4-1BB activation and this on-off, and we have a very good data around the fact that these patients maintain T cell activity, engage CDAs, expand CDAs and how that relates to response. On the monitoring, there's 2 things to be said. Initially in this protocol, we were very focused on making sure that we had a good handle on elevations because this is a known challenge, 4-1BBs, if you go back in the history of 4-1BB and you look at BMS's attempt over 10 years, that was the main reason they were unable to move forward with that particular program with this particular biology. So the testing initially was quite intense in order for us to learn more about it and come up with an appropriate mitigation plan. A lot of these LFT innovations are actually asymptomatic, like almost all of them. Generally, monitoring is even standard today for pembro as well for actually all And so on the Phase III, we will get to a place where there will be more comparable to standard of care monitoring. And so I don't see there are any issues. On the question on whether or not we can expand this, where there's always a balance between safety and efficacy. I think what we saw relatively early is when patients discontinue. And I mentioned this, for example, right? We had 2 patients with an unconfirmed response but then they stopped. They basically only got the dose once. And then there was this whole debate about getting these patients reexposed on a patient program, which in both cases actually did on the, of course, not part of the data set. What we learned there is that if you don't give it in a reasonable frequency, the tumor actually will come back. So I think we feel that Q6 is probably the perfect spot to manage T cell recovery, maintain T cell activity, have a safety profile that, broadly speaking, is extremely well tolerated. I mean, if you talk to the physicians on this trial, these patients are doing well. These are lab optimal as most part, they are not actually real AEs in the sense of that they impact the quality of life and the durability of responses.

We will now take the next question from the line of Vikram Purohit.

So we had 2. Going back to the topic of safety for the Phase II acasunlimab update. I guess just to put a fine point on the topic of asymptomatic liver enzyme elevations. In a real-world setting, would you expect these levels of ALT/AST increases to actually result in discontinuation of treatment? Or do you think it would be manageable just kind of based on the protocol you've laid out here? And then secondly, on the Phase III program, I just wanted to clarify, are there any regulatory interactions pending before you can start that Phase III program? Or is it just a matter of blocking and tackling and just administrative issues before you can start that up? And then lastly, I guess, on the same topic, I guess what can you tell us at this point about the size and the scope and kind of the nature of the Phase III study you hope to run?

Thanks, Vikram. Tahi, I think it's, again, you.

LFT elevations, I say it again, they are manageable. We have significant experience that patients can be reexposed. This is also now widely being appreciated and accepted by the physicians. And the protocol language will be such that patients will have a mitigation plan. I won't get into the mitigation plan because it's obviously a competitive space, and this is part of our learning how to mitigate and manage this and then they will get reexposed, and this has been working really well, particularly in the second half of the Phase II. And so we're very comfortable with that, that this is also going to play out in the real world. Regulatory, we already had all regulatory interactions with FDA, cHMP and PMDA. So we're just basically in the site selection process and so on. And the last part is we don't tend to kind of communicate these things, sort of very competitive landscape. It will be in a publicly Phase III and there have been many Phase IIIs that have recently failed in that setting, so they can give you a guidance to where the size and the scale of the study will be.

Our next question comes from the line of Kaveri Pohlman.

This is Christian, I'm on for Kaveri. So just 1 on the acasunlimab data. We were wondering, why is there a big difference between PFS and OS? Like the 6-month PFS rate suggests that median PFS is going to be lower than docetaxel 6-month PFS, but there's a big difference between the OS and those 17 months for acasunlimab versus around 10 months for docetaxel. So where do you think this OS benefit is coming from?

I think, Tahi, it's you again.

I'm going to take this again. Thank you for the question. Median PFS, I said about is driven by the nonresponders. What is important is not the median PFS and thing like this. What is important is the tail. I think this is the of a number of failed Phase IIIs in recent setting that people don't appreciate that the primary endpoint OS, not medium PFS. What is the conclusion, what is driving out there? Two things. One is the durability of response. It's not reached, it's currently estimated to be 17 months. It's the stabilization of diseases for those patients who are on it. That leads to a 6-months PFS of 35%. And if you overlay that with docetaxel or any chemo's driven PFS curve. And you can see that the PFS curves for chemotherapies tend to have like a relatively straight line going down. What we're seeing here is essentially an old phenomenon that maybe has been forgotten in the wave of ADCs. And that is that immuno-oncology approaches tend to win on the tail by stabilization and long duration of responses. And that this tail was a not the median PFS, but the tail of the PFS growth, and that also drives the OS. I hope that explains.

Next question is coming from the line of Yaron Werber.

Congrats on the data. Two questions for you. Maybe the first one for acasunlimab. So in the Phase III, I don't know you can share, is there a chance that survival is going to be the primary with PFS over the secondary, just given the importance of survival? And then secondly, for epcoritamab, would you take the C1 OPT dosing into DLBCL studies from now on?

Tahi, I think it's for you again.

Well, I think we have been very, very clear on this. And by the way, the health authorities with whom we had the interactions have also been crystal clear on this. The [indiscernible] primary endpoint in this setting is also [indiscernible]. Period. Now on the optimization data this is a little bit of a different disease. It tends to be more aggressive. We had a different approach for optimization in diffuse large B-cell that will also be presented in the second half of this year. That was trying to take into account that the time to the full dose, particularly in the refractory setting, I should say, as a monotherapy is probably equally important. And so there are other ways how you can manage the CRS, which, by the way, in diffuse large B-cell is anyway lower. So we'll present some data there, also part of the outpatient data that will show a CRS rate that we feel is quite manageable and comparable to follicular lymphoma with a slightly different approach that takes into account also the efficacy concerns for diffuse large B-cell. And equally will support, in our mind, the ability for epcoritamab based on inconvenience, safety and overall efficacy to also be a medication or a medicine that can be provided to patients and setting outside of specialized experience centers where currently almost all commercial activities are ongoing. Meaning right now, for all [indiscernible] for all and the myeloma field, patients who get access to these drugs in the U.S. are primarily treated in very large academic institutions. The vast majority of patients are not seen in these institutions. And so we have always said from the very beginning that the appeal of eculizumab in our mind is subcutaneous administration to an avoidance of PK and a reduction in CRS, that it is a mechanism that could make or should be made available for patients in other hospital settings or non-hospital settings, health care settings, I should say, outside of hospitals.

The next question comes from the line of Michael Schmidt.

This is Paul on for Michael. My first is a quick follow-up for acasunlimab on safety, specifically on the protocol-mandated treatment discontinuations due to LFT elevations. Were all patients who had any Grade 3 events immediately discontinued or was that only those who are symptomatic or persistent after mitigation? And then my second question is just on TIVDAK. It would be great to get your comments on the evolving landscape in head and neck cancer, particularly given the possible higher bars set by petosemtumab in second-line and today in frontline. Would the innovative 207 studies results in a randomized study be sufficient to be approved in second line? And what's your path forward in the frontline setting?

Thanks, Paul. And maybe, Tahi, you can take the first one, which would be straightforward, and then Judith can take the landscape for in head and neck cancer for TIVDAK. Tahi?

In the protocol for this [indiscernible] study, the protocol-mandated language was all patients with Grade 3 LFT had to discontinue. And this will not be the language in the Phase III. And then I'll hand it for TIVDAK.

Thank you for the question. So in the second, third-line setting, the data on TIVDAK stayed very strong even, of course, [indiscernible] study comparison is always not best practice. But in this particular case, if you even take the moment to compare, you see how strong is the TIVDAK data. Moreover, as I highlighted, 67% pretreated with cetuximab and pure intention to treat. So this ORR of 40%, of 32.5% is really strong. Now with regard to the first-line setting, as I said before, we have an arm, called arm F that is recruiting patients in the combination with pembro and potentially, we would expand to pembro chemo. So more data is awaited to decide how to strategize the data in the second, third-line and potentially move to other lines.

Next question comes from the line of Xian Deng.

Two for Tahi, please, for 1046. The first one is related to your previous comment on the importance of the tail of the curve. And also apologize if I missed how you explained the big drop towards the end. But if I look at your OS curve, let's say from month 9 or so, the number of patients at risk is actually relatively small, and this is typically the part of the curve where since the data can kind of have an impact on the shape of the curve and you have quite a few sensor data here. Appreciate this is very relatively early-stage data. Just wondering how confident are you with how the OS data kind of persists with longer-term data, longer-term follow-up? And what are sort of the incremental data that you have, you have seen that kind of support your confidence? That's the first question. The second one is just wondering, what do you think as sort of the read-across to your other 4-1BB assets? Do you think this could be seen as a sort of a positive read-across for both of them, the other 2? Or do you think this is more sort of related to the one 4-1BB Abcam because both are sort of doing -- bridging the T cell and the cancer cell whereas the one with CD40 is sort of with antigen presenting a bit different. Thank you very much.

Tahi, please cover.

Let's go back to the OS curve. So the big drop-off, I explained before. I'll do this just again so that everybody understands this. There was a safety run-in initially Q6 weeks in combination pembro, 3 patients, followed by a safety run-in. And for Q3 weeks, there was a DLT. So that led to a delay, so the time difference between the Q6 patients and then the start of the randomization, the 3 Q6 patients who were part of the safety run-in is 5 months. That's why you have this weird-looking cliff. As it relates to sensoring, there are some sensing but there's also a decent number of patients beyond 12 months. So at 9 months, it's actually, I think, 9 patients at risk. What I mentioned before, and this will hopefully become a little bit more clear when we get to share this data at World Lung is that we have actually a pretty decent understanding now in terms of translational data along changes to CD8 T cells, exhaustion markers [indiscernible] for example, one of them to understand which patients are actually benefiting, which are not. And so we feel very confident, which is why we started the Phase III activities. So I think I cannot be clear on this. On the readout to 4-1BB programs, you're absolutely right. We have actually 4-1BB in collaboration with BioNTech and there are 2 other assets in that collaboration. One is [ CD40 4-1BB ] and one is [indiscernible] 4-1BB. I would say CD40 4-1BB is slightly more complex biology because you have 2 agonist on both ends. So there are some questions to be answered there. But I think I also answered this before. It's probably a fair conclusion that as we learn more about 4-1BB biology, and as we have learned more about 4-1BB biology, this obviously has a readout how we approach other assets and that particular to these 2 assets may be more concrete come from 4-1BB.

The next question comes from the line of Peter Welford.

I just want to be crystal clear that -- so with regards to the regulatory interactions, the regulators are happy that there are sufficient patients who have been on every 6-week dosing with the 100-, 400- dosing regimen to enable that regimen to be taken directly into the pivotal study without any sort of Phase II run-in period or similar, but it will be directly to start a pivotal study? And related to that, can you just confirm that is that going to be the only dosing regimen with acasunlimab that is going to be initiated in the Phase III? So this will be a direct sort of 2-arm 1:1 type study using the every 6 weeks dosing? And then finally, just to return. I think you sort of answered this, but just to be clear, with regards to the change in LFT monitoring and mitigation requirement that you introduced halfway through the study, can you give us any sort of clarity in terms of what that is? So if you look at the percentages that we can see on that safety chart, can you perhaps, to some extent, put in context for us what perhaps it looks like in the first half versus the second half, appreciating this is small patient numbers?

Thanks, Peter, for the questions. Very good. And I think, Tahi, you can give a bit more color on the Phase III protocol and then the LFT monitoring question, very important.

Yes. Very good questions, Peter. So when I say we have had positive FDA interactions and we -- and cHMP and PMDA interactions, we are moving forward, and that means that agreement, the protocol is being submitted, has actually been submitted. And this is what it is. So the data is fine and we are moving to Phase III. When I say Phase III, in contrast to other companies, we don't mean Phase II. We mean Phase III so it's a randomized Phase III, not with a Phase II run-in. And when we say Phase III, Q6 weeks, it's 1 arm versus the other, not some other arms. On the mitigation, I do not want to go into the details, frankly, on how we mitigate because this is a space that is heating up, as you, I'm sure, are all aware. What I can leave you with is that since the mitigation was implemented in general, not a single patient has discontinued treatment. That should give you a sense of that this is a successful intervention.

Next question comes from the line of Matthew Phipps.

I'm curious what your expectations are for docetaxel OS in only a PD-1 positive patient cohort. Just because the CONTACT-01 study did show OS by PD-1 status, and there might have been a higher median OS for those in those high PO1 expressers. And is that a valid think data point that you're considering in the design of your trial?

Tahi, can you comment on the docetaxel OS curves there?

Well, PD-L1 positive, 1 plus positive, it's 10 to 11 months.

Next question comes from the line of Yifeng Liu.

I just wanted to follow up on the OS [indiscernible] So could you talk about the consistency about your sensory role to quarter 3 arms and it's mainly due to the adverse events with a continuation or there's other reasons for it? And as you are also -- the second question is you're still recruiting and your target, it seems to be 130 patients. When do you set that complete? Third one [indiscernible] on the responders. Could you maybe give some color on the biomarker status?

Tahi, can you comment on that?

Yes. So I can comment on the first question. I didn't really understand the last question. Maybe you can repeat that. But the first question is OS, the sensory way forward. It's like you are -- I don't want to sound like this, but it's you're either dead or you're alive, and there's no difference between the 3 arms. I didn't get the second part of your question, though, I'm sorry.

Sorry, yes, the second part is it's just only present about 100 patients. If you look at clinical [indiscernible] target sample is about 130 patients. I just wondered when you expect that the rest of the patients to be recruited on [indiscernible].

Got it. So no, assuming these clinical trial of numbers are usually like before you start kind of like a frame of like how many patients you want to enroll. This was initially based on the idea that we would take 40 in all 3 arms forward. What we're just doing right now is like fitting up a little bit to get a little bit more better handle on really the accuracy of our safety interventions and learn a little bit more while we start in the Phase III. So we don't actually use that data for efficacy readout. We're using it more to fine-tune some of the things that have been done in the Phase III. And there's not that many patients, like a handful. So actually, I think it's a practical purpose of this call actually is [indiscernible] should see that's no patient is going to be enrolled.

Understood. And also on the last one, on the patients who achieved a very durable response, any colors on the biomarkers or PD-1 spaces or any clarity on that?

So as I said before, there's really, honestly, no difference really between whatever categories at least one commonly looks at primary factor, secondary factor, squamous, non-squamous. PD-L1 high, PD-L1 low, the differences are really marginal. It works. It appears to be working independent of all of these things. On the biomarker data, you will appreciate that I'm not really going to comment on this. This is, to some degree, proprietary data for us to guide us. At an appropriate time, we will share this with the investor community, with the community, but it's also something that has a readout also to other programs, frankly, and learning that came with a long period of studying this and this biology over the last, what is it now, 5 years.

We will now take the next question from the line of

From Deutsche Bank. Just wanted to get your thoughts on what do you make of some of the advances recently in the IO PD-1 space, specifically [indiscernible] with, for example, PD-1 that combination.

Thank you, Manos, for the questions. Tahi, maybe you can start with that and then maybe Judith can also add to that. Tahi?

Sorry, it was a little bit hard to understand, but if I understood correctly, your question was what is our thought on a constantly emerging competitive landscape, including PD-L1 VEGF? So my general comment on all of this is that this is great for patients and that when you are working in drug development oncology, you don't walk alone. It's a highly competitive environment, and so we welcome and applaud any and all approaches that have the potential to help patients with PD-L1 VEGF in combination as actually series of failed trials, [indiscernible] , PD-L1 VEGF as a bispecific construct is something that is emerging. I think there was some data presented it. I think this is early emerging data, interesting data. I thought the working data, and we'll see where it lands.

Thanks, Tahi. Judith, you want to add to that?

Yes. I mean, of course, this is a space of such an unmet medical need that it's expected that every company tries to make a difference on patients and add value in every [indiscernible] patient setting. We are very confident about our data. And if you compare every Phase III that failed, for every ongoing Phase III, the strength of the evidence on the Phase II before jumping on the Phase III, nothing compares to the data set that we just disclosed at ASCO. So we are very confident that with this Phase II data, we are in a very solid ground to start the Phase III and potentially make a difference for patients.

Okay. Let's move on to the next question, maybe the last one, operator?

There are no further questions at this time. I would now like to turn the conference back to Jan van de Winkel for closing remarks.

All right. Thank you for joining us today to discuss some of the exciting data presented at ASCO in Chicago. If you have any additional questions, please reach out to our Investor Relations team. We very much look forward to speaking with you again soon.

This concludes today's conference call. Thank you for participating. You may now disconnect.