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 beliefs, anticipate, 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 may contain 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 in 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 in 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, too, during two rapid oral presentations. Finally, you will hear from Tahamtan 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.
Yeah. Thank you, Jan, and good morning, everybody from sunny Chicago. I will update you on the data just presented by Dr. Sun at ASCO on innovaTV 207, part C, which is exploring tisotumab vedotin in head and neck cancer. 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. Tisotumab vedotin 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 mg per kilo every other week. Next slide, we have patient characteristics, some just median age, 61 years, and some important points, 37% of patients were exposed to three lines of therapy. All the patients were exposed to checkpoint inhibitors.
All patients, except one, were exposed to platinum. 67% of patients were exposed to cetuximab and failed cetuximab, and 57% of patients received prior taxane. So what we see a heavily pretreated population encompassing prior 1 to 3 prior lines. In the next slide, we see the main efficacy. 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 present the data on the full data set, which is 40 patients, and in the patients pretreated with one or two lines, which encompass 25 patients. As we see, the ORR for the full population is 32.5%, while the ORR for the one to two prior lines is 40%.
Interestingly, duration of response is 5.6 for the two subset, you know, which is considered pretty durable in this very setting. In the next slide, we see the waterfall plot, which again, you know, illustrates that almost many patients, you know, had tumor shrinkage, and very importantly, that the assessment that the response was not influenced by prior taxane or non-prior taxane, which was a relevant question, given the nature of the payload at MMAE. In the next slide, we see the main safety findings. So in as a conclusion, you know, 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 conclusions, is we see this 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, yeah, to Tahi.
No, I think I will 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 mg for the first dose, 0.8 mg for a second intermediate dose, and then 48 mg with the full dose, and 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 CD3, CD20s, that the CRS rate in Follicular Lymphoma is slightly differentiated from the one diffuse large B-cell. It's 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, PK modeling, get more data in Follicular Lymphoma, we settled on a second step-up dosing, so introduced another step-up of 3 mg before the full dose exposure with 48 mg. So if you go to the next slide, patient characteristics. This is mainly to emphasize the point that there's really no relevant difference between the original pivotal study as well as the optimization cohort of 86 patients.
Patients were, broadly speaking, heavily pre-treated and refractory, and present a population of unmet medical need in this relapsed refractory follicular lymphoma setting. If you go to the next slide, you'll see a graphic presentation of the most common treatment-emergent AEs, the cutoff of 25%. Most importantly, of course, for this presentation, this discussion is the focus on CRS. We will have a little bit more detailed look in the next slide. And the objective, of course, for this was a reduction of CRS Grade 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 leads to a significant clinically meaningful reduction of CRS. Also, a 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 in Follicular Lymphoma. That, based on the convenience of the subQ administration and the safety now with this particular, step-up dosing in Follicular Lymphoma with a 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.
Reset everybody, there was a delay of one 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 three CRS, significant reduction in grade two, no ICANS, 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.
If we go on to the next presentation, this was the presentation of epcoritamab in combination with rituximab and irinotecan in previously untreated patients with follicular lymphoma, as well as a separate arm out of the O2 study that was looking at the question of maintenance. If we go to the next slide, you'll see the two designs for these separate arms. I don't want to spend too much time on this. If you go to the next slide, baseline characteristics for the frontline patients. A good mix of frontline patients, predominantly Grade 3 and 4, as well as a significant portion with a FLIPI of three and five. 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 you go to the next slide, this is the efficacy that was presented. A very high overall response rate and a significant complete response, which was 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 and overall survival on this phase II data set. Safety, as expected, mainly CRS, Grade 1 and Grade 2. The rest is as has been previously reported, no new change to the safety profile with more follow-up.
If you go to the next slide, and we have the maintenance portion, the Arm 7 of the study here, the question was really two. One was the feasibility and safety of a every two months or every eight-week dosing schedule in a maintenance setting, fully conformer. A sub-question 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 eight patients who had actually PR as the response to their prior CD20 containing chemo regimen before being enrolled on this study. CRS, as expected, in line. If you go to the next slide, we see the maintenance swim lane, and excitingly, here is the conversion of the PRs to CRs.
So the conclusion here is maintenance with epcoritamab at a Q 8-week schedule is feasible, is safe, can be performed after patient had received additional induction therapy, and does lead to conversion of PRs into CRs. There will be additional data in the future presented also on MRD negativity. So as we conclude the presentation of epcoritamab, we wanted to make a significant shift, and we go to atezolizumab. 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 atezolizumab as a single agent, and in a quite elaborate PD/PK modeling, we ended up on a dose of 100 mg Q 3- weeks.
The important to understand here is that there are essentially two 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 three weeks. What we had observed back then was, particularly in non-small cell cancer, not only, but particularly non-small cell 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 mg, the PD-1, PD-L1 axis is insufficiently inhibited. This was the rationale for the design as it is laid out in front of you, where there were essentially three distinct questions. Question one, for the monotherapy arm, was whether through a play on the dose, where you increase from 100 mg to 500 mg, and then shift from a full engagement of 4-1BB to a sufficient blockade of the PD-1, PD-L1 axis. So in essence, a sequential 4-1BB activation followed by PD-L1 blockade, you could address the issue of durability. These are the two combination approaches.
One, where 4-1BB is continuously activated over a period of three weeks. This is the atezolizumab 100 mg plus pembro 200 mg Q3-week schedule, or based on the PK modeling, where you have a three-week off period. So three-week 4-1BB activation, three-week holiday of 4-1BB activation. And we use 400 mg Q6 because this is the proof dosing regimen for pembro, where Amgen's 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 we go to the next slide, what you see is that broadly speaking, the patient characteristics are comparable.
The main takeaway is that the study involved patients who were PD-L1 positive, and by PD-L1 positive, we mean 1+ 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, patient could have pembro and chemotherapy, either sequential or combination, although I would note that 70% of the patient received the combination therapy. Patient had squamous and non-squamous. The only patient who 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 9-10 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, 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 cohorts, responses did occur, but were extremely short-lived at 1-2 months. So this arm was first stopped. Later on, we also, as we evaluate the q3 week and q6-week schedule, preferentially, expanded 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 you look at the efficacy, as I said, there were unconfirmed responses in all three arms. However, the confirmed responses are significantly different in the sense that the monotherapy has only 12% confirmed response rates.
The two combo arms are comparable. I should note that on Q6-week schedule, there were two patients who had an unconfirmed response, who had to be taken off because of initial protocol specified rules for discontinuation for LFT elevations Grade 3. These 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 and have experience that with proper management mitigation, patient can be safely re-exposed without experiencing these LFT elevations. There's also two responders who are still on treatment and have the opportunity to confirm, and we'll hopefully be able to update you on a update of that, 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, with two months. With Q3, Q3-week schedule, the median duration of response was significantly longer, but still short at five months. In the Q6-week schedule, the median duration has not been reached. Again, this is a second part of the puzzle of that, that can explain the observation of data. This, together with stabilization of disease, leads to a siix months PFS rate, which was non-zero at the monotherapy, 14% with the Q3 week, and 34% with Q6 weeks. It's important that the median PFS is usually driven by the non-responder, but the tail of the PFS curve is driven by the patients who benefit. This antitumor activity is independent of whether patients were high or low PD-L1, were primary or secondary refractory, or squamous or non-squamous.
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, but is three distinct biological questions. You see a complete separation with an overlap of the overall survival curves for arm A and B, but a distinct separation for arm C, with a 69% 12-month OS. To explain the drop at the back end, what happened was we had a safety run-in initially, before the phase III was run for the safety of Q6, three patients were enrolled in that arm. Then this was followed by a safety run-in for the Q3 weeks, in which we actually had a DLT that led to an expansion of that particular safety cohort to six patients.
These patients are included in the overall data set, of course, because they have been exposed and are relevant. This explains a period of roughly five months between the first patient's dose with q6 week schedule, the three 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 and 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 this vacation from 4-1BB activation, which is the flip side of the coin. So lower incidence of Grade 3 treatment-related AEs are consistent, including lower treatment-related, liver-related 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 a 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 an 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 EPKINLY 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. 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 two 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. As we have stated, we and our partner, BioNTech, are 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.
Thank you. To ask a question, please press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one and one again. We will now take the first question. Coming from the line of Asthika Goonewardene. Please go ahead.
Hey, guys, good morning, and thank you for taking our questions. Wanna offer congratulations on the data, particularly the acasunlimab data, which you got on Saturday. Wanna dig into that a little bit more, and ask: Was acasunlimab able to drive a response in patients who were primary progressors or immediately refractory to prior PD-1? I note that in the baseline characteristics, you've looked at prior duration of PD-1 treatment; it was about a third of the patients who had it for less than six months. Were those patients also seeing a benefit from the acasunlimab T-V regimen? And also, were those patients out there in the latter end of 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 experiments, Q 6W or other versions of these regimens and other tumor types to answer those questions independently? Thanks.
Thanks, Asthika, for the questions. I think, Tahi , you can dive in here on both. Yeah.
Sorry, I jumped ahead. Yes, thank you, Asthika. Good questions. First one, yes, I said it, and I'm gonna repeat this again. There was no difference in terms of efficacy as well as, oh, 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 gonna do with this asset? Now, 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 we may 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.
Of course, we will now start looking at other opportunities, and reask questions that, in the past, maybe with a different approach, were not successful. More to come.
Thanks, Tahi . Thanks, Asthika. Operator, we can go to another question.
Thank you. We will now take the next question from the line of James Gordon. Please go ahead. James Gordon, your line is open.
Hello, James Gordon, JP Morgan. Thanks for taking the questions. So for GEN 1046, strong overall survival data... Hello, can you hear me?
Yes, we can hear you, James.
Can you hear me?
Go ahead. Yes, we can hear you.
Hello, can you hear me? All right, great. Thank you.
We-we-
That's it. Great. Great, so, two questions on GEN1046. So strong OS data for the six-weekly arm, but still quite a wide confidence... If you can hear me again, the question was on the confidence in the OS data for the six-weekly arm. Are you gonna be enrolling more patients into the arm to increase the robustness of the data? And/or following it, the patients for any longer?
... before you definitely kick off a phase III with this, this regimen? Because I noted it's still quite a wide confidence interval, and it looks like two patients are driving quite a lot of the need to know it. And the other question, I hope you can still hear me, was just on liver tox. Still 12% of patients getting Grade three 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 would be good to improve the liver profile further and or maintain or improve the efficacy?
So there's three questions. Sorry,
Jump, jump in, Tahi . Yeah.
I'll just take-
Tahi .
Thank you. Sorry. So first question. As our enrollment is ongoing, but I would say, we are actually quite confident, and I would disagree with this, is driven by only two patients. If you look at the plateau at the 12 months, where the 69% point estimate comes from, I think there are nine patients there. So it's a little bit more than that. It's probably a larger data set than any of the other data sets that we use to justify start of phase III in this setting in the past. So given this and the fact that there is a strong biological hypothesis and a strong biological supporting data set, you know, what I usually say is when these three things line up, we start to believe them.
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 very good data around the fact that these patients maintain T cell activity, engage CD8, expand CD8, and how that relates to response. On the monitoring, there's two things to be said. Initially, in this protocol we were very focused on making sure that we had a good handle on LFT elevations because this is a known challenge for 4-1BBs. Indeed, you know, if you go back in the history of 4-1BBs 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 elevations are actually asymptomatic, like almost all of them. Generally, monitoring is even standard today for Pembo as well, for actually all IOs. And so on the phase III, we will get to a place where this will be more comparable to standard of care monitoring. And so I don't see there any issues. On the question on whether or not, you know, we can expand this. Well, there's always a balance between safety and efficacy.
I think, you know, what we saw relatively early and is when patients discontinue, and I mentioned this, for example, that we had 2 patients with a 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 an inpatient program, which we in both cases actually did. This data is, of course, not part of the data set. What we learned there is that, you know, 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 the trial, these patients are doing well. These are lab abnormalities for the most part. They are not actually real AEs in the sense of that they impact their quality of life, and the durability of responses.
Thanks, Tahi . Let's go on to the next question.
Thank you. We will now take the next question from the line of Vikram Purohit. Please go ahead.
Hi, good morning. Thank you for taking our questions. So we had two. Going back to the topic of safety for the phase II acasunlimab update. I guess just to put a fine point on the, the topic of the 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?
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.
Thanks, Vikram. Tahi , I think it's again, you.
All right. LFT elevations, I'll say it again, they are manageable. We have significant experience that patients can be reexposed. This is also now broadly being, you know, appreciated and, and accepted by the physicians, and, and the protocol language will be such that patients will have a mitigation plan. I won't get into the detail of mitigation plan because it's obviously a competitive space, and this is part of our learning, on 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 this 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 the FDA, CHMP and, PMDA.
We're just basically in the site selection process and so on. The last part is, you know, we don't tend to kind of communicate these things, you know, it's a very competitive landscape. It will be an appropriately sized Phase III, and, you know, there have been many Phase IIIs that have recently failed in that setting, so they, they can give you a guidance to where the size and the scale of the study will be.
... Thanks, Tahi . Let's move on to the next question, operator.
Thank you. Next question comes in of Kaveri Pohlman. Please go ahead.
Hi, this is Christian. I'm on for Kaveri. Thanks for taking our question. So just one on the acasunlimab data. We were wondering why is there a big difference between PFS and OS? Like, the six-month PFS rate suggests that median PFS is going to be lower than docetaxel's six-month PFS, but there's a big difference between the OS in those two, like 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 gonna take this again. Thank you for the question. Median PFS, I say that a lot, is driven by the non-responders. What is important is not the median PFS in a setting like this. What is important is the tail. I think this is the fallacy of a number of failed phase IIIs in recent past in this setting, that people don't appreciate that the primary endpoint OS, not median PFS. What is the conclusion? What is driving it? There are two things, right? 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, are on it.
That leads to a six months PFS of 35%, and if you overlay that with, with docetaxel or with any chemo-driven PFS curve, then 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 immune oncology approaches tend to win on the tail by stabilization and long duration of responses, and that this tail drives a, not the median PFS, but the tail of the PFS curves, and that also drives the OS. Hope that explains.
Thank you very much.
Thanks, Tahi . Thanks, Christian. Let's move on to the next question, operator.
Next question is coming from the line of Yaron Werber. Please go ahead.
Great, thanks for taking my questions. Tahi , and congrats on the data, too. 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 gonna be the primary, with PFS sort of the secondary, just given the importance of survival? And then secondly, for epcoritamab, would you take the C 1 opt dosing into the LBCL studies from now on? Thank you.
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 sine qua non primary endpoint in this setting is overall survival. Period. Now, on the optimization data, diffuse large B-cell 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 at 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.
There are other ways how you can manage the CRS rate, 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 convenience, safety, and overall efficacy, to also be a medication or a medicine that can be provided to patients in a setting outside of specialized CAR-T experience centers, where currently almost all, you know, commercial activities are ongoing.
Meaning, right now, for all CD3, CD20, actually, for all bispecific, even in the myeloma field, patients who get access to these, to these drugs, in, in the US, are primarily treated in, 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, the appeal of epcoritamab in our mind is through the subcutaneous administration, through a, avoidance of peak decay and, and a reduction in CRS, that it is a, a, a mechanism that could be made or should be made available for patients in, in other, hospital settings or non-hospital settings, healthcare settings, I should say, outside of hospitals.
Thanks, Tahi . Thanks, Yaron, for the questions. Let's move on.
The next question comes from the line of Michael Schmidt. Please go ahead.
Hey, this is Paul on for Michael. Thanks for taking our question. 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 three events immediately discontinued, or was that only those who were symptomatic or persistent after mitigation? And then my second question is just on Tivdak. Would be great to get your comments on the evolving landscape in head and neck cancer, particularly given the possible higher bars set by petosemtamab in second line and today in front line. You know, would the innovaTV 207 studies results in a randomized study be sufficient to be approved in second line? And what's your path forward in the front-line setting? Thank you.
... Thanks, Paul. And maybe, Tahi, you can take the first one, which should be straightforward, and then Judith can take the landscape for Tivdak. Tahi?
In the protocol for this 204 study, the protocol-mandated language was all patients with Grade 3 or higher have to discontinue. This will not be the language in the phase III. And then I hand it for Tivdak to Judith.
Well, thank you for the question. So in the second timeline setting, the data on Tivdak stayed very strong, even, you know, all-- of course, you know, cross 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, you know, as I highlighted, 67% pretreated with Cetuximab and pure intention to treat. So this ORR of 40% of 32.5%, it stays 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 will expand to pembro chemo. So more data is awaited to decide, you know, how to strategize the data in the second timeline and potentially move to other lines.
Thanks, Judith. Let's move on.
Thank you. Next question comes from the line of Xian Deng. Please go ahead.
Thank you. Thank you for taking my questions. 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, you know, the big drop towards the end. But if I look at your OS curve, let's say from month nine or so, the number of patients at risk is actually relatively small, and this is typically the part of the curve where censor data can kind of have an impact on the shape of the curve, and you have quite a few censor data here. Appreciate this is very relatively early stage data.
Just wondering, how confident are you with you know, 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 seen that kind of support your confidence? That's the first question. And 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 two, or do you think this is more sort of related to the one, 4-1BB EpCAM?
Because both are sort of doing bridging the T cell and the cancer cell, whereas the one with CD40 is sort of a, you know, with antigen-presenting cells a bit different. Thank you very much.
All right.
Tahi , please go ahead. Yeah.
All right, let's go back to the OS curve. So the, the big drop-off I explained before, but I'll do this just again so that everybody understands, is there was a safety run in initially Q6 weeks in combination with pembro, three patients followed by a safety run in 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 three Q6 patients who were part of the safety run, was five months. That's why you have this weird-looking cliff. As it relates to censoring, there are some censoring, but there's also a decent number of patients beyond the 12 months. So at nine months, it's actually, I think, nine 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 the world launch, is that we have actually a pretty decent understanding now, in terms of translational data, around changes to CD8 T cells, exhaustion markers, TIM-3, for example, one of them, to understand which patients are actually benefiting and which are not. And so we feel very confident, which is why we started the phase III activities. So I'm... I think I cannot be clear on this. On the readout to 4-1BB programs, you are absolutely right. We have a actually broad 4-1BB collaboration with BioNTech, and there are two other assets in that collaboration.
One is CD40 4-1BB, and one is EpCAM 4-1BB. I would say CD40 4-1BB is slightly more complex biology because you have two agonists on board end. So there are some questions to be answered there. But I think I also answered this before. It's probably a fair conclusion that, you know, 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 two assets, maybe more concretely for EpCAM 4-1BB, actually.
Thanks, Tahi.
Thank you.
Thanks, Xian, for the questions. Let's move on to the next one.
Thank you. The next question comes from the line of Peter Welford. Please go ahead.
Hi, thanks for taking my questions. 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 six-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 into a pivotal study. And related to that, can you just confirm that, is that gonna be the only dosing regimen with icatibimab that is gonna be initiated in the phase III? So this will be a direct sort of 2-arm, 1-to-1 type study, using the every six-week 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 at all in terms of what that did? So if we 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? Thank you.
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, very important.
Yeah, very good questions, Peter. So when I say we have had positive FDA interactions, and CHMP and PMDA interactions, we are moving forward, then that means that we are in 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 the phase II running. And when we say phase III, Q6 weeks, it's one 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, you know, 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 January, not a single patient has discontinued treatment. That should give you a sense of that this is a successful intervention.
Thanks, Tahi . Thanks, Peter. Let's move on to the next question, operator.
Thank you. Next question comes from the line of Matthew Phipps. Please go ahead.
I thank you for taking my question. I'm curious what your expectations are for docetaxel OS in only a PD-L1 positive patient cohort. Just 'cause the KEYNOTE-001 study did show OS by PD-L1 status, and there might have been a higher median OS for those PD-L1 expressers than those high PD-L1 expressers. Is that a valid, you think, data point that you're considering in the design of your trial?
Tahi , can you comment on the docetaxel OS curves there?
For PD-L1 positive, 1+ positive, it's 10-11 months.
Thanks. Thanks, Tahi . Is that okay, Matt?
Yeah, I appreciate that.
Okay, thank you. Let's move on to the next question, operator.
Thank you. Next question comes from the line of Yijing Liu. Please go ahead.
Hi, thanks for taking my question. I just wanted to follow up on the OS curves, if I may. So could you talk about the consistency about your censoring rules across the three arms, and is it mainly due to adverse events or, adverse event discontinuation, or there's other reason for it? And the second question is, you are still recruiting, and your target, it seems to be 130 patients. When do you expect that's completed? The third one, if I may, on the responders, could you maybe give some color on biomarker pathology, status? Thank you very much.
Tahi , can you comment on that?
Yes, I can comment on the first question. I didn't really understand your last question. Maybe you can repeat that. But, the first question is OS. The censoring is quite straightforward. It's like you are... I don't wanna sound like this, but it's, you're either dead or you're alive, and there's no difference between the three arms. I didn't get to the second part of your question, though. I'm sorry.
Oh, sorry. Yeah, the second part is, it's because in this part, you only present about 100 patients, whereas if you look at ClinicalTrials.gov, the goal target sample is about 130 patients. Was just wondering when you expect that the rest of the patients to be recruited?
Yeah.
Yeah, from that.
Got it. Got it, got it. So, no. So, meaning these, these, ClinicalTrials.gov numbers are usually like, you know, 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 three arms forward. What we're just doing right now is, like, filling 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're starting the phase III. So we don't actually use that data for efficacy. We're often using it more to fine-tune some of the things that are being done in the phase III. And there's not that many patients, like a handful.
So, actually, I think it's, for practical purposes of this call, actually, it's all that's done. I see there's no patients gonna be enrolled.
Understood. And also on the last one, on the patients who achieve a very durable response, any colors on the biomarkers or you know, PD-L1 status or pathology, any colors on that front?
So, as I said before, right, there's really honestly no difference really between whatever categories, at least, you know, one commonly looks at primary factor, secondary factor, screeners, non-screeners, 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, you know, to some degree, proprietary data for us to guide us. In appropriate time, we will share this with the investor community and with the scientific community, but it is also-...
something that, you know, has a readout also to other programs, frankly, and it's a learning that came with a long period of studying this CF and this biology over the last, what is it now? Five years.
Okay. Right. Thanks very much.
Thank you. Any other questions, operator?
We will now take the next question from the line of Manos Papadakis. Please go ahead.
Yes, hello. Thank you for taking my question. Manos Papadakis from Deutsche Bank. Just wanted to get your thoughts on what do you make of some of the impressive advances recently in IO PD-1 space, specifically in NSCLC, with, for example, PD-1, VEGF combination. Thank you.
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 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 analysis is, that this is great for patients and that, you know, when you are working in drug development oncology, you never 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. PD-L1 VEGF in combination has actually a series of failed trials, either with pembro or with nivo. PD-L1 VEGF as a bispecific construct is something that is emerging. I think there was some data presented here last summer.
I think this is early emerging data, interesting data, thoughtful working data, and we'll see where it lands.
Thanks, Tahi . Judith, do you want to add to that?
Yeah. I mean, of course, you know, this is a space of such an unmet medical need that, you know, it's expected that every company tries to make a difference on patients and add value in a very, you know, pretty sad, for 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 compared to the data set that we just disclosed at ASCO. So we are very confident that with this phase II data, we, we are in a very solid ground to start the phase III and potentially make a difference for patients.
Thanks, Judith. Thanks, Tahi . Okay, let's move on to the next question. Maybe the last one, operator.
Thank you. There are no further questions at this time. I would 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.