Okay, so we are ready for our next panel. I have here with me today, Judith Klimovsky, CDO of Genmab. Thanks so much for joining us. Thank you for having me. Perfect. Maybe we can start with kind of introductory question. Give us the lay of the land, how is Genmab, past 12 months, next six to 12 months? Obviously, it is a huge year for the pipeline. Yeah. We are in a great point in our journey, and with a very nice full development pipeline in compass with our three major phase III asset, epcoritamab, Rina-S, and petosemtamab. We are very excited because we just guided in Q2 that three big phase IIIs will be disclosed in next quarter. Super excited. Great. Maybe we can, lots to discuss today, maybe we can start with epcoritamab. In the past few months, we got the EPCORE DLBCL-4 data, so reduced risk of progression by 60%, death by 56% versus R-GemOx. What does this data mean for EPCO's market opportunity, and is there any read-through to the upcoming EPCORE DLBCL-2 readout? This is a great question. As you said, DLBCL-4 tested epcoritamab plus lenalidomide versus R-GemOx in the relapsed refractory second-line plus setting. The study we disclose grade PFS 0.40 or 0.44. What I would say is talk about the versatility of EPCO in terms of being able to combine with lenalidomide. DLBCL-2 is a different hypothesis, a different combination, and a different line. Basically, there is not a read-through, but the fact that all over and over again, we saw. Because the DLBCL-4 is based on NHL-5, arm one, so we see how the phase II translates into solid phase III behavior. We expect the same for NHL-2 arm two FALC with the DLBCL-02. There are separate designs, hypotheses, and that to be treated independently. Got it. In terms of market opportunity, how does this fit to EPCO's potential? Yeah. The big potential is for the first-line opportunity in combination with R-CHOP, the study that will be read. We have the approval on DLBCL in phase III+. Again, everything adds on, but the big commercial opportunity is DLBCL-02. Got it. Let's talk about this first-line study that is going to read out in the fourth quarter. Yeah. As you mentioned, the primary analysis is conducted for the IPI three - five population, but you do include about, what, 30% of patients that are IPI 2. What is the benchmark for these different patient populations, and how should we be thinking about this readout? Yeah. The primary is for the three - five and is hierarchical testing. If we pass the boundary for the three - five, then we will test two - five. The study has statistical assumptions, so to be positive, it has to cross the boundary for efficacy as the statistical assumptions. Now, if you ask me what is the hazard ratio to be an option chosen by physicians or patients, this is a different story, and it is a more nuanced, because it is not just a hazard ratio, but how the subset will behave or what convenience means to patients in terms of subcutaneous. I cannot establish a threshold, but what I would say that if the study is positive and based on what we know from the phase II, it will be able to offer a tangible benefit for patients and physicians to consider as a good option. Got it. The primary endpoint, it is for PFS, and it is unlikely for us to see mature OS at any time soon. I guess, is PFS alone sufficient to drive meaningful adoption in the first line? Or from your diligence, does it feel like physicians want to see survival benefit? Yeah. From a regulatory perspective, PFS is an endpoint validated for first-line DLBCL. We know from POLARIX, we know from frontMIND as well, that were approved based on PFS with POLARIX five years, OS is still 0.89, or for frontMIND is 0.85, but it is immature. So PFS is a regulatory well endpoint. From a clinical perspective, it is the totality of the data, and we will see what is the maturity of OS. But it is not expected to be mature enough to be statistically significant with this short-term follow-up. Got it. Just to give us a sense, what is the median OS expected for the control arm? For the control arm, what we know is that the PFS, two years PFS, is around 65%, give or take. Got it. For OS, I would say at two years would be like 70%, 75%. Very helpful. Maybe just a little bit on the treatment duration and cycles. It seems like the phase III employs a shorter treatment duration for EPKINLY than what we saw with the phase II. Do you foresee any impact? Thank you for the question, and we were asked this question before. The phase II has 12 cycles of EPCO. When we discussed the design with the health authorities in order to mimic the duration on both arms, we were asked to limit to eight cycles. We do not think that this will have any meaningful impact on efficacy because from the phase II data, we know that responses come early, and MRD negativity come early. It is pretty standard in aggressive diseases that you treat short and hard. We do not expect any efficacy compromise. Got it. How important are complete responses and MRD negativity? It's very important because there is a correlation between CR and duration. Patients who are in CR are more likely to have sustained and non-progress than patients that are on PR. Although PR is still relevant, CR has a better correlation with duration. Got it. Very helpful. Have you disclosed whether the planned analysis for this first-line pivotal study will be interim, or is it the final readout? Can you repeat that? Have you discussed if this analysis is an interim analysis or it is the final readout? It is interim analysis. Got it. Okay. Maybe just following the March label update, eliminating the 25-hour mandatory hospitalization in the third line, what impact have you seen in the community uptake, and do you expect this impact to continue? Yeah. We have seen an acceleration on the uptake on the community sites given by the removal of the hospitalization as well as the approval of the FL-2, second-line FL. Brad mentioned at Q2 that most of the new sites are community sites, and 91% of our key customers are two + sites, which are this big conglomerate of sites. We are very happy that EPCO, different than other CD20s, it does not need hospitalization because it makes much more easier on patients and the health system. Got it. You mentioned this second quarter growth was both because- Yeah of the label- Yeah and the FL- Correct right? Correct. Would you say that it's been mostly the FL inclusion, or it's been more of the update label? I think that it's very hard to quantify. It's a combination of everything, and even it's very hard on these later stages to dissect the particular indication. We see that both the LBCL are contributing, and we see a cross-pollination. New sites that start prescribing on FL, then they go to LBCL and the other way around. This is a very important strategic value of having the double indication. Got it. Very helpful. Maybe just moving on to petosemtamab. We have the first-line readout in the fourth quarter this year. We've discussed before how you increased the enrollment in the first line study to improve the probability of success. Given the studies were already well-powered for response rate, is this more of an OS kind of play? How should we be thinking about the heterogeneity expected for the control arm? Yeah. We increased the enrollment to ensure that we have a robustness of different subsets pre-specified in the study. Because enrollment was so ahead of schedule, putting more patients didn't impact timelines. On the contrary, accelerated the potential to have OS sooner because the curve is like this. If we enroll more, we get more events. Okay? Got it. In terms of the control arm, the primary is dual. The interim will be based on ORR and duration of response. What is expected for the control is 19% ORR, with 12 months median overall survival. This is based on pembrolizumab alone, KEYNOTE-048. As you well know, in the phase II proof of concept, pito-pembro led to 63% ORR tripling. 12 months, 79% OS, where pembrolizumab alone is 51% OS. It is a major difference from the phase II comparing to benchmark and control. Got it. Last year from our conversations on petosemtamab, for Project Frontrunner, it seemed like just doubling the response rate from pembrolizumab was enough. Is that still your understanding with regulators for Project Frontrunner, or are there any changes in the way you view the requirements there? Yeah. The plan is, we will have the results next quarter. We will disclose, we will engage with the health authorities, and we will align on the strategy for filing and submission, including Frontrunner. Got it. In terms of the patient population, enrolled in the study, you included both HPV-positive patients and HPV negative. Is there any cap to the HPV-positive patients? Can you remind us of the efficacy we have seen for the pito-pembro combination there? Mechanistically, why would it make sense to include this patient population? We didn't cap. What we do is we stratify for HPV to ensure that we have balance between the two arms, and the reason is more than one. Biologically, there is no reason for pembro IO to work on HPV positive or negative. KEYNOTE didn't differentiate HPV positive or HPV negative, neither extreme. The study that led to cetuximab approval showed benefit of cetuximab, which is an EGFR, in HPV positive, on HPV negative. This is external data. Most importantly, in pito-pembro, eight patients, which is around 20% of 43, were HPV positive, and the response there was 50%, 5 0, which is much more better than 19. There was no reason for us to exclude those patients that can derive benefit, but we are stratifying to ensure balance. Given the sample size, 700 patients, we expect the percentage of HPV positive to align with the epidemiology of the disease, which is around 20%, 25%. Got it. Very helpful. Maybe just touching upon the phase II data that you showed for this first-line opportunity. It's been a while, right? The overall survival was still in progress. We didn't have enough data. Are you planning on sharing any of this data before the phase III, and how should we be thinking about this? Yeah. For that study, we will share more translational data at ESMO. But the reason we think that 12 months is a very good indicator is because of the IO curve, where after 12 months, for example, for O48, the OS at 12 months is 51%. At three years, it's 25%. At five years, it's 18%. This is the tail effect. 12 months, 79%, we are very confident that it will be carried to provide potentially a very sustained overall survival benefit long-term because IO is in both arms. So expect the shape of the curve to be an IO curve. This is why, and because the phase III will come imminently. There is no reason that, again, the 79% at 12 months overall survival first is best in class, above ficerafusp alfa, above amivantamab, and it's a very, very good predictor of long-term survival benefit. Got it. Maybe for the second-line opportunity. You also recently changed the study. Now primary endpoint is overall survival. Can you just remind us, does that mean you are not pursuing accelerated approval and you are just going to pursue a full approval there? How do you envision Pito's market opportunity in first line versus the second line? Yeah. You just hit the nail on the head. When we assessed the time advantage of filing Frontrunner for second line vis-à-vis OS, there was minimal or no time advantage. So there was no reason to have two filings one month apart. So we decided to allocate all the alpha to OS and have a study that can support full approval in a global manner rather than do two cuts. To gain three weeks did not make any difference. Of course, the huge unmet medical need and the larger opportunity is the first line. The second line commercially is a much less opportunity. Still, we could benefit patients, and the data is strong. But the data from the phase II of petosemtamab pembrolizumab could transform the landscape of head and neck treatment. Got it. Very helpful. Maybe just in terms of how are we going to see this data, how should we be thinking about the top-line readout for the first line, more importantly, but also the second line. Should we expect any patient subpopulation information, or is it more going to be like, "Oh, the study is positive primary endpoint," and that is that? So, we will operate according to standards in industry, which is we will have the data, we will share because it is material, top-line data. We will engage with health authorities, and in parallel, we will plan for a full disclosure at the medical congress. This is pretty standard, yeah. Got it. Should we be expecting the full disclosure before the overall survival endpoint? We haven't guided yet on when overall survival could come because we don't have these projections firm enough to communicate. As soon as we have these, we will communicate. I cannot say because we don't have a firm projection. Got it. Maybe just touching upon the locally advanced opportunity, how do you see that opportunity for Pito in head and neck, and how does it compare given competitive landscape? In head and neck? Head and neck, yeah. We think that Pito will have not only time advantage in being first in line for the first line, but has the opportunity. It will be best in class as well. Based on, again, cross-study comparison are never very clean. But when we see the data of pito-pembro versus ami-pembro or ficerafusp-pembro in terms of efficacy, overall survival, safety, convenience, we see as a very, very attractive value proposition potentially, for first-line patients with head and neck. Got it. And maybe just touching upon the competitive landscape, does the potential approval of amivantamab in later-stage head and neck impact your strategy for Pito at all? On the contrary, we know that J&J filed and will get priority review, but this will be accelerated approval on the second line plus second, third line. Right. Whether the phase III for the first line will provide the approval on the first line. It's something will strengthen the hypothesis of EGFR bispecifics, but they are not in direct competition. We have a very important time advantage vis-a-vis OrigAMI-5, which could potentially will lead to the approval of ami in first line. In addition, it's a separate strategy. We chose to go with a chemo-free because of the depth of response and the superiority of this combination vis-a-vis chemo or chemo pembro. It's different, and we will be two years ahead, which is massive. Got it. Maybe just based on your diligence with physicians, what percentage of patients get treated right now in first line with pembro alone versus pembro and chemo? Is there any specific- Yeah. patient subpopulation that benefits? Yeah. It's a great question. There is a Flatiron real-world evidence published around three years ago, and this is after KEYNOTE-048. Both arms were approved six years ago. That showed 2:1 pembro alone, two pembro versus one pembro chemo. Of course, this is published three years ago based on the U.S. Flatiron data. When we talk to sites or investigators, it's very individualized based on CPS, frailty, or comorbidities of the patients, tumor size, or speed of tumor growth. For example, if the patient is CPS above 20, more likely pembro alone than pembro chemo. If the patient is frail or elderly, more likely many patients are tobacco consumers or alcohol that have more comorbidities. For those patients, same thing, more likely they won't get exposed to chemo, although if the patient is young and has rapidly proliferative, we'll take pembro chemo. But it's a very individualized patient and physician decision. Got it. Do you feel like the due diligence gives similar data or provides similar data in the U.S. versus the EU in this sense? I haven't seen the data for the EU, but when we talk with sites, they all say the same. It's individualized. Just remember, the chemo in combination with pembro is carboplatin 5-FU. 5-FU is IV weekly. It's not very friendly on patients. So there is a- Yeah, it's an individualized patient by patient. But as per published data, it's 2: 1 pembro single agent versus pembro chemo. Got it. Very helpful. Maybe just moving on to CRC, we're going to see some data at ESMO, and you presented also some data towards the end of last year. Can you just remind us what's Pito's opportunity there, and how you're thinking about the development strategy given that amivantamab is ahead? Yeah. We think it's the data that Meadow showed in the EORTC NCI meeting is very strong, with an ORR of 80% in first-line, independent validating by an ORR of 62% in the second line, which is unprecedented and doubles everything published. And with a very solid biological foundation. I mean, Pito was discovered through a library of colorectal organoids and shown in every preclinical model to overcome, to be superior than cetuximab. Very strong data. Amivantamab is earlier, but we will present more data at ESMO that position the Pito combination as potentially best in class, not just in terms of efficacy, but also safety. Got it. You just initiated the phase III- Two phase IIIs. Two phase IIIs. Can you just remind us which patient populations are you targeting? Yeah. For the first line, we are combining with FOLFOX or FOLFIRI in the KRAS, BRAF wild left side patients. For second-line, same thing, KRAS, BRAF wild both sides in combination with FOLFOX and FOLFIRI. But the comparator will be bevacizumab plus FOLFOX or FOLFIRI, or cetuximab plus FOLFOX or FOLFIRI. Got it. In terms of the LGR5 part of Pito, I guess, what's the rationale on CRC? I mean, this is where, as you mentioned, the molecule was discovered for this indication. What gets you confident that this is not only like a cetuximab-like molecule? Oh, no. I mean, if you look at this paper from Eduard Batlle, it's clear that LGR5 plays a central role. Mechanistically, two very important things. First, the binding to LGR5 promotes internalization and degradation of EGFR. In addition, in the context of treatment with Pito, LGR5 is overexpressed, and the binding of the bispecifics on LGR5 strengthens the ADCC and ADCP properties. It's so beautifully demonstrated on those paper where in organoids, when they treat the organoids, patient-derived organoids from colorectal cancer with Pito, more organoids are stopped because of the LGR5 by. It's related to stem cells-like, so it stop growth and metastasis. So very strong preclinical and biological foundation that LGR5 is key for the activity of Pito. Now, the problem with LGR5 is the plasticity. Only few labs can measure it accurately, but it's no question that LGR5. Pito was discovered among 500 other bispecifics that were tested, same organoids panel of colorectal cancer versus normal cells, and Pito was the winner, killing 100 more times tumor cells than normal cells, 100. So it's clear that LGR5 is the one to drive. Again, the problem with LGR5 is that not every lab can measure because of the plasticity of the cells. Got it. Maybe just last question on CRC. How are you thinking about the commercial opportunity relative to head and neck? It's much more bigger. So in terms of population, I don't know on the top of my head, but I would say it's at least double the commercial opportunity than head and neck. Got it. Okay. That makes sense. Maybe just with the last few minutes, just switching gears to your folic receptor alpha ADC, Rina-S. You are going to read out the phase III in the fourth quarter. I guess maybe to start, we've seen a little bit of data in the phase II, not a lot in terms of follow-up. I mean, how should we be thinking? Are we just going to get the phase III? Also, the phase II, are we going to see this read and how much information are we going to get? Yeah. So what we message is that we will have both arm C, which is the phase II with around 100 patients, and the phase III in Q4 this year. A lot of data sets coming like boom, boom. But again, we are very confident on the data that Dr. Li presented in terms of ORR, duration, safety, convenience. So we are looking forward and very enthusiastic about the potential of Rina in PROC. And it's the time advantage because potentially Rina-S will become the first second generation ADC to show positive data for patients with PROC. Yeah. Got it. And maybe just touching upon the study design. Based on our calculations, it seems like the study is well-powered to detect around 1.5 months mPFS if we assume control arm around four months. That would put it on par with ELAHERE. However, in your view, how much better than ELAHERE would Rina-S need to be? When you design a study or your power, you establish your hazard ratio based on the control. It doesn't mean that the data will behave that way. Right. You need to power to be statistically positive. We know, based on the data from Dr. Lee, by 12 months, a single patient progress that we expect to be much more better than the minimal assumptions. But again, the statistically, and the clinical, the actual data, we expect that the data will be better than ELAHERE in terms of PFS, duration of response, differentiation on safety with no ocular toxicity, or the burden on patients to have this visual test, and potentially the double indication in the future for endometrial and non-selective for folate receptor. So we expect to be really differentiated and superior. Got it. And in terms of the folate receptor, high versus low patients, based on the data we have so far, are there any signs of difference in efficacy? What we showed is that in the 20 patients for ovarian, in the high, the response rate was five out of 6, versus 5 out of 10 in the low. But still, 50% is very good with consistent durability across the board. This is why we don't believe there is a need to enrich or to have a test that pose another burden on patients. The strategy is in all comers because the efficacy does support it. Got it. Given that ELAHERE is approaching blockbuster status, how should we be thinking about Rina-S' commercial opportunity, given we've seen so much better efficacy in the phase II? Thank you, Eva, for the question. Today, our estimate for Rina-S is DKK 2 billion peak sale. The DKK 2 billion includes all the gyn-onc opportunities, PROC, PSOC, and endometrial. We expect to serve a very. Today it's like 27,000 patients in the U.S. with PROC. Again, this is the number that we estimate for now. Got it. Based on the early data you have in endometrial and what we've seen for other folate receptor ADCs in PSOC, how should we be thinking about indication expansion and Rina-S' progression? Yes once we get the PROC data? Yeah. So I think that the breadth of the clinical development plan is. We started with PROC and endometrial O3, which is after PD-1 and chemo failure. We expanded to PSOC in second line maintenance and replacement, and we plan to expand even further in both indications, ovarian and endometrial, to cover every setting where Rina-S can help and to position as the ADC of choice. Excellent. Well, this was incredibly helpful. Thanks so much for joining us today. Thank you, Eva. Thank you. Thank you.