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Okay, so we're ready for our next panel. I have here with me today Judith, CBO of GenMap. Thanks so much for joining us. Thank you for having me. Perfect. So maybe we can start with, you know, kind of introductory question. You know, give us the lay of the land. How's GenMAP, you knows, past 12 months, next 6 to 12 months? Obviously, it's a huge year for the pipeline. Yeah, so we are in a great point in our journey with a very nice full development pipeline encompassed with our three major phase three assets, epcoritamab, RINA-S, and pitocetamab. And we are very excited because we just guided in Q2 that three big phase 3s will be disclosed in next quarter. So super excited. Great. So maybe we can, you know, lots to discuss today. Maybe we can start with EPCOR-RITA map. We got, you knows, in the past few months, we got the EPCORE DLBCL4 data. So reduced risk of progression by 60%, death by 56%, versus R-GemOx. So what does this data mean for EPCOR's market opportunity? And is there any read-through to the upcoming, you know, EPCORE DLBCL2 readout? And this is a great question. So as you said, you know, DLBCL4 tested EPCO-LEN versus R-GEMOX in the relapsed refractory second line plus setting. And the study, we disclosed grade PFA 040 or 044. Now, what I would say is talk about the versatility of EBCO in terms of being able to combine with LEN. Now, DLBCL2 is a different hypothesis, a different combination, and a different line. So basically, there is not a read-through, but the fact that all over and over again we saw because the DLBCL4 is based on NHL5 ARM1, so we see how the phase two translates into solid phase three behavior. We expect the same for NHL2 ARM1 falchi with the DLBCL02, but there are separate designs, hypotheses, and they're to be treated independently. Got it. And in terms of market opportunity, how does this fit to EPCOR's potential? Yeah, so the potential, the big potential, is for the first-line opportunity in combination with our job, the study that will be read. we have the approval on the LBCL in phase three plus. So again, everything adds on, but the big commercial opportunity is the LPCL O2. Got it. So let's talk about this first line study that's going to read out in the fourth quarter, as you mentioned. So the primary analysis is conducted for the IPI 3 to 5 population, but you do include about, what, 30% of patients that are IPI-2, and so, you know, what's the benchmark for these different patient populations, and how should we be thinking about this readout? Yeah, so the primary is for the 3 to 5 INS hierarchical testing, so if we pass the boundary for the 3-5, then we will test two to five so 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's a more nuanced because it's not just a hazard ratio but how the subsets will behave or what convenience means to patients in terms of subcutaneous or so it's, 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 two it will be able to offer a tangible benefit for patients and physicians to consider as a good option. Got it. And the primary endpoint is for PFS, and it's unlikely for us to see mature OS at any time soon. So 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. So 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's immature. So PFS is a regulatory well endpoint. From a clinical perspective, it's the totality of the data, and we will see, you know, what the maturity of os but it's not expected to be mature enough to be statistically significant with this short-term follow-up got it just just to give us a sense what's the median os expected for the control arm so for the controller what we know is that the pfs two years pfs is around 65 percent give and take and for always i would say at two years would be like 70 75 percent very helpful um and maybe just a little bit on the you know treatment duration and cycles it seems like the phase three has it employs a shorter like treatment duration for epkinley than what we saw with the phase two. Do you foresee any impact? So thank you for the question. And we were asked this question before. So the phase 2 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 ask to limit to eight cycles. We don't think that this will have any meaningful impact on efficacy because from the phase two data, we know that responses comes early and MRD negativity come early. And it's pretty standard in aggressive diseases that you treat short and hard. So we don't expect any efficacy compromise. Got it. And how important are complete responses and MRT negativities? It's very important because there is a correlation between CR and duration. So 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. Maybe in terms of, you know, have you disclosed whether the planned analysis for this first line, pivotal study, will be interim or is it the final readout? Have you discussed if this analysis is an interim analysis or it's the final? It's interim analysis. Got it. Okay. And 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, so 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 FL2, second line FL. Brad mentioned at Q2 that most of the new sites are community sites and 91% of our key customers are two plus sites, which are this big conglomerate of sites. So we are very happy that EPCO, different than other C20s, it doesn't need hospitalization because it makes it much more easier on patients and the health system. Got it. And you mentioned this second quarter growth was both because of the label and the FL. So would you say that it's been mostly the FL inclusion or it's been more of the, you know... I think that it is 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. So we see that both the LBCL are contributing and we see a cross-pollination. So, you know, 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 pitocentumab. You have the first-line breathe-out in the fourth quarter this year. maybe just you know we've discussed before how you increase the enrollment in the first line study right to improve the probability of success given these studies were already well powered for response rate is this more of an os kind of play and how should we be thinking about the heterogeneity expected for the control arm yeah so the we increase the enrolment to ensure that we have robustness of different subsets pre-specified under study and because enrollment was so ahead of schedule that putting more patient didn't impact timelines on the contrary accelerated the potential to have OS sooner because the curve is like this so if we enroll more we get more events okay so in terms In terms of the control arm, so the primary is dual. The interim will be based on ORR and duration of response. So what is expected for the control is 19% ORR with 12 months median overall survival. This is based on PIMBRO alone, Keynote 048. As you well know, in the phase two proof of concept, pitot-pembro led to 63% ORR, tripling, and 12 mounds, 79% OS, where pembro alone is 51% OS. So it's major difference from the phase two comparing to benchmark and control. Got it. And last year from our conversations on P.O. Centumab, it seemed like for, you know, Project Frontrunner, it seems like just doubling the response rate from Pembroke 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. So the plan is, you know, 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. And in terms of the patient population enrolled in the study, I mean, you included both HPV positive patients and HPV negative. Is there any cap to the HPV-positive patients? And can you remind us of the efficacy we've seen for the PDO-Pembroke combination there? And mechanistically, why would it make sense to include this patient population? So 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. So biologically, there is no reason for PEMBRO-IO to work on HPV positive or negative. So Keynote didn't differentiate HPV-positive or HPV negative, neither extreme. So the study that led to cetuximab approval showed benefit of cetuxima, which is an EGFR, in HPV positive on HPV negative. This is external data. Most importantly, in Pitopembro, eight patients, not 30%, eight patients which is around 20% of 43 were HPV-positive, and the response there was 50%, five zero, which is much more better than 19. So there was no reason for us to exclude those patients that can derive benefit, but we are stratifying to ensure balance. And 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 two data that you showed for this first line opportunity. And it's been a while, right? But the overall survival was still in progress. There were, we didn't have enough data. Are you planning on sharing any of this data before the phase three and how should we be thinking about this? Yeah. So, you know, 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 IEO curve, where after 12 months, for example, for 048, the OS at 12 months is 51%. At three years, it's 25%. At five years, it's 18%, and this is the tail effect. So 12 months, 79%, we are very confident that it will be carried to provide potentially a very sustained overall survival benefit long term because IEO is in both arms, so expect the shape of the curve to be an IEO curve. So this is why, and because the phase three will come imminently, there is no reason, but again, the 79% 12-month overall survival first is best in class, you know, above Fisera, above amivantamab, and it's a very, very good predictor of long-term survival benefit. Got it, and maybe for the first, the second-line opportunity, I mean, you also recently changed the study now. Primary endpoint is overall survival. Can you just, like, remind us, does that mean you're not pursuing accelerated approval and you're just going to pursue a full approval there? And how do you envision PDO's market opportunity in first line versus the second line? Yeah, so you just hit the nail on the head. you know we when we assess the time advantage of filing front runner for second line vis-a-vis OS there was minimal or no time advantage so there was no reason to have two filings one month apart so I 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 cats you know to gain three weeks didn't make any difference and 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 we the data from the phase two of pitopembra could transform the landscape of head and neck treatment got it very helpful maybe just in terms of you know how are we going to see this data and how should we be thinking about the top line readout for you know the first line more importantly but also the second line should we expect you know any patients of population information or is it more gonna be like oh the study is positive primary endpoint and that's that so you know we will operate according to standard in industry which is you know will have the data we will share with because it's material, top line data. We will engage with health authorities and in parallel we will plan for a full disclosure at the medical congress. And this is pretty standard, yeah. Got it, should we be expecting the full disclosure before the overall survival endpoint? We haven't, we haven't guided yet on when overall survival could come because we don't have these projections firm enough to communicate. So as soon as we have these, we'll communicate. So I cannot say because we don't a firm projections. Got it. Maybe just touching upon the locally advanced opportunity. I mean, how do you see that opportunity for PEDO in head and neck and, you know, how does it compare given competitive landscape? In head and the neck? Head and neck, yeah. So we think that PITO will have not only time advantage in being first in line, for the first line, but has the opportunity, will be best in class as well. So based on, again, cross-study comparison, are never very clean, but when we see the data of Pitopembro versus Amipembro or Fiserapembro in terms of efficacy you know overall survival safety convenience we see as a very very attractive value proposition potentially you know for for first-line patients with head and neck got it maybe just touching upon the competitive landscape does the potential approval of amibantumab in later stage had a neck impact your strategy for pedo at all on the contrary I think that so we know that J&J filed and we get priority review but this will be accelerated approval on the second line plus second third line whether you know the phase three for the first line will provide the approval on the first so it's something will straighten the hypothesis of you know EGFR by specifics but they are not in direct competition and we have a very important time advantage vis-a-vis origami five 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 chemopembro. So it's different and we will be like two years ahead. it is massive got it and and maybe just based on your diligence with physicians what percentage of patients get treated with right now in first line with like pembrolone versus pembro and chemo is there any specific patients of population that yeah it's it's a great question so we there is a flat iron real world evidence published around three years ago and this is the after keynote or 48 both arms were approved six years ago that show two to one PEMBRO alone, two PEMBROS versus one Pembro chemo. Of course, this is published years ago based on the U.S. Flatiron data, but 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. And for example, if the patient is CPS above 20, more likely pembro alone than pembro chemo. If the patient frail or elderly, more likely many patients are tobacco consumers or alcohol that have more comorbidity. So for those patients, same thing, more likely they won't get exposed to chemo, although if the patient is young and has a rapid proliferative, we'll take Pembroke chemo. But it's a very individualized patient and physician decision. Got it. Do you feel like the diligence gives similar data or provides similar data in the US versus the EU in this sense? I think, I haven't seen the data for the you, but when we talk with size, they all say the same, it's individualized. And just remember, the chemo in combination with PEMBRO is carbophage fuel. Phage fuel is IV weekly. It's not very friendly on patients. So there is, yeah, it an individualized patient by patient, but as per published data, it's two to one, PEMBRO single agent versus PEMBO chemo. Got it, very helpful. Maybe just moving on to CRC, we're gonna see some data at ESMO, and you presented also some data towards the end of last year. Can you just remind us what's PEDO's opportunity there and how you're thinking about the development strategy given that amivantamab is ahead? Yeah, so we think it's the data that Nemeru showed in the ERTC NCI meeting is very strong with an ORR of 80% in first line, independent validating by an ORF of 62% in the second line, which is unprecedented and doubles everything published and with a very solid biological foundation. PITO was discovered through a library of colorectal organoids shown in every preclinical model to overcome, to be superior than cetuximab. So very strong data. Amivantamab is earlier, but we will present more data that esmo, that position, the pitot combination as potentially best in class. Not just in terms of efficacy, but also safety. Got it. And you just initiated the phase three. Two phase threes. Two phase three's. Can you just remind us which patient populations are you targeting? So for the first line, we are combining with Folfox or Folfiri in the KRAS, K-RAS, B-RAF-WILD, left side patients. And for second line, same thing, you know, K-RAB, BRAF, WILD, both sides in combination with FOLFOX and FOLFIDI. But the comparator will be bevacuzumab plus FOL FOX or FOL FIDI or cetuximab plus for FOLX or Folfidi. Got it. And in terms of, you know, the LGR5 part of PDO, I guess, like, what's the rationale in CRC? I mean, this is where, as you mentioned, the molecule was discovered, right, for this indication. What gets you confident that this is not only, like a cetoxymab-like molecule? Oh, no. I mean... So, if you look at this paper from Edward Battles, it's clear that LGR5 plays a central role. So mechanistically, I mean, two very important things. First, the binding to LGR promotes internalization and degradation of EGFR, and in addition, in the context of treatment with PITO, LGR is overexpressed, and the binding of device specifics on LGR straightens the ADCC and ADCP process. properties. And so beautifully demonstrated on those paper were in organoids. When they treat the organoid, patient-derived organoides from colorectal cancer with PDO, more organoïdes are stopped because, so the LGR, it's related to stem cells-like, so it stops growth and metastasis. So very strong preclinical and biological foundation that LGR is key for the activity of PETO. Now, the problem with LGRis that is the plasticity. So only a few labs can measure it accurately, but it's no question that LGR, and 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 two more cells than normal cells. 100. So it's clear that LGR is the one to drive. Again, the problem with LGR 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, and I don't know on the top of my mind, but I would say it's at least double the commercial opportunities. Okay, that makes sense. Maybe just, you know, with the last few minutes, just switching gears to your folate receptor alpha ADC, RINA-S, I mean, you are going to read out the phase three in the fourth quarter. I guess maybe to start just, we've seen a little bit of data in the phase two, not a lot in terms of follow-up. I mean how should we be thinking? Are we just going to get the phase three also the phase two are we going to see this readout on how much information are we gonna get yeah so what we message is that we will have both arm c which is the phase two with around 100 patients and the phase three in q4 this year so a lot of data sets coming like boom boom boom but again we are very confident on the data that dr lee presented in terms of you know what are duration safety convenience so we we are looking forward and very enthusiastic about the potential of rena in prog and there is the time advantage because because, potentially, RNA-S will become the first, second-generation ADC to show positive data for patients with PROC. DR. Got it. And maybe just touching upon, you know, the study design, I mean, based on our calculations, it seems like the power, like the study is well-powered to detect, like, around 1.5 months in PFS. If we assume control arm around four months, that would put it on par with ELA here. Or in your view, how much better than ELA here would RINA-S need to be? So, you know, so when you design a study or your power, you establish your hazard ratio based on the control. Now, it doesn't mean that the data will behave that way, but 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, statistically and the clinical, the actual data, we expect that the data will be better than Elagera 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 like the fuller receptor high versus low patients, based on the data we have so far, are there any signs of difference in efficacy? So what we showed is that in the 20 patients for ovarian, in the high, the response rate was 5 out of 6 versus 5 out of 10 in the low. But still, 50% is very good with consistent durability across the board. So this is why we don't believe there is a need to enrich or to have a test that pose another burden on patients. So the strategy is in all cameras because the efficacy does support it. Got it. And given that Ella here is approaching blockbusters status, how should we be thinking about RINA-S's commercial opportunity, given we've seen, you know, so much better efficacy in the phase two? So thank you, Eva, for the question. So today, you now, our estimates for RINA is 2 billion peak sale. And the 2 billions include all the Gynon opportunities, P-ROC, SOC, and endometrial. Yeah. So, but we expect to serve a very, so today it's like 27,000 patients in the U.S. with PDOC. But again, and this is the number that we estimate for now. Got it. And based on, you know, the early data you have in endometrial and what we've seen, you know, for other, for the receptor alpha disease and PSOC, like how should we be thinking about indication expansion and, you know, renaissance progression once we get the P-ROC data? Yeah, so I think that the breadth of the clinical development plan is, so we started with P-Roc 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 farther in both indications, ovarian and endometrial, to cover every setting where Rina can help and to position as the ABC of choice. Excellent. Well, this was incredibly helpful. Thanks so much for joining us today. Thank you, Eva. Thank you. Thank you very much. Thank you so much.