Welcome, everyone, to this webcast that is hosted by Medivir, and we are going to talk about the evolving treatment landscape and the unique treatment challenges in hepatocellular carcinoma, liver cancer, or HCC. We are here in Amsterdam, and the ILCA, the International Liver Cancer Association meeting, is ongoing, and that's why we have the pleasure of having Dr. Jeff Evans here, expert in liver cancer from Glasgow, and also PI in the Fostrox study that I will talk a little bit more about in a minute. We also have Dr. Maria Reig. She is the head of the cancer clinic in Barcelona, and also a PI in the Fostrox study. I am Pia Baumann, and I'm the CMO for Medivir. So what are we going to do here? The agenda is that I will talk briefly about the Fostrox clinical development program, and then we will hear from Dr. Evans about HCC and the current and evolving treatment landscape. Maria Reig will follow, talk about the current state of the art in second-line advanced HCC, and also why it is important to control the tumor burden, particularly in HCC. Then we will hear from both Dr. Evans and Dr. Reig about their experience from the clinical trial that is ongoing with Fostrox and Lenvima. Also Dr. Evans will present early phase 1b data in the combination Fostrox and Lenvima. Then we will have a Q&A, and in order for you to have your questions submitted, you will see, like, an empty little box under the presentation that you can use to submit your questions. So, why are we doing what we are doing with Fostrox? The background is really that we still have a huge unmet need in HCC, despite that we have now new approvals of anti-PD-1 and PD-L1 and TKIs. And both Dr. Reig and Dr. Evans will talk a little bit more about that. But what about chemotherapy? Traditional intravenous chemotherapy is not used in HCC, and the reason behind that is that the doses required is so insufficient to have enough liver exposure to actually see any clinical benefit, and it is an unacceptable tolerability issue. The HCC patients have specific issues, that they are sensitive to toxicity, primarily in the liver, due to the fact that the tumor is in the liver, and also they have this underlying disease, the majority of the patients with the cirrhosis. We also see a general detoxifying mechanism in liver cancer cells, where the deaminases cause inactivation of many chemotherapies locally. So how is Fostrox addressing that? And that is really a combination of proven mechanism. The Fostrox is a prodrug. It has a prodrug tail, and this makes it possible to have an oral administration and use the first-pass metabolism. And with that, we can achieve more than 100-fold higher targeted exposure than what you see with traditional intravenous chemotherapy. The active substance in Fostrox is troxacitabine. It's a nucleoside analog, and it's cytotoxic, and it has a high cell-killing activity of the tumor cells and sparing the normal cells. The last is that with this cytotoxic drug, the structure is an unnatural L-nucleoside, which means that the deaminase doesn't really see the structure, and it's not deactivated. So these are really the mechanism. And since we talked briefly, it's liver-directed, right? And fostrox need to be combined with a more systemic therapy. And what we have been looking at in the clinical trial program is the synergistic mechanism of action that you can use with the DNA, inhibiting DNA replication, together with an anti-PD-1 or a multi-kinase inhibitor. So and if you look at the, y eah, you will come back to that a little bit more in detail, I think. So it's literally with the anti-PD-1, you see when you inhibit DNA replication, that you get an increased tumor antigen presentation and potentially also higher PD-L1 expression, which activates the immune response. And when you use a TKI, you are blocking the blood supply to the tumor, which induces the enzyme, the PGK-1, that is used to activate Fostrox in the liver, so you get a higher efficacy of Fostrox. It's two mechanisms, but we will come back to that in a minute. So last here, I will just talk about the program. We are with Fostrox right now in phase 1b and 2a that we finally enrolled just recently. The decision has been made to continue with Fostrox plus lenvatinib combination in second line due to the fact that we have the treatment algorithm that you will talk more about in a second. And we have chosen 30 mg for the combination with lenvatinib. We also have the Fostrox plus pembrolizumab combination, where we have a safe dose, and for that, we are again looking at how it looks like in the standard of care. So aligned with that, we are exploring it, this as an opportunity in first line instead. So now I will leave this little clicker to Dr. Evans, who will continue talking about the current and evolving treatment landscape. Thank you, Pia, and welcome, everyone. So advanced hepatocellular carcinoma, I think it's always appropriate to put a bit of background to this, in that this is a very prevalent problem worldwide. It remains a major cause of cancer-related death and one of the most prevalent cancers that we see right across the world. And no longer is it predominantly an Asia-Pacific disease, but increasing incidence in other parts of the world, driven by different and varied etiologies of the underlying chronic liver disease. The majority are diagnosed with advanced disease, with a short overall survival. Cirrhosis, which is a major driver of development of HCC, is also challenging when we come to treat the tumor, because we have to be mindful not only of the anatomy of the tumor, but also this underlying synthetic liver function, as well as the overall performance status and comorbidities of the patients. Although we've had significant and enormous advances in the treatment options of advanced disease in the last few years, I think we would all agree that overall objective responses and survival remain disappointing for where we want to be, and we clearly urgently need new novel therapies, either alone or in combination with our existing treatment options. This shows a little bit of a timeline in that sorafenib was the first systemic therapy approved for advanced HCC way back in 2007. Then it was almost a decade before we had approvals of regorafenib and nivolumab, again, in treatment-refractory disease or second-line post-sorafenib. Then followed by lenvatinib and pembrolizumab, and then subsequently, a number of other TKIs, including cabozantinib, ramucirumab, and then the generation of the immunotherapy combinations, as the original monotherapy studies in frontline compared to sorafenib showed a trend which did not meet statistical significance. These are now combination therapies that have got either positive phase III trial data or are approved in various territories across the world. Now, this is the staging algorithm developed by Maria and her team over many decades, and this is the updated iteration. And we can see here that there are patients who are recommended for potentially curative approaches, but also those with inoperable disease, which is the vast majority, and certainly for those with intermediate-stage disease, where there may be intrahepatic disease without involvement of the vasculature and without, e.g., disease outside of the liver. This can be a broad heterogeneous group, which can potentially be treated curatively, may be treated with local regional therapy approaches, but also may be most appropriately treated with systemic anticancer therapy. And trying to improve the response rates within the tumor bulk is something Maria will come back to, and clearly is a strength of a liver-activated prodrug like Fostrox. So these are the NCCN guidelines, which are applicable in the North America territory, but and there are similar guidelines in other parts of the world, which are fairly consistent. And we have IO combinations in the first line and TKIs in the second line as potential therapy options. So we also need to discuss synergy, because I've mentioned that in terms of immunotherapy, we see some activity with checkpoint inhibitors monotherapy and also with tyrosine kinase inhibitors as monotherapy. But can we improve on those in combination, either by improving overall response rate and overall survival, as well as usually patient's quality of life in addition? And we can do this by either blocking growth factor signaling, blocking the negative immune checkpoints, that is, by avoiding immune exclusion or immune desert. Of course, if we induce DNA damage, which is one of the hallmarks of classical cytotoxic chemotherapy drugs like the Fostrox molecule when it's activated, then this can both lead to cell death, leading to increased tumor antigen or neoantigen expression, as well as potentially influence the immune microenvironment in combination with either TKIs or immunotherapies or both. Now, we are become accustomed as oncologists to develop systemic therapies in advanced unresectable disease. But having demonstrated efficacy there, we can also begin to think about using these treatments earlier on. Historically, we've been accustomed from moving from my left to right, from patients who are suitable for surgery, then they relapse, suitable for local regional therapy, they may relapse or not be eligible at all, and become suitable then for systemic therapy. But we can also begin to think about, can we use systemic therapy in combination with local regional, and in fact, those treated with curative intent with surgery, either together in combination and maybe displacing some of those treatments in future years as well. So we have great opportunities now of trying to interrogate more the different scenarios in this disease, not just those with unresectable advanced disease, to potentially exploit our increasing options or systemic therapies. And just as an exemplar of that, this is the IMbrave050 study. This is patients treated either with resection or ablation for high-risk patients with curative intent. This is systemic therapy postoperatively to reduce the risk of recurrence and delay recurrence and improve overall survival in the adjuvant setting, which we're familiar with as a concept in oncology from other tumor types, including breast, colorectal, and so on. And here we are demonstrating for the first time that systemic therapy can influence the risk of recurrence following resection or ablation, and we look excitingly for the mature data to become available in long-term follow-up. Now, we've mentioned the intermediate group previously, and some of these may be suitable for transarterial chemoembolization, which is a well-recognized therapeutic strategy in this disease. But there is always a debate in our multidisciplinary tumor boards between patients who should get TACE, who should get systemic therapy, and having made a commitment to TACE as a first round of treatment, how many times do we need to keep going, and at what time point that is either futile in terms of ongoing response, as the response decreases with each round of TACE. But also, we can increasingly cause damage to the underlying non-malignant, but still abnormal cirrhotic liver with each round of TACE. And this is some evidence from Japan, which is a real-world analysis from Up-to-7 criteria. So these are patients with bulky intrahepatic disease, and intermediate disease, and thought to be beyond control with TACE. Here we have an analysis comparing systemic therapy with lenvatinib versus treatment with TACE, showing very encouraging and superior response rates of progression-free and overall survival with systemic therapy, with a TKI, lenvatinib, in this context, compared with TACE in this patient population. In summary, we have a fast evolution of treatments in advanced disease over the last five years, since 2017, 2018, both primarily with immune checkpoint inhibitors, tyrosine kinase inhibitors, either alone or in combination. Chemotherapy hasn't been explored so much since the traditional intravenous chemotherapy, notwithstanding TACE, but intravenous chemotherapy resulted in a less than favorable benefit-risk balance. But now, with the liver-directed chemotherapy, we have the option of mitigating some of the toxicities noted with intravenous systemic chemotherapy, as well as giving an enhanced delivery of potential cytotoxic agents to the liver tumor, of giving combinations with standard of care, current and new treatments, particularly those with bulky disease within the liver, combining with systemic therapy to control the non-liver disease as well. And therefore, there are emerging changes in the treatment algorithms, looking with systemic therapy beyond advanced unresectable disease to these earlier disease settings, where a liver-activated prodrug would be a particularly attractive option for future evaluation. And with that, I hand over to Maria. Perfect. Thank you. Thank you very much. Very good introduction for my topic. First of all, good morning or good afternoon, everybody. Now we are talking about the current state of the art in second-line treatment for advanced ATC. To be brief, this is the situation that we have. For first line, we have evidence base in term of overall survival. For following lines, we have expert opinion, and that's why is an unmet need, the treatment of second line and following lines. The other thing that we have is, as he presented before, the adjuvant therapy. We have results, phase III, in term of recurrence free survival, encouraging data, but we do not have using in general standard of care until having the results. Then we have other scenario that we will not talk about that, but it could impact the result of the trials that we are ongoing in the future in this population, that is liver transplantation patients using for downstage or also for conversion. But again, I will focus now on second-line treatment because it's an unmet need in our clinical practice. In general, we can say that we have in the monotherapy until 2018, when appeared, Atezo-bev, and now we're in the era of combination. And this combination is also applicable for the clinical trial that we are waiting to have the results. This slide is a very busy slide. It's just to show you why I'm saying that it's an unmet need. All the clinical trials in first line had a control arm of sorafenib. It's not anymore the standard of care. The positive trial that we have in clinical practice use sorafenib as a control arm, so the main problem that we have is we have several options in the term of immunotherapy combination with TKIs, but we do not have data to support the use of this combination in second line based on the clinical trial results. But we need to focus on the topic. Just to summarize, first-line treatment, Atezo-bev. Here we have the overall survival of the standard extend overall survival, around 19 months for the combination arm. We also have tremelimumab, also outdated data presented by Bruno Sangro, in this case, 16 months. Keep in mind that these two trials are not comparison, direct comparison between each other because the population is advanced, but there are some differences in the inclusion and exclusion criteria. But the key point here is unpredictable overall survival in the past, and this population need to have a second-line treatment. So now we are really focused on second line, and this scheme try to summarize the clinical issues that we have. We have first-line treatment and at one point, the patient need to go to a second-line treatment. So the key question is: What is the alternative? What is the evidence to support that? As I mentioned before, we do not have this data. We usually stop treatment for severe adverse events, symptomatic progression, or patient decision. However, if we have an alternative treatment, we can stop the treatment at the time of treatment failure. That means at the time of patient develop progression or intolerance. but we also could stop the treatment when the patient achieves substantial response, and that's why I introduce the idea of liver transplantation and downstaging. However, all of these questions are open. We do not have the answer at this day, and that's why we encourage the patients to consider the clinical trials because we do not have evidence base to support that. So if we go in-depth, we have certainties and uncertainties at the time of deciding following lines. We usually use the BCLC upon progression at the time of shifting from first line to the following lines, and also we could consider the patient profile. When I talk about the pattern of progression, means what is the characteristic of this progression at the time of developing that point? It is with symptoms, without symptoms, liver function, and I will talk about that in the following part of the session. The key point here is, what is the best option after first-line treatment? Several systemic line treatment, combination of local regional treatment, plus systemic therapy or other combination, and this is why we are working on this area. So to link this problem with the clinical practice, I would like also to share with you that as a clinician, we usually consider the first treatment, but also the evolutionary event. What that mean? As I mentioned before, the patient could achieve substantial response and go down to the previous treatment, or the patient develop untreated progression. This is the most frequent scenario to have at this day. Again, we could consider treatment migration if the patient evolve to, upon progression, we move to the clinical trial, but in some specific cases, we could consider early treatment at this, moment. In summary, here we have the evidence that we have. We have regorafenib, cabozantinib, and ramucirumab after sorafenib treatment. Phase III trials approved based on overall survival. But we do not have any treatment for patients who were treated with Atezo-bev, Durval-trem or patients who were treated with lenvatinib or durvalumab in the first-line treatment. That's why the clinical trials are the best, option in this case for a patient. However, some of these patients are not candidate for the second-line trial, or they are not second-line trial for them. In this case, we also consider, according to the last version of the BCLC staging system, alternative sequences, but it's not the topic for today. That's why I introduce the complexity of the second-line treatment and introduce also other topics that we usually consider at the time of treated patient, but also at the time of designing the trials. That's why when we design the trials, it's essential to characterize very well the population and also the evolutionary event to understand the impact of the potential results. This slide is just to summarize another important point. Some years ago, when we have only two first-line treatment, the patients started the first-line treatment at very advanced stage. Now today, we have several options, and as you can see here, the patients receive different lines after the first progression. This is a study published from Pinato's group, and here I would like to highlight the first-line treatment, second-line treatment, and beyond the second-line treatment. As you can see here, 42% of patients were under condition to receive a second-line treatment. This is completely different as we have several years ago, when the majority of these patients didn't have the chance to receive a second-line treatment due to symptomatic progression or decompensation. As you can see here, also, around 13% of patients is also in condition to receive a following line. That means this is a population that we don't have the treatment, and we need to have something for them. However, when they focus on the post-progression survival, they also show that those patients who didn't receive treatment have worse overall survival, as we expected. However, in this case, we need to discriminate and have more granularity if these patients were not treated because they didn't have an option to be treated or because they have a liver dysfunction, and this is key for the clinical trial design. If you have a patient with decompensation, the outcome is worse, but sometimes we don't need to enter this patient into a treatment that don't have a impact in their overall survival. But this is the second part of my presentation. So if we focus on post-progression survival, we work on the pattern of post-progression survival. It is not the same to develop a new lesion outside the liver as you develop new lesion inside the liver, or only growth the tumor that you have. In all of this scenario, we need to have a very good liver function to continue, but it's also important to characterize the pattern of progression to analyze the post-progression survival. This slide is to summarize the clinical activity that we have at this stage after first-line treatment. So in brief, several options that the patient need to have because the survival is better than we have in the past era. And with that, I would like to convince you that this is a target population that we really, as a clinician, consider an unmet need because we do not have the data to support the treatment beyond an expert opinion. The other important thing, I'm a hepatologist, is the consideration of the liver function beyond the tumor burden based on the CT scan on MRI. In the next 2 slides, I try to summarize this problem into cartoon. This is a graphic that I did with other colleagues, and it is already published in Hepatology, and I tried to summarize. I don't know, it's not working? No, it doesn't. If you start from the treatment outcome of patient could be three different scenarios. The green one are those patients who are under control with the first-line treatment. The control means a stable disease, partial response, or complete response. In this case, the complication of patients are more related to other comorbidities than to the tumor burden or the liver function. We have a second group that is the most difficult group, those patients who develop extrahepatic spread and also decompensation of the liver function. The patients usually death due to cancer-related event. However, if we identify this patient as soon as possible, we could consider this patient for clinical trials. But up to now, we are not have any predictor for this characterization. And then we have the third group, the yellow one. That is the most tricky group because in this case, the patients are under good condition, good liver function, however, develop new lesions inside the liver, and then they evolve in two different way. They could be under control and could convert to the green group, or they move to the red group. In this case, it's essential to manage the liver function because the option to receive a second or third-line treatment is more related to the liver function and the performance status of patient than to the tumor burden. If you have a patient with good liver function, good performance status, we have several options to consider in that. But if you have several options, but you do not have patients, we will not have the chance to treat them for control the disease. So the cartoon try to summarize the three scenarios in a simple way that we could fit in our clinical practice. And the other thing, it is the complexity of interpretation of the result. If the liver dysfunction related to the tumor burden is related to the function of the patients, and this cartoon tried to summarize this scenario. If you go to the top of the slide, the patient have better outcome, alive. If you go to the down, the probability of death is higher, and here we start with a patient with preserved liver function and receive the first-line treatment. The evolution could be the patients evolve to develop progression with different degree of liver dysfunction. At the bottom, you have a patient with severe liver dysfunction, without option for liver transplantation, and the probability of death is very high, regardless of the tumor control. In the top of the slide, we have a patient who develop progression inside the liver. However, if the patient, as you can see here, evolve to liver dysfunction, this patient is not candidate for any treatment, and we would not have option to treat them with nothing. So the main aim for the physician is control the tumor burden and also the liver function, and this is key. That's why it's also important to control the tumor burden, to have preserved liver function in the patients. And this is why I prepared this slide, to summarize that if you have progression in the liver but good liver function, you could be unfit to continue this career. If not, you have high risk of death due to symptomatic tumor progression. So in summary, we have three different scenarios, and we call that time to failure the treatment strategy. Here we have three patient who started the same treatment. The reason of death is completely different. You could have a patient who develop progression, however, good liver function, good performance status, and could continue under treatment. If you have another patient who developed toxicity, regardless of the tumor progression, the patient is not candidate for this treatment, and we need to move to another one. And maybe you have an indolent patient who have never achieved any complication, progression, or toxicity, and they could continue under treatment without the need of stopping that, but the patient die for other reason. Indeed, we need to focus on those, on these two factors: liver function, tumor burden. If we control tumor burden, we have more chance to have a liver, a liver-compensated patient, and this is why I tried to summarize the importance of identify as soon as possible the potential liver decompensation in this population. With that, I believe that I'm finished and move on again to Jeff to continue with the presentation. Thanks. Thank you, Maria. So the clinical experience we've had so far, I had the pleasure of being an investigator in the original monotherapy study of Fostrox and now in combination with lenvatinib. So the combination was chosen for second line, and the dose has been secured of Fostrox with pembrolizumab as well, and this shows the algorithm by which we've done these clinical trials. So initially, it's monotherapy to determine the monotherapy dose, and then in combination with lenvatinib, which is the regimen that we now propose to pursue. And this study is now fully recruited. The primary endpoint, of course, at this early development was safety and tolerability, but with secondary endpoints, including objective responses. I'll come back to how we measure and define objective responses shortly. But also disease control rate, progression-free survival, and the dose of 30 mg has been selected to facilitate a prolonged duration of treatment schedules with optimal benefits, and reducing risk to the patients. We're accustomed in oncology when we determine the doses of novel agents or novel combinations to look at acute toxicity when we define dose-limiting toxicity for starting dose. But we also have to bear in mind that some agents may have a more protracted toxicity profile rather than acute toxicity, and therefore, we have to look at long-term disease control schedules, as well as the acute toxicity when we decide upon the dose, as we have done here, to land on 30 mg. Now, the patients who are included have all progressed on prior treatments. That was one of the eligibility criteria to enter into the study. This shows the patient characteristics of the first 6 patients. Median age is fairly typical for HCC studies, as is the gender distribution, which is a predominantly male disease at the moment. 50% were good performance status 0, 50% performance status 1, so still relatively fit patients. Again, the majority of patients have a background of either treated or active viral hepatitis. Extrahepatic disease was present in approximately 50% of cases, and 2/3 of the patients were from Asia, with 1/3 from Europe. 83% had prior treatment with a combination of atezolizumab-bevacizumab, and half of the patients had prior TACE as well, and all had progressed on prior treatment. Of these patients, half had started on 20 mg, and half started on 30 mg of Fostrox administered orally, daily for five days, repeated every three weeks, with standard doses of lenvatinib based on body weight and continuous administration schedule. So we did see transient neutropenia, but transient neutropenia without neutropenic fever. So the patients who develop complications of neutropenia are either neutropenic sepsis or neutropenic fever, but note we don't see that. We see uncomplicated Grade 3 neutropenia. And we didn't see any effect on the platelet count or thrombocytopenia, and this is all Grade 3 toxicity, using standard toxicity grading that we use always in oncology clinical trials. We did see some fatigue, hypotension, related to the lenvatinib, and of course, the protocol included dose modification interruptions based on hypotension, how to manage that, again, standard of care with lenvatinib. And about half the patients with lenvatinib required a dose reduction. Again, that's not unusual for what we see in other lenvatinib studies. And approximately under a fifth of patients, 17%, required a dose modification of Fostrox, usually for uncomplicated hematological toxicity. Now, this is independent radiologist review. What do we mean when we talk about responses in cancer medicine? Well, it's a radiological assessment where we measure the longest diameters and look for either a reduction by 30%, that would be a response, or an increase by 20% would be progression, with everything in the middle being stable disease. And here we see a modified swimmer plot showing the duration of the patients have been on, and we show that we have stable disease in five out of six patients, and these are patients with a combination of lenvatinib and also with Fostrox. Now, that's the RECIST 1.1 criteria, which, like all the RECIST criteria, is based on tumor dimensions and the longest tumor diameter. But liver cancer is very complex and also has sometimes benefit, which is measured not so much on the dimension reduction, but also reduction of blood flow, vascularity, appearances of viable tumor on the scan. And for that reason, the HCC field has developed modified RECIST criteria, which takes account of those subtleties seen in HCC radiology. Here we have the independent review of modified RECIST, with 3 out of 6 patients responding and 1 complete response by mRECIST. That is, taking account of the vascularity and viable tumor, as well as a reduction in the tumor dimension. Encouraging response from a small cohort of patients. Therefore, we come to the question and answer session. Thank you very much. A fabulous presentation, and we also have another person here in the room, the ghost person, who is actually going to forward the question that we have received from you as an audience. So, and you will ask directly to either Dr. Reig or Dr. Evans. Okay, so I will start with a question that's actually maybe directed to both of you. Given the advent of Avastin in first-line HCC, most patients still progress to second-line disease. Does it make sense to explore a triple combination with Fostrox in the first-line setting, in your opinion? There's a lot we do and don't know about why patients do respond or don't respond or have stable disease with immunotherapy combinations, either tremelimumab or, as said, A tezo-bev. There's intense focus at the moment to try and understand who will potentially benefit from immunotherapy and what the mechanisms of escape from immunotherapy control. Nevertheless, if we do see that we have a group of patients who where we could potentially give triple therapy with a liver-activated prodrug in addition to Atezo. Atezo-bev, then we have the option of getting better intrahepatic disease control, as, as well as that we would achieve with the immunotherapy combination. Furthermore, it may well be that by increasing DNA damage, because this is a chemotherapy drug, after all, has a cytotoxic effect on cell kill, that that can release neoantigens, which in addition may have synergistic effect, we would hypothesize, when given in combination with an immunotherapy combination backbone. Therefore, I think the not just with the addition of the extra option for disease control, but also a potential synergy with, with, we may speculate and hypothesize, with immunotherapy that might overcome some of those either innate resistance or acquired resistance to immunotherapy by influencing the tumor microenvironment with cell kill of the tumor. Note that when we, and I borrow examples here from other tumor types that I've treated in the past, when we add additional therapies, we sometimes get additional toxicities. But here we're taking a non-cytotoxic backbone of Atezo-bev and adding something which will give you intrahepatic, directed exposure to chemotherapy, minimizing peripheral exposure to chemotherapy, and therefore overcoming the challenge we've had in the past of adding more and more agents, which can sometimes add more toxicity and compromising efficacy and treatment intensity. But we do not anticipate that would be the case with a triple combination. I would like to add that I believe that it's essential to put on the table what kind of line that we are talking about. If we are talking about- Yes First-line treatment, according to the data that he present, is encouraging in term of safety, if you combine with pembro or if you are combined with lenva. So if we think about first-line treatment, I'm, I believe that it's important to keep into consideration safety and not only adding. Maybe the strategy that we could apply is not adding several options at the same time, it's the add-on based on the biology of the tumor, and it is more than adding. It is the background that we need to think about for sure, a new combination could be interesting. For the second-line combination with the treatment that already receiving first line, maybe need to think, a second thinking about what is the strategy. But again, I would like to highlight the clinical trial design beyond adding different mechanism function to keep more effective result in this setting. Thank you. And I actually think that we skipped one part of the agenda that we promised to talk a little bit about, and that was your experience from the Fostrox clinical trial. So maybe we can just, we will continue with the Q&A in a couple of minutes, but if I'm just asking you, what is your experience with the patients that are ongoing in the clinical trial when it comes to safety, duration of treatment, patient experience? If you could just- Yes A little bit about that. Obviously, it is very preliminary data- Yeah T o say the experience for our specific center. I will talk about as the meeting that we usually have. Yeah. The treatment is very well tolerated. The result in terms of response is encouraging, and we have a specific patient that developed, for example, pruritus or developed a neutropenia that was transient neutropenia. So I believe that with this data, I feel comforted to continue recruiting patient. That is the best thing that you have as a clinical researcher. Yeah. Thank you very much. And I would also add, I assume that the prior question was going with three-drug combination in the first-line setting, rather than a progression of Atezo bev adding in another drug, because I think trying to overcome immune resistance has been a challenge that I think has confounded a lot of approaches once you've acquired immunotherapy. So I think we want to clarify that I assume what we were talking about in the prior question was a triplet in the first-line setting, rather than attempting to reverse acquired resistance to immunotherapy, which I don't think we should pursue. Yeah. Thank you. One minute. So, the same question that I asked Dr. Reig, did you, a ny sort of comment on your experience with the Fostrox development program and the study that is ongoing? It's been a straightforward study in terms of managing the patients and managing any emerging toxicity, because clearly, these are patients with liver cancer and invariably underlying chronic liver disease. It's an oral administration. Patients can take it at home. I've had one patient who did stop the lenvatinib ultimately for recurrent hypertension. She had preexisting hypertension, which was managed before we went to the trial, but has continued with Fostrox now for over a year, and has had a dose modification, and continues with a RECIST 1.1 objective response with good quality of life after that duration of exposure. Thank you. Thank you. We have a question which I think relates to the sequencing of treatments, and that is: might some previous treatment, like a checkpoint inhibitor, change the microenvironment of the tumor and influence the choice of second-line treatment? Yes, for sure. Depends of the treatment that the patient receive, at this day, we need to play what we have. That's not mean that is the best that we can offer for patients. So that, at for this point, I would like to differentiate it, clinical practice, that clinical trials. If we're talking about only clinical trials, for sure, we try to find or prioritize those clinical trial that have encouraging data in term of safety, response, but also mechanism of action to avoid the potential resistance between the, the treatment. Clinical practice is a different story because we can offer the patients the treatment that are reimbursed in the different countries, and, and this case, the priority is based on the treatment that you have to character as a patient in term of comorbidities and potential adverse events. For example, if you have a patient that have arterial hypertension, diabetes, you try to avoid those who increase arterial hypertension. But as Jeff mentioned before, for example, lenvatinib, we know that it's associated to arterial hypertension. So if the patient is under control, it is not a contraindication. It's very complex, the decision in clinical decision-making. Mm-hmm. I believe that, Jeff, you can also add your thought about that, but for clinical trials, it's easy to characterize because you can design and follow according to the best knowledge that you have at this time. Yeah, I very much agree, and I would add that, as the questioner, person who submitted the question has intimated, in an ideal world, we'd know more about the biology of the tumor after they progress on first-line treatment, whatever they've received, tremelimumab, ipilimumab, TKIs, and learn more about the mechanisms of escape from control of, or systemic treatment failure, and how we might tailor that approach based on the biology of the tumor. I don't think we're there yet. And we all are aware that there are challenges about repeated liver biopsies, circulating tumor DNA. What is the most appropriate measure? Is that something that's a research-only tool, or will it be applicable anytime soon, in routine standard healthcare settings? So I think there's enormous challenges to try and tailor outside of a clinical trial, treatment based on the emerging biology, such as we understand it at present, and therefore, there are pragmatic decision-making in assigning second-line trial, but those efforts are, are ongoing. And I see it very much as a companion to when we are a bit interrogating things in clinical trials, that we learn more about the disease as we learn more about the drugs we're using. We learn more about the emerging disease. Indeed, if I make a comment. Sure. Nowadays, we are working in morphological medicine- Yeah Because we are based on the CT scan, and we know, and it's validated that depending on the pattern of progression, the outcome is different. Yeah. Now, the trials engage to perform biopsies, and we will have the biology of the tumor and all the BCLC also biopsy the surrounding to understand the change in the microenvironment- Yes and also link with potential other factors such as microbiome and other things, and we are evolving for more precision medicine, that morphological, that I believe it is the current situation that we have. I have a question about the prognosis for second-line advanced HCC patients. How unusual are complete responses in this patient subpopulation? How usually? How unusual- Or usual. Or usual are- Complete responses. In, uh- We have. It is more than an anecdote. If I talk about two decades ago, it's completely unexpected. Now, that's why I'm saying that we are moving on to more precise medicine than morphological medicine, because complete response, according to RECIST, it disappear the tumor. It happened with TKIs. We also know it's happened with immunotherapy, more percentage than. We also observe in this trial that some patient achieve complete response, but it's not feasible to say who will be the patient, and this is what the clinician needs to know. Yeah. Having said that, I'm more in favor to control disease. A stable disease, we will not change the clinical decision-making. At the early phases of the clinical trials, we usually want to have the complete response, but a stable disease is even more important. Right. Because if you have a stable disease, you continue in treatment, the patient continue on, the chance to achieve complete response or not. And if you have a patient who control the disease, is that the goal. So I agree that complete response is what everybody wants, but I encourage to give more attention in a stable disease. That is the most important part of the population. And I agree, and we've already discussed the importance of biopsies and learning more about the biology of the disease each time we change treatment. But as well as focusing on a precision medicine approach on the biology of the disease of predictive and pharmacodynamic biomarkers, imaging, and blood- or tumor-based, we're also having a more precise approach to pharmacology and the design of novel therapies rather than what's available out there in the community. We're now using drugs in clinical trials in cancer that are tailored towards good scientific rationale. And in this case, for example, with Fostrox, we're getting intratumoral, intrahepatic activation of a cytotoxic agent that overcomes some of the systemic toxicities associated with that class of drugs, while aiming to reduce the tumor bulk intratumorally and in combination with systemic therapy for overall disease control. There's also an ongoing discussion as to whether different classes of drugs are more suitable for viral or non-viral HCC etiologies. How do you see the profile of Fostrox in relation to that discussion? If I start? Mm-hmm. The first question that I propose to the audience and to all the clinician is, why do we need to focus on that, and what is the rationale for that? It's completely different if you're talking about animal models, that you're talking about patients. What that means, not viral. It is a huge number of patients with different profile, that is alcohol, it is NAFLD, it's a combination of that, and there are not robust data to support that. So I, I believe that it's more important in the setting of clinical trials to characterize the profile of patients instead of focus on that. And the other question is: How do you characterize a patient who was cured for hepatitis C and now have obesity and also they hypertension and a little steatosis in the liver? If you're involved in clinical trial design, I allow you to characterize all of these things instead of focus on that. Personally speaking, I believe that at least in clinical practice, clinical trial design, they are not rational to stratify about a factor that is very heterogeneous, because the non-viral group in this trial will be completely different as the other, and it is not possible to control. But you can properly control if the patient is diabetic, if the patient have hypertension and different factors, and then you can analyze based on all of these factors to be objective at the time of deciding. But I know that I'm very critical. I don't know, what do you think, Jeff? No, no, I agree. I'm not sure how we can summarize the first two days of the ILCA conference for you in answer to the question, but I think also with this specific compound, we do have mechanisms by which the drug is activated within the liver and preferentially within the liver tumors. I don't think we've got any evidence from your laboratory studies to suggest that that's any difference, whether the underlying etiology, however we define it, is viral, non-viral, or other etiologies. We have a cytotoxic agent, which is designed to kill cancer cells, and what is different about Fostrox is that it does so preferentially within the liver tumor rather than the periphery, overcoming some of the toxicities that's compromised dose and administration previously, by therefore giving more of the cytotoxic molecule to the liver tumor. I have a question about the tumor burden in the liver in advanced metastatic hepatocellular carcinoma. How much of the tumor burden is actually located in the liver, usually, in second line? I mean, even if there's extrahepatic disease, let's not underestimate the importance of the liver tumor burden, as- Yeah Maria has already presented. And, I think it becomes into the question here, because we have a drug infrastructure, which we believe has effect intrahepatically. But that doesn't stop us using it in combination with lenvatinib or with IO in patients with extrahepatic disease, because there is clearly an important bulk. And we're increasingly seeing patients who might not have been through screening programs, who present with really bulky disease, as de novo disease, and then still have very bulky disease when they progress. Yes, they may have small, asymptomatic, extrahepatic disease, small lesions on the lung that you see on CT scan, but the burden of what's driving their morbidity and their eventual survival is based on what's going on in the liver rather than what's going on on the outside. In addition, if you change a bit the question, it's anecdotal to have a patient who have extrahepatic spread without TACE in the liver. Mm. Almost all patients have intrahepatic lesion plus extrahepatic spread. We demonstrate that the outcome is defined by the extrahepatic spread, but if you do not control the liver, the liver enter into decompensation. So it's a mix, and this is something that it is important to know. To be, simple, almost all patients have intrahepatic lesion, and the probability to have, only local extrahepatic spread or only portal vein invasion, I assume that is less than 10% of patients. So the majority of patients could benefit with these type of schemes, I think. I have a question about combinations and recent failures. Are there any hypothesis with respect to the recent failures of checkpoint plus oral TKI combinations, specifically pembrolizumab, nivolumab, or atezo plus cabozantinib? Is there a difference between VEGF agents and TKIs, or are there other reasons? I'm more in favor to critical review the trials instead of say that the combination is failure. Because as I present in one of the slide, we have different mechanism function, regardless of if they're in the same group of- in the same family of drug. We usually talk about immunotherapy plus TKIs or immunotherapy plus antibodies, anti-vascular endothelial growth factor, but this combination in a different trial design was positive, and the best example is Pembro. In the Asia community, the trial is positive, outside is negative. So I prefer thinking about the characterization of trials, how the trial was designed, what was the population that was included, and what were the assumptions that they used? Because for the LEAP-002. Mm T he key thing is the control arm. Mm. The expectation for the control arm was completely different as they, and they observed. So in this case, it's really the combination, or it is the assumption that is not meet the criteria that was. So it is very complex to answer in two sentences, but my advice is characterize- T rial by trial before consider the combination is not working. No, I absolutely agree, and it's—I'd be very cautious about labeling a trial based on the headline news of the press release from the outcome and saying, "Oh, this was a treatment failure." That it may not have met its primary endpoint, but we only, as we mentioned right at the very start, if you look back at some of the immunotherapy monotherapy checkpoint inhibitor studies that were done compared to standard of care, be it sorafenib or in second or subsequent lines with versus best supportive care. They didn't meet their primary endpoint, but there was certainly a hypothesis there to be tested that came out of those trials. So rather than label these as a treatment failures, I think they, if they're labeled as, "What did we learn from this study? Why didn't it meet its primary endpoint? And how we do our future studies differently to make sure that we do not underestimate the true value of combinations? Thank you. I think we are running out of time a little bit. So, I just want to thank you so much. It has been an honor to have you here. Excellent presentation, and I hope that you who are listening, actually got your questions that you wanted to ask responded. Otherwise, there's hopefully a way of communicate, in the future as well with us. So thank you for listening. Thank you for all the good questions, and as you could hear from this, we are super excited about the development of Fostrox and what we have seen this early with the safety and the, preliminary efficacy data. And, we are so much looking forward to, in the future, being able at another event to present a little bit more details and also somewhat more mature data. Thank you again for listening, and have a nice weekend!