Medivir AB (publ) (MVIR) Earnings Call Transcript & Summary

Hello, and welcome to a live update with Medivir, who will present live from ESMO in Barcelona. The presentation will be done by Dr. Chon and Pia Baumann, and it will be followed by a question-and-answer session. Everything will take around 1 hour. And I encourage you, if viewers -- if you have any questions, please enter them in the website, and I will select the most relevant ones. Then I leave the word then to the Medivir team.

Thank you very much, and welcome to this webcast where we need to present and discuss second line treatment in advanced liver cancer and also the new data presented here at ESMO with the potential new treatment combination on the development as fostrox plus lenvatinib. So important notice always here. I'm Pia Baumann, and I'm the CMO at Medivir, and we are presenting live here from ESMO in Barcelona, as Richard said. And I have the pleasure of having here Dr. Chon from Bundang Hospital in Korea with me here. And you can see the agenda here. It includes a short intro from me about fostrox and how this has been designed to really address the specific challenges we have on treating advanced liver cancer. I will then hand over to Dr. Chon, who will talk us through data from the ongoing Phase Ib/IIa study that was presented here today at ESMO and also some slides about what was presented at ESMO GI in June. Dr. Chon is an investigator in this study and a renowned global expert in liver cancer. After this, he will share his experience from the ongoing study with fostrox and LENVIMA and he will also talk about his experience from his clinic about how to treat advanced liver cancer and what can be expected in the second-line setting of liver cancer today. The objective is really to better understand and put fostrox plus lenvatinib data into the context of second line. And finally, I will talk a little bit about the future development plans for fostrox and lenvatinib and you, as Richard said, have a possibility to ask questions. So please submit your questions in writing during the presentation, and our moderator will direct them to myself and to Dr Chon in the Q&A session. So here's some nice pictures. I'm trying to note which for what. Yes. So just a little bit of a level set about liver cancer. Liver cancer is a fast forward type of cancer and currently the third leading cause of cancer in the world. It is fast growing cancer form, where hepatitis was sort of the leading force, the leading etiology before. And now it has sort of moved into a little bit of how we live our life, where we have other etiologies as well as, for example, alcohol and obesity. So's there's an increase expected as you can see on this slide, actually, 120% in the U.S. and 80% in China by 2030 and already now as many as 25% is estimated to have fatty liver disease in the U.S., which is sort of one of the risk factors for having HCC. So there's a high need for effective treatment in this patient population. Very, very nicely since 2020, a new therapy combination has been established in the first line for advanced liver cancer, and there are currently several ongoing studies with this sort of IO combination in first line. Yet, outcome is still poor in the median time before progression is around 6 months in the first-line setting. And there's though no consensus what to treat -- how to treat the patients when they progress on the first-line standard of care. And the reason for that is that there's no prospective clinical trial data in the second-line setting after IO. A clinical trial is recommended. And in case it's not available. the recommendation is to use TKI as monotherapy. That has been either approved in the first-line setting or have data after the prior standard of care, which was served. So lenvatinib is considered as the most effective TKI and is approved again for patients in first line but not in second line. So second lines that are ongoing currently are mainly using some kind of combination with an immune therapy. And that is an immune therapy after an immune therapy. And unfortunately, this has been really disappointing and there were data presented that as for this year was shown. So fostrox plus lenvatinib could therefore become a promising treatment with a unique combination of liver targeting approach together with a complementary and also potentially synergistic possibility. So -- and there's also one other thing about liver cancer and that is it's a little bit different from other cancer types in a couple of important ways. First, patients with liver cancer have a cirrhotic liver in more than 80%. And with the dysfunctional liver, which is really responsible for metabolizing or detoxifying drugs, also the antitumor drugs. It means that if you have a limited liver tissue that can actually do this the size of the liver tumor in the liver is directly affecting the possibility to tolerate the antitumor treatment. So the larger tumor, the less chance of tolerating the anticancer treatment. That's one thing. The other thing is that in liver cancer in contrast from many other cancer types, the tumor growth primarily occurs in the liver. So even if there are metastases outside the liver, it is of critical importance to achieve a selective targeting of tumor cells in the liver while sparing sort of the nontumoral tissue as much as possible. And here comes fostrox . So fostrox is designed to deliver the active compound directly to the liver cancer cells, while sparing the surrounding normal cells. And to achieve this, the approach is to use what actually revolutionized hepatitis treatment once upon the time, which if I put it simply means that you add a tail to an active substance in this case, fostroxacitabine to get an approved drug that you can take oral as a capsule. This program is stable when it travels through the GI tract and gets activated, when it reaches the liver. In the liver, fostrox induces DNA damage, selectively in the tumor cells amidst sparing the normal tissue as we talked about here a few minutes ago. So fostrox is liver targeted and in order to provide best possible efficacy since it's liver targeted. It need to be combined with an effective systemic drug that has the best complementary activity as well outside of liver. So in second line liver cancer that optimal combination partner is lenvatinib, that, in addition also, is the preferred second-line treatment if you don't have a clinical trial after an immune therapy. So the key question that we are looking to find out the answer when we are doing this development on fostrox and lenvatinib are safety and tolerability. Are these 2 drugs safe to combine also during a longer period of time. Secondly, efficacy. Does the combination provide a meaningful clinical benefit. And last, contributional components. Do we have an indication where we are right now that fostrox + plus lenvatinib better than lenvatinib alone. And, hopefully we will know more. I will leave now the word to Dr. Chon, who will present the fostrox plus lenvatinib data that we had here at ESMO and a little bit from ESMO GI as well and also talk about his own experience. And hopefully, this will provide insights into the answer to the specifics. [indiscernible]

Thank you, Pia. Nice to meet you. Today, I will introduce our combination treatment. This study included dose escalation cohort and dose expansion cohort -- dose extension cohort. In dose escalation code, 2 milligram was selected as a recommended dose and in this trial, advanced HCC and inoperable HCC patients were enrolled, and this fostrox and lenvatinib combination therapy was treated as a second line or a third line treatment. And fostrox was given orally daily, once a day and 5 days in 21-days cycle and lenvatinib was also given orally occurring at the standard dose of monotherapy and primary endpoint was safety and secondary endpoint was objective response rate, dose control and time to progression and progression-free survival. This study enrolled advanced HCC patients at 15 sites in South Korea, Spain and U.K. And fostrox and lenvatinib was treated as a second line or a third line study and median follow-up period was 10.5 months. Before showing the data presented here at ESMO, we presented pharmacodynamic data at ESMO GI in June this year. In this data -- in that data showed that paired biopsy showing increased liver damage in proliferative region and increased the hypoxia after treatment. And this DNA damage was selectively observed in -- only in tumor tissue, not in normal tissue. So this indicates that this combination therapy target the HCC Select. And in addition, longitudinal liver enzyme and liver function using RV score was evaluated at ESMO GI and presented. These values did not show deterioration during treatment. This is very important because, as Pia explained, when we treat HCC, liver function preservation is very important. So this kind of data is very important for tolerability of this combination therapy. At ESMO earlier today, we presented updated data from ongoing study. On this slide, you can see the baseline characteristic of patients. Around 70% of patients showed extra hepatic lesions and 20% of patients had prior treatment line was third line and 100% showed progression of disease on prior treatment. And 1% patients showed the primary refractory on prior therapy. This means usually patients who showed progression within 12 weeks, those patients usually show rapid progress after a subsequent treatment. So those patients have very poor prognostic patients, but we included 1% of these patients. When it comes to safety profile, there were no unexpected adverse events. And hematology adverse events were transient and 52 patients experienced grade 3 over all treatment-related adverse events, but it was -- most of them are transient. And there were no patients with febrile neutropenia or low player count with bleeding and no fostrox related deaths were found. And most of adverse events were -- SAE were related to lenvatinib rather than fostrox. When it comes to longitudinal measurement of neutrophil count for patients until cycle 14, they showed absolutely neutrophil count showed cycling pattern with recovery before day 1 in next cycle, and we could not find a grade 3 hematological cyst. We barely find dose toxicity. And when it comes to platelet count, it showed a very similar cyclic pattern and with recovery before day 1 in next cycle. And we also barely find grade 3 intoxicity. So this indicates that this combination of therapy is very safe and tolerable. This slide shows individual patients and their dose reduction and dose hold due to adverse event. And fostrox dose reduction due to adverse events were 29% and 5% of patients showed discontinuation due to adverse event. Lenvatinib dose reduction due to adverse event was 57% and 10% of patients had to discontinue due to adverse events. Lenvatinib dose modification was in line with previous lenvatinib monotherapy in HCC. When it comes to efficacy, with the median follow-up period of 10.5 months, time to progression was 10.9 months and longest-running patients still on treatment more than 2 years and 3 patients -- 3 remaining patients are still on treatment at the time of data cutoff. When it comes to response rate, the overall response rate was 24% and duration of response was -- median duration of response was 7.0 months and more than 75% of patients experienced tumor shrinkage in their target lesions. Patients benefited from treatment regardless of outcomes in previous line of patients who showed the primary refractory [indiscernible] both of them showed very good tumor shrinkage. As Pia mentioned, I included -- I enrolled a lot of patients in this clinical trial and will share my patient case. This patient is a 67-year-old male and this patient's etiology was hep B, hepatitis B virus and HCC with portal vein invasion. His first line of therapy was nivolumab and regorafenib combination therapy as clinical trial setting, but he showed progression of disease after this combination, and he enrolled in this clinical trial as a second line therapy. So he was treated with fostrox and lenvatinib since 2023 January. After offline, fostrox and lenvatinib combination treatment for more than 1 year, we found that the tumor was shrinked a lot. So more than around 40% of tumor shrinkage and we found that. And when it comes to tumor marker, field cut 2, it became -- it was reduced by 1/10. It should -- and if the function was stable without change in our risk score during 1.5 years over treatment and platelet and neutrophil count remained stable over 16 months with showing cyclic pattern with recovery before day 1 index cycle. So finally, I want to compare the efficacy of lenvatinib or fostrox therapeutic efficacy. I will share my data recently published in paper, and you can see that. Actually, this study is a retrospective study, and we enrolled the patients who showed the progression after atezolizumab. So 86 patients were treated with sorafenib as a second line therapy and lenvatinib was treated -- or the patient was treated with lenvatinib as a second line therapy. The initial intention of this study was to compare the efficacy of lenvatinib and sorafenib, but this is not a focus on our presentation. We will focus on the lenvatinib monotheray efficacy in this presentation. Over 90% of patients showed Child-Pugh A good liver function and more than 73% of patients showed extra hepatic disease. And when it comes to response rate, the lenvatinib monotherapy response rate was 7.5%, and disease control rate was 68% and by RECISTv1.1. And progression pre-survival was 3.5 months, and overall survival was 10.3 points. When it comes to safety toxicity, there was no specific toxicity, which was very consistent with previous binding. This is a final slide. There is significant unmet medical need in second-line HCC treatment after immunotherapy -- after first-line immunotherapy because there is no stability to second-line treatment after combination immunotherapy. So as you checked earlier, lenvatinib monotherapy, the efficacy is not satisfactory. Progression-free survival is just 3.5 months and objective response rate is just less than 10%. But in our combination therapy, fostrox and lenvatinib showed promising survival outcomes. Time to progression was 10.8 months and objective response was 24%, [indiscernible]. So I look forward to evaluate and confirm the benefit of this combination in the outcome in randomized Phase IIb study. And if these results can be replicated in the study, both fostrox and lenvatinib has a strong potential to be an effective treatment option for second-line therapy after combination immunotherapy. Thank you. And I hand over to Pia.

Thank you very much, Dr. Chon. [indiscernible] Sorry, there's a part of the presentation left. So I will just go to the next slide. And just before talking about how we see the future development of fostrox in liver cancer, let's go a little bit quick back to the initial question. And also after listening to Dr. Chon's presentation about our data and his own experience to see if we can sort of answer this a little bit better than we did before we started today. So the results from the Phase Ib/IIa study support that the combination is safe and tolerable. And then we have the efficacy results with a median time to progression of 10.9 months. It is actually 10.9 months. I know the slide said 10.8 months and a response of 24%, which is a meaningful clinical benefit. Yes. And particularly in this poor outcome patient population. So the encouraging efficacy results in this study when compared with retrospective data that you showed -- just showed Dr. Chon when you use lenvatinib alone, do indicate that adding fostrox to LENVIMA provides improved clinical benefit over lenvatinib alone. And naturally, this needs to be confirmed in randomized setting, which is really the next step in the development of fostrox, and we have an upcoming Phase IIb study. So -- and this is the study design for that study. It is to evaluate and confirm the benefit of fostrox. And it also reflects the advice we have received from regulatory authorities with the need for an initial dose optimization, followed by randomization and using the selected dose. The primary endpoint here will be efficacy and secondary include safety, but also quality of life, which is really important for these patients. We started to enroll patients in Asia, in the U.S. and in Europe. And at this point in the development, we are aiming for a robust study design that pending result, obviously, will enable a breakthrough designation and increase the possibility for having an accelerated approval. So the preparation for this study is well underway. And currently, study feasibility and protocol are under finalization. So -- and already during our Phase Ib/IIa study, there was a high interest in enrolling patients in the study. And this interest is becoming even stronger now, and we are doing this kind of feasibility where we look at those who are interested and this is obviously coming back to also what you presented Dr. Chon is driven by the lack of effective treatment options, together with the fact that fostrox brings this liver targeted mechanism of action -- another action than what you actually are using with immune therapy. So finally, with the clinical element of fostrox, we hope to contribute to the change of the core trajectory of patients with advanced liver cancer and to be the optimal treatment in second line. That is all right. And fostrox again, saying it again, is really a uniquely targeting the liver and selectively kills the tumor cells, while we're sparing the healthy cells together with lenvatinib in the ongoing Phase Ib/IIa study. And I'm repeating this because this is quite encouraging number, right? We have a promising efficacy with a median time to progression of 10.9. So a requirement for having this kind of data is obviously to be able to stay on the treatment. And the patients could do that in this study. It means that it's tolerable, I would say, and we have shown that we can have patients ongoing for a longer period. So with that, thanks all for your attention and special thanks to you Dr. Chon. But despite your super, super, super busy schedule here at ESMO, has taken time to present our fostrox data and share your experience.

Thank you for having me.

Yes. So now we will open up for questions.

Okay. Thanks for that. I have some questions before we open up with the viewer questions. I'd like to ask Dr. Chon what do you think stands out from this trial thus far, do you think efficacy or safety or some other feature or the most outstanding data that has been presented. And also, is there anything negative?

Actually, the data itself is very compared to other study data or any other results of -- and safety, as Pierre said, it's very important because preserving liver function when we treat HCC is most important. But it's selectively HCC preserving normal lever. So it's very big. But still, we need to a large number of patient samples because it's a small number of early phase clinical trial. So if we confirm the efficacy and safety, we need larger scale of clinical trial. That is most important. Just the result itself is very satisfactory.

Yes, yes. I think that sounds logical. The only thing negative you could say is the somewhat small sample size. But could you expand on why is it important to preserve liver function. What's the problem with other drugs to treat liver cancer?

HCC is very...

Yes. I mean HCC, late-stage HCC.

Liver cancer, HCC is very special cancer. So we usually treat cancer with very toxic drug. But we cannot apply those toxic drug to HCC because it can ruin liver functions. But once actually recently, our team published interest in data patients who showed progression of during atezolizumab and patients who show liver function deterioration during atezolizumab. Who do you think live longer? That answer is, patients who should progression they live longer than patients who showed deterioration of liver function. Because liver function deterioration patients, they don't have subsequent treatment option at all because as their liver is already gone. So we cannot apply any subsequent treatment or other treatment options. So those patients survival outcome is just less than 10 months. But patients who showed progression of disease during atezolizumab, their survival outcome is almost over 1 year. So [ totally ] even though the patients showed the progression of disease. So preserving liver function is more simple. So in 1 side, we have to pursue efficacy. On the other side, we also have to pursue preserving liver function. Without that, we cannot make success in Phase II or Phase III trial.

If I understand it correctly, in other types of cancers, patients usually die of metastases, which could be in the liver or the brain. But in this case, it's the primary tumor that kills the patient in deliveries. Is that correct?

Yes, we talked about this. It's so important to control the tumor of liver, not harming the liver because the -- but it's a little bit different from other tumor types where you can die on metastasis. Here, they die of liver decompensation or...

Most patients die from liver deterioration -- hepatic deterioration. So even though patients have extrahepatic spreading, it doesn't affect when it comes to overall survival. So lesion in liver targeting lesion in liver itself is most important, but we have to also pursue the preservation of liver.

That makes this type of cancer a bit different from any other cancer types. Could you say something about what are the -- what liver function do patients present with in the second line HCC, how deteriorated are they typically?

Usually after first-line setting, we recently published some data. We collected Asian-Pacific data, in the data we collected more than 1,000 patients who treated with atezolizumab, only 0.5% of patients -- 50% of patients had chance of subsequent treatment after progression of our atezolizumab, that means even if their liver function is okay, we can apply subsequent treatment. But if patients with liver function deterioration, we cannot apply subsequent treatment options. In the data, only 50% of patients have subsequent treatment options. That means first-line is very much important. And second line, third line still the efficacy is important, but [indiscernible] in liver function, the patient cannot maintain their...

Yes. I think 1 of you mentioned in the presentation that liver cancer is increasing in incidence. Is that something you noticed in your clinics that you get more patients each year?

Yes. Actually, in Korea, #1 cause of HCC hepatitis B, accounting about 70% of total HCC patients. But nowadays, because our food is westernized and a lot of obesity and metabolism -- metabolic related disease we have. So more and more people -- patients are diagnosed with HCC without viral disease, without Hep B or Hep C so they are related to obesity or metabolic diseases.

Maybe I should have a viewer question here. A few patients needed a lower dose of fostrox? Was this level of dosing still efficacious in these patients?

I can respond to that, actually. So yes, it was. And we have done a dose escalation which means that we are coming up to the maximal tolerated dose. We didn't really reach that dose because we were hoping to see what we actually saw long-term benefit that it could be on the treatment for a longer period of time. But also those who actually dose reduced since it's quite individual, what you can tolerate in some cases, depending on what kind of previous treatments you have received as well, they benefited for a long ago period of time.

Another viewer question. Well, I guess this is also for you, Pia, what is the number of patients for the next Phase IIb study? Or could you expand a bit, I guess, on the design?

Yes. So the design is a first part where we are trying to have actually as few patients as possible in order to select a dose. We will have 2 dose levels of fostrox, the same dose for lenvatinib, and then we will do a randomization against lenvatinib alone. And the reason for this is twofold. I just mentioned 1, actually, and that is that there's a project ongoing in the U.S. FDA has project optimus where you also need to look at the minimal effective dose coming back to the question that we had before. So we will look at -- but for us, we have already done the escalation, right? So for us, it's more like a safety dose question. The other reason is that we are developing a commercial formulation and then you need to have 2 doses. So this first part is really trying to select the dose. And when we have done that, then we are going to expand and have a little bit larger number of patients. We have shown a number of patients before and it's pretty much in line with what we have shown before, but I can't go into exact details in how many patients we will have. But you can maybe extrapolate a little bit since we are going to Asia, we are going to the U.S. and we are on to Europe. So it needs to be a substantial number of patients.

Okay. The next few questions is about the second-line treatment. I could formulate it a bit like what are the options? And this is for, I guess, both of you, what options are there in the second line? And also what other interesting options? Are there in development in the second line that compete with -- that could compete with fostrox+lenvatinib?

In second line, we can use lenvatinib or fostrox or other TKI options. But it's not established through a Phase III clinical trial. It's just empirical prescription because it was first-line setting or second-line we used a lot. So we are very much experienced these kinds of drug. And many people think we apply a combination immunotherapy. So we changed the class. So many doctors treat their patients this kind of TKI monotherapy. And as I told just response rate of lenvatinib as a first line setting is around -- more than around 20%, but because in this clinical trial setting, atezolizumab was first line, lenvatinib anti-VEGF, anti-angiogenic agents. They are already exposed to those kinds of agent. So usually, lenvatinib monotherapy is a second line setting, they're response rate is just 5% to 10%, very low. But this combination therapy showed promising response rate, even though the number of sample size was not that high. And on other competing potential second line clinical trial is maintaining immune checkpoint inhibitor like this, atezolizumab -- and after patients who showed the progression, maintaining atezolizumab with lenvatinib that kind of lenvatinib monotherapy, those kind of Phase III clinical trials are ongoing. So we will see the data sooner or later.

Yes. I think also, if we talk about sort of what kind of other treatments that uses another mechanism of action, an immune combination in the first-line setting, it is established. I mean it will continue, right? So in other tumor types, it has not been successful to continue with another immune therapy. Here, we see that, as you said, you continue with a new therapy and you try to resensitize the patients by using another combination. So let's see if this is going to be a successful approach, but the criticism is, as you also said, is that if you don't use another mechanism of action, those who are not having a good response on your first treatment are unlikely to respond on your next treatment as well. So other combination -- do you have any other sort of clinical trials that is using another mechanism of action in the second line setting.

Really this is more promising study [indiscernible] for continuing immunotherapy with TKI. But as Pia said, just changing the class is very important because patients show the progression of disease with the first line setting. So they usually don't respond well to the same strategy. So even though in this clinical trial, we enroll second line and third line and patients who showed refractory to prior therapy, but in my patient case, they showed dramatic response to lenvatinib and fostrox combination therapy, patients who didn't show response to atezolizumab prior therapy. So I think the test is very high as long as we can replicate this efficacy in random Phase II trial.

Yes. I mean it's a good thing that you actually brought that up because I'm not sure that you saw that. We looked at the patients who were primary refractory on the prior treatment. And when we looked at overall response in our study, and they responded also to fostrox and lenvatinib. And...

In other studies, they usually exclude to those kinds of patients because they are prior prognostication population. So in second-line setting, they usually the prior clinical trial I mentioned, that study also exclude patients who showed progression within full cycle of atezolizumab, automatically excluded. So -- but what I was surprised with this combination of therapy was patients who showed prior refractoriness to atezolizumab showed very good response on our trials.

Would you say that Medivir has been -- how do you say has recruited a more difficult population than other companies to considering the, like you said, the recruited primary refractory patients and also some third-line patients instead of like, for example, recruiting only second line and nonprimary refractory patients?

But that reflects real practice very well because we cannot exclude those kind of patients. We still have to treat those patients, which showed refractory to prior therapy. So it's more reflectable to our real practice.

Thinking about -- when you hear these numbers, you mentioned in the new second line that's developing after bevacizumab with the combination. Those numbers seem quite similar to the previous second line, which was after sorafenib or lenvatinib, that is -- the previous second line was drugs such as regorafinib, cabozantanib occasionally ramucirumab. Would you say -- is that your impression as well that the second line is -- hasn't improved much?

So I think that the question is that you have other options in the second-line setting as well. And some of them have only data after sorafenib. But still, they show about -- he is asking, do you think that they show about the same response rate, the same poor response rate and outcome compared to lenvatinib. No, that hasn't happened much in the second-line setting that what you use in the second line setting is that comparable to what you've shown with lenvatinib.

True, we have several data on retrospective study setting, but it's retrospective study setting. So we cannot say that it's robust data and sample size is small. But -- it's similar to regorafenib and cabozantanib. We can apply those kind of TKI in second line. But as I mentioned, after exposure to the bevacizumab as our first line therapy, that is another anti-VEGF agent and second line, usually monotherapy TKI or of the TKI anti-VEGF agents. Their efficacy can be naturally reduced as a second line after atezolizumab. So we need more just better than monotherapy to increase -- enhance the efficacy, in that sense, I think fostrox is good partner with regorafenib.

And how important do you think the treatment. So -- the order of the treatment is that you have, first checkpoint inhibitor with VEGF inhibitor since especially considering that checkpoint inhibitors usually change the tumor microenvironment, could that have an impact on using a drug such as fostrox in the second line after that?

Yes, that can affect, yes that's right. Theoretically, it's correct. But it's theoretical idea, but after [ ICI ] after anti-VEGF, they can change it to microenvironment. But first principle, I think if patients for immune checkpoint inhibitor, I think it's better for patients to have holiday for immune checkpoint inhibitor. And then we can move to like a TKI or TKI combination with other options rather than combination with immunotherapy. And then patients showed the progression. We can retry, immune checkpoint inhibitory. But just immunotherapy immunotherapy, immunotherapy, it's not good sequential way [indiscernible] but there is no robust data for now. We have to find out.

I have some new viewer questions. What do you think about going into the first line with fostrox + Lenvima?

Actually, it's tough because all the investigators and experts think combination immunotherapy is the standard of care already. So it's difficult to change. But maybe in random Phase II trial in larger scale patients you showed higher -- good efficacy -- promising efficacy, we can try as a first line therapy because lenvatinib monotherapy is the first line therapy showed comparable efficacy with pembrolizumab and lenvatinib combo. So maybe fostrox and lenvatinib combination therapy showed promising efficacy even though that is in the second line, but we can try next time as a first line therapy.

There's a little bit of a change potentially also, if you look at an earlier stage, if you use your immune therapy combination already when you are in intermediate stage.

Yes, yes. We're going upward. Nowadays, we apply that [indiscernible]. So -- it can be tough, but it's still possible. So who knows if this second line combination therapy show good efficacy. We can do that. We can try. But if we persuade other investigators [indiscernible] data.

Yes. I wanted to go back to safety profile. How important do you think -- or how important is the quality of life? And how does fostrox perform there?

Actually, I still treat 2 patients, just -- it was 3 patients, just in 1 month total 1 patient showed the progress first. But most of the 3 patients maintain their treatment more than 1.5 years and 2 patients are ongoing. They don't have any specific issue with this combination. And there is no liver function deterioration. There was no delay of treatment, those kind of things, just sometimes proteinuria they have because of lenvatinib. So in that case, I skip the lenvatinib temporarily. And the patient showed no proteinuria, I just maintain lenvatinib. But in terms of fostrox, it's a [indiscernible].

Sorry Richard, but Dr. Chon has taken his time, as I said, and I really mean it, so he needs to go back to the Congress now. So if there's no more real burning question for him...

Nothing on the web.

Okay. So thank you very much, everyone, and thank you to you, Dr. Chon. This was excellent, and thank you for answering all the questions, and also sharing your experiences, it's invaluable, right? We can sit and talk about sort of our development program, but if we can't put it into the context of actually hearing how you treat your patients, it's not worth that much. And I will leave it back to Richard.

Yes. Thank you very much, Dr. Chon and Pia. And well, that's all for today. Thanks for listening in.