Pharma Mar, S.A. (PHM) Earnings Call Transcript & Summary

Hello, and welcome to the Small Cell Lung Cancer: Today, until Tomorrow, US & Europe Call. My name is Katie, and I'll be coordinating your call today. [Operator Instructions] I will now hand the call over to your host, Ali Zeaiter, Director of Clinical Development of PharmaMar, to begin. Ali, please go ahead.

Thanks, Katie. Good morning, good afternoon, everyone. Welcome to our key opinion leader webinar called Small Cell Lung Cancer: Today, until Tomorrow, US & EU. Before we start, I just want to inform you that this webinar is being recorded. I am Ali Zeaiter, Director of Data Development at PharmaMar. Small cell lung cancer has been a very difficult cancer to treat, with few advances since the '90s until immuno-oncology drugs got approved in first-line in 2019 and our lurbinectedin for second-line in 2020. With these new moving parts, the landscape is changing. And without -- now it's a good time to look at where we are and where we are going. So we have with us today 2 experts in the field to guide us. First, Dr. Benjamin Besse will start, who is the Head of the Cancer Medicine Department at Institut Gustave Roussy in Paris and is the Chair of the EORTC Lung Cancer. He's also the PI of the LAGOON Phase III study in second-line small cell lung cancer, which aims to serve as the confirmative trial in the U.S. and other regions and also as registrational study, where lurbinectedin has not been yet registered, including for EMA. Following Dr. Besse, Dr. Jacob Sands, who is an instructor in Medicine at Harvard Medical School and a thoracic medical oncologist at Dana Farber Cancer Institute, will follow. He's also a national spokesperson for the American Lung Association. Also with us today, my colleagues, Jose Luis Moreno, Director of Capital Markets; and Pascal Besman, Chief Operating Officer, PharmaMar U.S. Before we get started, I will remind you that lurbinectedin is approved in the U.S. for adult patients with metastatic small cell lung cancer with disease progression on or after platinum-based chemotherapy. None of the information presented today should be interpreted to mean that PharmaMar guarantees an upcoming confirmatory approval in the U.S. or an approval in EU or elsewhere. Now I would like to turn you over to Dr. Benjamin Besse, who will give us an overview of his experience with lurbinectedin in the Expanded Access Program in France or ATU and discuss the LAGOON study in their last setting of small cell lung cancer. Dr. Besse, to you.

Thank you very much. So the goal is really to briefly cover the landscape of small cell lung cancer and give you an example of 2 patients I have treated with lurbinectedin and to explain to you why it's a very active and convenient drug. So I'm a medical oncologist. I work at Gustave Roussy. It's the larger cancer center in Europe. And we had done early trials of lurbinectedin, so we have quite an experience with the drug. Small cell lung cancer is around 40% of the lung cancer. It's a very aggressive cancer. It's often called the leukemia of cancer because it's so aggressive. Typically, you have a heavy smoker that is the effective fit in January, and in March, he will be highly symptomatic with weight loss and because the disease is so aggressive. Also, it's prevalent in males and it's really prevalent in heavy smokers. The 2-year lung cancer survival is very, very poor. It's lower than 15% in male, around 15% in female, but it's a very, very poor prognostic cancer, very aggressive. So etoposide and platinum salts, cis-platinum or carboplatin, has been standard of care for years, for years. I mean my mentors treated small cell lung cancer with etoposide and platinum salt. This is an example of the extreme chemo sensitivity of the cancer. You can see on the left side of the slide, a very bulky small cell lung cancer. It's the usual presentation, bulky lesions, very proximal, with a lot of mediastinal nodes. And you can see the red arrow that shows the cancer, and you can see that after only 2 cycles, so 6 weeks of chemo, I mean, you have almost a complete response. I mean really what we see, 85% of the patients show a partial response after platinum-based chemotherapy, so it's highly sensitive. The main issue is that it works for a few months and then it relapses. An example of the disease, you can see before on the left side, after 3 cycles of chemo on -- in the middle and then after 6 cycles of chemo. This is a refractory disease that has relapsed during chemotherapy. So it's so aggressive that you need very strong chemo. In the last years, we had a new standard of care in first-line that is the combination of etoposide and platinum salt. This is an example of a study with carboplatin and immunotherapy. So we have 2 drugs now approved, atezolizumab, based on the IMpower133 study, so first-line treatment, extensive-stage small cell lung cancer, and those patients receive either the irinotecan plus placebo, either chemo plus atezolizumab, full cycle of chemotherapy and -- or chemo I-O and then atezolizumab. And we have a 2-month improvement of the overall survival. It's not that big, but it's highly significant in the field because we had absolutely no new drugs in first-line. So this was the first study presented. It was -- immediately, a standard of care on the uptake of the triplet chemo I-O is very, very high. Then the CASPIAN study comes next, with etoposide plus platinum salt, either combined with durvalumab, either combined with 2 different immunotherapy, durvalumab and tremelimumab. While the light blue arm with the quadruplet, 2 chemo and 2 immunotherapy, is, let's say, negative, but the triplet, durvalumab plus EP, was positive, exactly the same design, fourth cycle of the triplet and then maintenance. And as you can see, we have exactly the same benefit around 2 months of overall survival benefit, the same kind of hazard ratio, 0.7-something. Highly significant, is not that much, but it's highly significant. And again, it has been approved as the standard of care, approved in Europe and in the U.S., and it's now used in almost most of the patients. What do we do at relapse because all this extensive stage will relapse. I can go back here just to show you that you see, at 2 years, roughly 80% of the patients will have a relapse. So what happens here, well, we have 2 different situations. The refractory situation, where the patients present a relapse of the disease during the chemo immunotherapy or within the 3 months after the end of the chemotherapy. It's a very aggressive disease. Quite chemo-resistant, the response rate usually reported is less than 15%. And we have the sensitive ones. All the other patients that had an initial benefit of the chemo and relapse, at least 3 months after the end of the chemotherapy, they are considered as sensitive, meaning platinum-sensitive. And there, the relapses -- the response rate is higher. In these patients, we tend to use a rechallenge of etoposide plus carboplatin because it's one of the most active combos. The only drug that is approved in this setting is topotecan. Topotecan is a bit effective. It's not that impressive. Compared to best supportive care, it increased the overall survival. Topotecan is not a very, very convenient drug. It was first developed as an IV drug, 5 days in a row, so 1 IV per day for 5 days, each 3 weeks. Then we have the oral formulation of topotecan, a bit more friendly for the patients because it's 1 day, 1 pill a day for 5 days, each 3 weeks, but it's still quite toxic. And the efficacy is not very convincing. Lurbinectedin came in this field of, let's say, fully active second-line treatments. It was treated in pretreated patients, so at least one prior line of chemotherapy. Prior immunotherapy was low. But at the time where the study was done, immunotherapy was not the uptake, immunotherapy was very low in the globe, now it's more than 80% of the patients receiving immunotherapy first-line, not at that time. And then lurbinectedin was given as a single agent. It's a 1-hour IV, each 3 weeks. Yes, but this was just to get some means of response. So the primary objective was response rate, and 35% of the patients had a response. And you can see, in purple, this is what we call the refractory disease. In green, this is what we call the sensitive disease, based on this free interval between the relapse and the last injection of platinum-based chemotherapy. And you can see that in both cases, the drug is highly active. It's not only active, it's a friendly one. For example, you have no alopecia with lurbinectedin. Whereas all the other drugs have alopecia. And in terms of side effects, it's very well-manageable. The PFS was almost 4 months in the global population. And this is how we can use the drug. So this is the first example. My first case is a female, 71. She is a heavy smoker. She stopped smoking a bit more than 10 years ago before her diagnosis, but still 1 pack -- 2 packs per year -- per day, sorry, during -- no, it was 1 pack per day during 40 years. And she had an underlying illness of the lung, where bronchos are a bit dilated, and then she has multiple lung infections. So she was known by our pulmonologist because she had a lot, a lot of lung infections, and then she had a lot of CT scans and this is how a localized small cell lung cancer was diagnosed like 1 year ago. So when you have a localized small cell lung cancer, the standard of care is a combination of chemo and radiotherapy, and she received that. Unfortunately, a few weeks after the end of the chemo and radiotherapy, she had relapsed dyspnea, lung infection. It was treated as a lung infection, but it was also a relapse of the disease, with liver metastasis. So we were exactly 3 months after the last injection of cis-platinum. This is really a case where you can't not state it's really a sensitive disease. You can't not state it's a resistant disease. But this is a frail patient, and this is usually the case after first-line chemotherapy. I mean it's tough chemo. And at the time of relapse, most of the patients are borderline PS2. So she was fit for a chemo, but frail. And because of this frequent lung infection, I wanted to use something that is active, but a good safety profile. So it started in November last year, lurbinectedin, so the standard dose. It's through an Expanded Access Program that is open in France, so it's quite easy to get the drug. [ At times, it was really ] good. Asthenia Grade 1 is really something that is, I would say, friendly for the patients. It means that she can go on with her daily life activities. Anemia Grade 1 is it's really something that is mild, more than 10 grams per deciliter of immunoglobulin. It's really something that is mild. And Grade 1 thrombocytopenia is also something very easy to [ end on ], you just have to check the blood tests, and that's all. And this is the result of the 2 cycles. It was very nice to see. So on the left side, you have here the CT scan. In the red cycle, you see the liver met. And you have here the PET scan where you see the FDG uptake in the liver. So this is where you have, in the red cycle, the liver met. And you can see that after full 2 cycles, you have a clear shrinkage of the lesion. It's only 2 cycles through 6 weeks. And she is still in response after 4 cycles. And the very good thing here is that you don't have cumulative toxicity of the drug. So when the tolerance is fine, it's always fine. So you can really use that as, I would say, a chronic treatment. So I explained to the lady that she's fine with lurbi. She doesn't have too much lung infection because she doesn't have neutropenia with the drug. So it's really the good balance between the efficacy and the safety and of course, the quality of life. So this is the first example. The second one is an older case. It's a man, 55, never a smoker, which is something not very frequent for small cell. No medical history, so he was quite [ highly sick ] because never a smoker, but we found a small cell with liver metastases. He had cisplatinum-etoposide as a primary treatment, without immunotherapy, because in 2016, we had no approved immunotherapy in that setting. And after 3 cycles of chemo, he got a liver progression, which means that he had a real, real refractory disease. He was entered in the clinical trial. He received lurbinectedin in -- as the standard dose. Asthenia Grade 1 for 2, 3 days, but it was a [ perfected fit, performance basis kept at 0 ], so he was able to work, for example. And after 3 cycles, he got a partial response and received 36 cycles of the treatment. He had a progressive disease in more than 2 years after he started lurbinectidin. Well, this is, of course, kind of an outlier, but it's just to show you that you can give lurbinectidin as really a chronic treatment. You have no issue with the cumulative toxicity that you might have with the other drugs, like etoposide or the anthracyclines that you can give. When he relapsed, we tried to rechallenge etoposide and carboplatin, but it was not successful. We tried as a frontline anthracycline-based chemotherapy, which we call CAV, but the drug was not active and the patient died. So lurbinectedin is a very nice drug, convenient drug, friendly drug as a second-line treatment. So the LAGOON study is a confirmatory trial of the activity of the drug against the standard of care that is topotecan, it's the only approved drug, or a similar drug that is irinotecan, it's also a topo 1 inhibitor, I mean, it's exactly the same class of drug. So the patients will have relapsed small cell lung cancer that will have one prior line of chemotherapy, so it will be roughly platinum-based chemotherapy. Most of these patients will receive immunotherapy, so we will be really in the realized setting of what we do today. The patient must relapse at least 30 days after the last IV of chemotherapy, and the PS is 0 to 2, so it reflects really the patients that we have to treat here. I won't go in depth with the certification factor. That sounds very logical. And so the control arm will be topotecan, either oral, either IV or irinotecan IV. And there will be, the main, I would say, experimental arm is lurbinectedin single agent in 3 weeks. So the primary endpoint will compare this arm to the control arm. And we want to see an overall survival benefit because those patients usually don't receive subsequent treatments. So overall survival is really what you want to see, with a hazard ratio of 0.81. There is a third arm that is the combination of both class of chemotherapy, so it's lurbinectedin plus irinotecan, but irinotecan will be used with a lower dose, so that -- so is lurbinectedin, and the combination will be each 3 weeks. It's a bit more toxic on the -- in the hematologic field, I would say. So in this arm, we will use hematologic support with G-CSF to raise the white blood cells, but it's something that is from the Phase II that are totally doable. With that, I thank you for your attention.

Thank you, Dr. Besse. I just want to remind everyone that lurbinectedin is approved in the U.S. for adult patients with metastatic small cell lung cancer, with progressive disease on or after platinum-based chemotherapy, and that none of the information presented today should be interpreted to mean that Pharma Mar guarantees an upcoming confirmatory approval in the U.S. or an approval in the EU. And now, I would like to hand over to Dr. Sands. Dr. Sands will discuss his experience with lurbinectedin with his patients. And then we'll discuss the current Phase III study, which is supported by Jazz Pharmaceuticals and sponsored by Roche-Genentech, testing lurbinectedin in combination with atezolizumab as maintenance therapy in extensive-stage small cell lung cancer after first-line induction therapy. Now to Dr. Sands.

Great. Thank you so much. Now I am going to cover my clinical experience in utilizing lurbinectedin, that's in the second-line and beyond. And then we'll kind of just talk about the first-line setting more conceptually as opposed to getting into real specifics. So first, I'm going to cover a little bit of what Dr. Besse covered, but I'll try not to speak too much on data that I think everybody is already familiar with, but more kind of just giving my clinical impression and how that impacts decision-making when I'm seeing patients. Now first of all, for the NCCN guidelines, this is, of course, the guidelines for second-line and beyond and some important things to point out here. Of course, topotecan has been the long-standing second-line approved regimen, although I'll point out that that's really not approved for everybody. For those with a chemotherapy-free interval of less than 45 days and less than 60 days for PO and IV, respectively, it's actually not approved, but has been really the standing second-line regimen. I'll also point out that there are many individuals, including myself, that actually prefer irinotecan. So that's not an FDA-approved regimen, but a commonly used one and certainly supported by NCCN guidelines as a preference to topotecan due to the toxicity profile. That being said, lurbinectedin is now really my common preferred second-line regimen and really the regimen that my colleagues and I have been using more so. But as I said, irinotecan is the other option that -- in place of topotecan. Now I'll also point out that, of course, there are checkpoint inhibitors here. And I think people are familiar with the data. But going from discussing data to actual clinical decision-making, I still deem nivolumab and pembrolizumab to be extremely important options in the second-line and beyond, in patients that have never gotten a checkpoint inhibitor. If someone's gotten one, then they've already progressed on it. This is not something that is really an option. If they have not gotten it before, these drugs are, to speak in an analogy, they're kind of like swinging for the fences. And unfortunately, the majority of patients strike out, or the majority of times, I should say, we strike out in treating their cancer, that the disease grows and the checkpoint inhibitor actually unfortunately does not work. But in the subset of patients where it works, it can be extraordinary. And it can really be years of ongoing disease control. And so, sometimes, I hear people say, "Oh, we really need to -- the next line now in research is how can we make the checkpoint inhibitors work better?" And really, I think, more accurately, it's how we can help it work for more people. Because, frankly, when it works, these are -- I have some individuals with years of ongoing disease control, although, unfortunately, it's smaller numbers that have experienced that. So I think as far as second-line, those are the different thoughts I have in evaluating a patient and the regimens that I think would really be considered. And so now, I'm not going to repeat too much. I know Dr. Besse has gone through some of the data already. So I'll just point out some things here. It's one thing when you're looking at it here, all sitting in front of the computer and looking at numbers, and so maybe I'll touch a bit on how this impacts decision-making in the clinic itself. So not surprisingly, lurbinectedin is chemo. It acts like chemo in the second-line and beyond in individuals with a shorter chemotherapy-free interval. This is really a challenging disease to control. And so not surprisingly, we see low numbers of responses. But -- well, let me just go through it rather than -- so partial response, about 1/3 of patients getting a partial response and about 1/3 of patients having stable disease. Now this really obviously impacts medians when we're talking about this. And so -- and something like chemotherapy-free interval of less than 90 days with a resistant disease, we're really seeing right around that 50% of stable disease and partial response. And so the medians really are not very impressive, at 4.7 months. And at greater than 90 days, it is certainly more at 6.2 months. But I think more importantly, when we're choosing regimens for patients, when you see the 6-month progression-free survival of 19%, now that's not a big number, and clearly, we want more. But in seeing somebody who has a horribly challenging diagnosis, with very limited options as to really anything that would really add much, and we say, "Hey, there's a 19% chance of having 6 months of ongoing disease control." That is extremely meaningful. Now obviously, not everybody gets that because it's only 19%. But when we're prescribing these drugs, it's individuals that we think legitimately have a shot at this kind of control. And 6 months of disease control in a setting where most people just have ongoing progression in resistant disease is extremely meaningful. And of course, in those with the sensitive disease, we see 43.5% of ongoing disease control at 6 months. And then overall survival, let me see, I'm trying to get my pointer here. Well, let me do it this way. Okay. Well, you can see, I think, further down in the overall survival, overall survival, of course, is extremely meaningful in trials outcomes. I think right here, when we're talking about such rapidly progressive disease, the progression-free survival actually is quite sufficient in demonstrating the disease control of the drug. So essentially, I'm making the point that the medians here are numbers that are, I think, highlighting the ongoing importance of clinical trials. But there is a decent percentage of patients that really are getting a good control from this. And I made the point earlier in saying that, with checkpoint inhibitors, it's kind of like swinging for the fences. And unfortunately, in most cases, we strike out in treating that. But when you connect, it's really -- it can be a home run. And in this case, it's really more like swinging for a single or double. You're getting a higher percentage of patients that are really benefiting from the treatment itself. Although the connection itself is not necessarily the many years of control, but you're getting more of these patients into the months of control and then a handful beyond. Now the curves themselves, I think Dr. Besse covered this to some extent, and this is another representation of what I showed. So maybe, for time, I'll skip by that. Now the swimmers plot here is another demonstration of that as well though. And this is where we see really there are multiple patients that are getting these months of disease control. And in this second-line setting, although that doesn't seem like a lot of months, that is extremely meaningful for these people that are in a really difficult scenario. And particularly the ones with that chemotherapy-free interval of less than 90 days, it's really unlikely that something is going to work for those patients. And so even to get 5 months of control in that setting is meaningful. Now we see one person up here at 9.1 months. And of course, there are a handful there around that year and beyond. And so when this is something that is considered realistically possible for patients, we start these drugs really hoping for those kinds of outcomes. And so to have 50% of patients not necessarily getting that kind of ongoing control, it's still -- this is still my preferred drug, and that this is something where these patients can get ongoing disease control and at a minimum, or at least many of them, are getting that kind of 5, 6 months of disease control. Now that's only something that I would say when a drug is generally well tolerated because if they're getting a lot of side effects and only having that 5, 6 months, then that's not nearly as meaningful. And of course, all options here, we're talking about our chemotherapy, and so these all have a side effect profile to them. Now the most meaningful in -- with lurbinectidin is, of course, neutropenia, and I think people are familiar. And in this trial, patients were not allowed to get primary prophylaxis, and so these higher numbers of neutropenia can be reduced likely by use of G-CSF. The other thing on here though is fatigue. And so that 7% Grade III fatigue, it is a side effect that I'll speak to in a moment as well. Thankfully, the majority of patients really end up going through this treatment. With some -- this is chemo, so there are some side effects, but generally, very well-tolerated. And to me, that's extremely important when we're talking about a situation where these patients are unfortunately at high risk for decline, to, at a minimum, not be hurting them in the process is really important. Now just within the other part of that spectrum is saying further out, when you're getting out beyond 6 months. it's very low numbers, but promising in a response rate of 60% of patients and overall survival that's beyond a year, the median again being in the 4- to 5-month range. But there's a tail to that that's even more meaningful. Now I'm going to discuss a couple of my patients, and I'll highlight a couple of aspects of this. But I have treated a number of people with lurbinectedin at this point. My clinical experience has been similar to the data I've just shown you. But I'm going to show you a couple of cases really to highlight some aspects of this. So this is a 67-year-old man initially treated for limited-stage small cell lung cancer. So he got concurrent chemo and radiation, completed that in February of last year and had recurrent disease in May. So this is an unfortunate situation, only about 3 months out from having completed chemo and radiation and had really aggressive disease, multiple very large liver mets that popped up in the large right supraclavicular node. Also, MRI brain showed metastasis. Had him see radiation oncology, but because his disease was progressing so rapidly, I really didn't want to him have any delays, and so started lurbinectedin as well. Now this was -- he unfortunately actually ended up going to the hospital for some shortness of breath, and so in the ER, ended up getting a CT chest. You can see that this is only about 8 days after his prior scan and when he started treatment. So he had this very large right supraclavicular node, that really in just the 8 days reduced quite a bit. So this is a pretty rapid response to the treatment in what had been a pretty aggressive disease. And I'll show you his liver here as well. So this was -- now keep in mind, this guy had limited-stage disease, so this is about 3 months out from completed chemo and radiation and had -- and this is just one image, but in scrolling through his liver, there are other cuts that are even more full. So this is not at all picking out the most impressive cut within the liver in scrolling through on his CAT scan. His liver was absolutely full with these. So really rapidly progressive disease. Now this is in July. So the prior image that I just showed you was only 8 days later, just to show you that rapid response. There was not a CT abdomen at that time because he had gone into the ER for shortness of breath. And -- but we do see in July, at this point, had really very impressive response through his liver. In his brain, he had his initial MRI brain -- and sorry, this is now on the right side, is the older one being in May. And that was that, the nodule, in his brain that led to referral to radiation oncology for SRS, stereotactic radiosurgery. And then the MRI that was followed really did not show any persistent disease. Now there was a little bit of motion artifact, but the radiation oncologist saw this and essentially said excellent response to lurbinectedin, and this is something that we can hold off and continue to follow. Now to my knowledge, there really isn't anything in the literature at this point around CNS response. And of course, the basket trial did not allow for active CNS disease as most don't. So this is something I'm sharing with you, but probably something to write up as well. So he did have a response to therapy, had an excellent response in the liver and of course, that supraclavicular node. Now his disease on August 24 really had some progression. And so that brain metastasis had progression of that and then also had this node that was considered progressive disease. So progression in August. So after a 3-month chemotherapy-free interval, after chemo and radiation, had a pretty dramatic recurrence and had only a little more than 3 months of disease control with lurbinectedin. But it's hard to say that that's only 3 months of real benefit because, as you see, his liver is also -- really looks quite a bit better, so even at the time of progression, had dramatically less disease than he had initially when starting treatment. And now, he was started on a clinical trial at that point and is currently on clinical trial, but did have pretty rapid growth. This is another experience, 71-year-old man with extensive-stage small cell lung cancer. He got his first-line of carbo-etop-atezo, started this in February of 2020 and had progression noted in July. So really had a limited chemotherapy-free interval. And I'm going back to this fatigue aspect. This is -- this case is really the most significant fatigue that I've seen out of a number of patients treated with lurbinectedin, and I'm showing you the most severe case of fatigue I've had. This is -- now he, in July, he had -- this represented a lot more progression in his liver as well. He got 2 cycles of lurbinectidin, and that was August and September and unfortunately, had really such severe fatigue, that we were holding his treatment and really had to continue to hold it. And so he actually did not get any more lurbinectedin. He only got those 2 doses, but after just those 2 doses, really had ongoing disease control. So from July, this really went until about March, so had ongoing control for quite a while. At the time of progression, he was started on weekly paclitaxel. And just as a statement of how challenging this clinical scenario is, really, unfortunately, the paclitaxel was not particularly effective for him. And ultimately, he did pass just a few months later. So to kind of summarize my clinical experience, it's very similar to what you see in the data. I think it is more meaningful though than we see in the data. Of course, the data does highlight the need for ongoing clinical trials and further improvement of overall numbers. But for patients, this is really quite meaningful, and there's quite good justification for using this and why it's my preference in the second-line setting. Now in talking broadly about the first-line setting, this is -- in this setting, we're giving chemotherapy plus immunotherapy. There are really 2 drugs that are approved as checkpoint inhibitors, with atezo and durva. And this is a way of really swinging for the fences with that checkpoint inhibitor, while also securing a single or double. And what we see in those survival curves is really just that. The patients that really get a benefit from the checkpoint inhibitor is probably more in that 10% to 15% range. And so there's really quite a steep drop-off at the point of which where the chemotherapy is no longer -- well, where the disease becomes resistant to the chemotherapy. And so something that could then further extend the line outward for those individuals that are having that progression, that are not benefiting from the checkpoint inhibitor, is really an area of broad opportunity. I know I've -- I think I've gone a little bit over on my time, so I'm cutting short here. But I'm happy to take questions. I think we'll have a portion for that.

Thank you, Dr. Sands. Now we will turn to the Q&A session, and we will focus on what was -- what we've talked today. Myself, Jose Luis Moreno and our experts will answer these. Jose Luis, do you want to kick off?

Yes. Katie, first, we'll make -- we'll see if we have any questions from the audience, and then we'll let them ask. And then we have some of the written questions from the platform [ that we can start out -- we can now start out with reading ].

[Operator Instructions] Our first question comes from Joe Hedden from Rx Securities.

Good evening, good afternoon. Just one for Dr. Sands on the NCCN guidelines, still in those patients that are kind of super responders, if you like, the ones with 6 months and 9 months post-chemo. With a recommendation remaining for only rechallenges, the preferred option, I just want to take your view on that. What are you doing specifically with those patients? And what does lurbi need to show to get a preferred recommendation in that group?

Well, I don't expect lurbi to get a preferred recommendation without running a trial specific in that and having numbers. On the NCCN guidelines, those randomized trials end up carrying a lot of weight. That being said, it is my practice to use lurbinectedin in that setting. The outcomes for platinum-etoposide in the second-line, although there was more than 6 months of chemotherapy-free interval in the beginning, we know that, broadly, the response in the second-line is not going to be as long. And so, now for some patients, losing their hair is a big deal. And for those individuals, retreatment with platinum-etoposide is quite a hit. And I think this is actually something we probably don't talk about enough because the broad perception of somebody that has cancer and is getting treatment is somebody without hair. And this really ends up emotionally impacting far more people than I think really say that in clinic. People don't want to say how hard it is for them because they don't want to seem like they're just thinking about their looks or something. But I think it's actually impacting people's self-perception when they're getting treatment. But even for individuals who don't care about that, platinum-etoposide does wear people down a bit. It does take some recovering from. And in the second-line, it's not as effective as it is in the first-line. And so, for that reason, I'm not particularly enthusiastic about it. That's not to say I wouldn't ever re-treat somebody or that I wouldn't use it again at some point. But it's not my preference despite what the NCCN guidelines say. The process though to changing the guidelines, it does take a lot. And this is where -- nivolumab and pembrolizumab are still on there. And I highlight that because I think that's very meaningful, the fact that those still exist on there, despite the fact that those applications were actually pulled by the companies. But to get a preferred status really takes a lot.

How many patients -- just to follow up on that last one, how many patients do you still see it second-line who don't receive I-O first-line?

It's pretty limited in numbers. It really, at this point, is only individuals that either cannot get a checkpoint inhibitor at all, which is rare, or individuals that were treated in limited-stage disease. And so with limited-stage disease, checkpoint inhibitor is not a part of it, although there are trials underway. And I -- that may become a part of the standard of care, pending what happens with those trials, but for now, really just individuals not -- I mean, treated for limited-stage, which unfortunately is not a lot.

Okay. And how much worse do you think the outcome would be or -- for a patient who got I-O second-line because, for instance, what you've just said about being treated in limited-stage disease? And then they don't respond and they quickly got on to receive lurbi. Are we talking it's going to be significantly a worse chance of response or outcome?

Sorry, it sounded like you're asking about outcomes using immunotherapy in the second-line setting, but then also wondering about lurbi after chemo and radiation?

No. So if immunotherapy is used at second-line, in your experience, how effective is lurbi at third-line? And if you wish to do that?

Yes. I don't really expect much difference in efficacy, quite frankly. And so if I have a patient that has never -- that did not get a checkpoint inhibitor in the first-line setting and has really limited volume of disease, then I may try pembro in the second-line setting. This is knowing that the majority of patients are really going to have progression. And so I wouldn't want to use that in a setting where it's my only shot. If they've got real volume and I think that, essentially, they need a response now, then I would be more inclined to use lurbinectedin, knowing that more patients are going to end up getting a response to therapy and then hoping to monitor that closely so that they then get pembro or nivo in the third-line setting potentially, if I can catch that quickly enough. I would want everybody to kind of have a shot at one of the checkpoint inhibitors. But like I said, it's knowing that really the majority are really not going to benefit from that.

[Operator Instructions] And we currently have no questions on the line, so I'll hand it back to our speaker team.

So thank you, Katie. We have some written questions from the platform. I'll just go through them, then we can allocate it. First one, he asks, if lurbinectedin, like other oncology treatments, comes with some side effects, including fatigue or nausea. In your experience, what portion of patients discontinue lurbinectedin because of adverse events and tolerability issues? That can go to Dr. Besse now.

Very few in my experience because as any chemo, you can decrease the dose. So when there is too much fatigue, which is quite uncommon in my experience, I use 20%, 25% decrease at cycle 2. And usually, I find a good balance between fatigue and efficacy. So I don't know, Jacob, but it was not really an issue. I see your clinical case, but I have to say that it's -- [ I stop lurbi usually because of progressive disease at what point, but on tox ]...

Yes, I agree. For me, it's similar. I mean the case I just showed you is the one case that I have stopped the drug for fatigue. No it is the case that validated that 7% as being real, in that some of those patients are actually having fatigue from the drug. I was a bit skeptical of the data as potentially just being from the disease itself. And of course, small cell lung cancer causes fatigue. And sometimes, that's hard to tease apart. But this was one case where there really was. This is the one case I've stopped the treatment. I've treated a number of people, so this is not common. And in that one case, he really ended up with ongoing months of disease control despite stopping it, which I found quite encouraging. So stopping because of toxicities is not common.

Okay. Thank you. We have another question here. [ So if a group in first-line ], will you use lurbi in first-line, or will you use immunotherapy in first-line and reserve lurbi for second-line, where there are so few options?

Well, I don't think there are any studies using lurbi instead of immunotherapy in the first-line setting. I think a cytotoxic with immunotherapy is a compelling combination in the potential for increasing immune response. And so adding lurbi within the maintenance setting may further enhance that immune response potentially. But that cytotoxic combination with immunotherapy actually is a good one. Now if you're talking about using lurbi instead of chemo, I'm not aware of any studies that are replacing that either. And there are probably more steps before. Well, I don't -- I guess I can't speak to that because I'm not aware of anything doing that. So if lurbi was approved in the maintenance setting, then that's certainly something that I would need to -- I mean I need to wait and see the theoretical data from all of this. But if it showed clear tolerability, which I would certainly hope for based upon my experience with patients, and it shows clear benefit in really further prolonging that median progression-free survival and likely a correlative overall survival, if that was all demonstrated, that's certainly something I would use.

And maybe immunotherapy is there in NCCI guidelines. But in most of the countries, there is no approval of immunotherapy in second-line. The Phase III trial with nivolumab against chemo was completely negative. So as we want to expose the patients to all the best drugs, it's clear that if we can use immunotherapy only in the first-line, it will probably be a preferred regimen, followed by lurbinectedin maybe in maintenance, as you say.

Okay. Thank you. We have another question. So now that lurbinectedin is approved in the U.S., in what setting, to you or your colleagues, you think you'll still prescribe topotecan? Jacob?

It's not really something I use. Now I do use irinotecan. So I tend to use lurbinectedin in the second-line. Irinotecan and weekly paclitaxel are each regimens that I tend to use as well. Temozolomide is a regimen that I'll use kind of further down the line or in people with CNS disease that's already been radiated without good options. And those are really the regimens I tend to use. So topotecan is really not part of my standard practice.

I fully agree with you. It's really not an easy drug. Now irinotecan or a combination like CAV or things that I like to use, and I sometimes rechallenge patients with etoposide and platinum salt, even if there is a randomized French study published in Lancet Oncology last year that shows that there is no OS benefit to rechallenge with etoposide and platinum salts. You have a higher response rate which can be sometimes convenient when the patients are highly symptomatic, but that's all.

From another question. Do you think there is potential for using lurbi earlier on top of immunotherapy in first-line?

Yes. I think there's an opportunity in the maintenance setting to potentially move those curves out for those individuals that are not experiencing a real response from immunotherapy. It's hard. I mean if there was a way to tease out who is not going to benefit from the immunotherapy, that would really be quite compelling because, of course, that 15% that have ongoing durable control are unlikely to really impact that. But the rest of the patients that really have progression within months, this would be very meaningful if you can shift that curve out further to the right.

We have another question. I guess these are -- will probably be for Dr. Ali Zeaiter because it's in relation to the trial. In the LAGOON study, what will happen if arm B were positive but arm A will be negative?

In either scenario, the data will be discussed with authorities. And decisions will be made at their discretion.

Okay. And we have got -- we have another one in relation to the trial. I guess this is someone that is working in a hospital. Is the Phase III trial still looking for more centers to participate?

Sure, we can always add centers. In case they were not contacted, we -- I mean, they can reach out to Pharma Mar, and we will do -- I mean, we will follow up. Right?

Okay. We have another one for the doctors. What do you think in second-line patients who got more -- who got 180-day CTFI? If not lurbi, what is your thinking? And would you consider that lurbi in second-line and platinum treatment in third-line, with platinum holiday, might be better than immediate retreatment, followed by lurbi in the third-line?

Okay. Increasing the platinum-free interval is, I think, an interesting idea definitively. The -- what is not known really is the cross-resistance between lurbi and subsequent platinum salts. So on the paper, it's a good idea, but it has to be proven that being resistant to lurbi at one point doesn't mean that you are resistant to platinum salt.

Yes. No real data for it, but that really fits more my bias. I would prefer to switch regimens knowing that that's something you can come back to at some point. Whether that's actually ultimately better in outcomes, I don't know of data to really go either way on it.

We have some other questions that, I guess, we have addressed. We're running out of time. So it's just a 1-hour [ show ]. Thank you, thank you very much.

Thanks to our experts. Thanks, everyone.