GSK plc (GSK) Earnings Call Transcript

Good afternoon, and good morning. and thank you for joining our analyst briefing to cover data presented at the European Society for Medical Oncology in recent days. Today's discussion will be focused only on recently presented clinical data. We will not be providing any commentary on performance as we report our Q3 results tomorrow. We are joined today by Nina Mojas, our President of Global Product Strategy; Hesham Abdullah, Senior Vice President and Global Head of Oncology R&D; and Ahmed Rabie, Senior Vice President of Global Product Strategy for Oncology. We're also joined by Eric Richards, Richard Davidson and Klaas Bakker from the oncology R&D team for the Q&A portion of this session. For the agenda, Hesham will take you through the data, and then Nina will provide some closing remarks before opening up for your questions. I will now hand over to Hesham.

Thank you very much, and it's a pleasure to be with everyone. Good afternoon to those in Europe. Good morning to those in the U.S. And thank you very much for joining us. Of course, we're just back from Madrid. Very exciting ESMO. More than 21 abstracts and a number of different oral presentations as well too from the GSK oncology pipeline. And I'm happy to take maybe the next 25 to 30 minutes to walk you through some of the key data from our oncology portfolio that was recently presented at ESMO in Madrid. With that, I think we could probably start off first with Ris-Rez, which is our B7-H3 ADC, of course. And I think, first and foremost, it's important to highlight that we actually presented some data from across our Phase I/II development program. This is the GSK development program, global development program more specifically as well too. We actually had data from our Phase I/II study and specifically in small cell lung cancer. And I think what's probably important to highlight is this data certainly showed consistency between the global data set that we've generated in terms of objective response rate in second-line-plus small cell lung cancer, with a 61% response rate in the 8 mg per kg dose cohort. This is actually the dose that will be used and is being used currently in the second-line Phase III small cell lung cancer study across our own global development program. And then, of course, data that's been generated recently at World Lung from our partners, Hansoh, and the ARTEMIS-008 study, where we saw an objective response rate of 58%. So I think probably the first key headline to take is certainly the data from our emerging global development program is very reassuring and confirms certainly the clinical activity that's being observed in the China Hansoh development program. Next slide, please. This is, of course, the data that was recently presented by Hansoh from the ARTEMIS-008 trial, looking at Ris-Rez versus topotecan in second-line small cell lung cancer. I think probably what's important to highlight and remind everyone of, of course, is the study was positive, demonstrating a statistically significant and clinically meaningful overall survival benefit for Ris-Rez relative to topotecan, with a median overall survival of 18.5 months versus 10.3 months of the topotecan arm. As you can probably see from the Kaplan-Meier curves, the curves separate early. That separation is maintained over time. And at a landmark of about 12 months, which is certainly the median duration of follow-up on the study, there were about maybe 64.5% of patients still alive on the Ris-Rez arm, versus 43.3% on the topotecan arm. Next slide, please. This is a slide showing certainly consistency of the overall survival effect across key subgroups, from the ARTEMIS-008 trial. What I'd probably call your attention to is the fact that about maybe 17% of these patients that were recruited into the study did have brain metastases at study on treat. And what we did observe was that there was certainly a consistent treatment effect across this subgroup as well too, with a hazard ratio of 0.36 for overall survival. But generally, certainly consistent survival benefit observed across all predefined subgroups, whether it be based on age, smoking [indiscernible] prior PD-L1 therapy and, of course, performance status as well. Next slide, please. Key secondary endpoints, of course, PFS by independent and investigator review. Quite consistent, with a hazard ratio of 0.33 for the BICR-assessed PFS, 0.35 for investigator-assessed PFS, with about maybe a 4-month delta on median PFS, certainly, whether it be based on BICR or investigator assessment as well too. Next slide, please. And then, of course, objective response rate, disease control and duration of response. What I'll probably call your attention to on the slide, of course, is the objective response rate that's been observed, that I've noted previously, 58.3% for Ris-Rez versus 12.8% for the control arm with single-agent topotecan. I would say maybe close to a fivefold difference in the magnitude of effect on response, supported, of course, by the median duration of response close to about maybe 7 months and the disease control rate as well too. Now one point to highlight here which I think is really important in terms of how we think about the extrapolation of data from China. And what you see in this study specifically is there's a really strong internal consistency of results. If you look at the primary endpoint and the magnitude of effect that's observed on overall survival with a hazard ratio of 0.46, key secondary endpoints like PFS with a hazard ratio of 0.33, and then this fivefold difference in response rate as well too, and that strong internal validity and consistency within the Phase III study itself gives us certainly strong confidence in its external ability as well too and broader application across other countries and regions. Next slide, please. So maybe just a quick summary then. And again, of course, just a caveat, as always, of looking at cross-study comparisons and the differences that's made between baseline characteristics across each of these studies, just taking that into account. But at least when we look at a high level, the median overall survival from the ARTEMIS-008 compared to some of the emerging data across the B7-H3 class, but also some of the existing data as well too in second-line small cell lung cancer with immune cell engagers, no doubt the median overall survival with Ris-Rez at 18.5 months, certainly quite well positioned in that regard. We have 2 Phase III studies in small cell lung cancer, an ongoing Phase III in second-line small cell lung cancer, which is the EMBOLD-301 trial, which is currently recruiting. And then a second study in first-line small cell lung cancer that will be initiated very shortly before the end of the year in the first-line setting as well too. Next slide, please. So one of the additional data sets that were actually presented as well too at ESMO was an analysis that we conducted from our own global development program, looking at the incidence of ILD, given that this is certainly an event of interest across the topo-1-based class of ADCs as well too. When we've looked at this across our, certainly, data set, whether it be across all solid tumors or specifically in non-small and small cell lung cancer, we do see a relatively low incidence of Grade 3 or greater ILDs [ events ] at 0.9%, so less than 1%. And then, of course, in the overall at least aggregate population from our own development program across all solid tumors, a 4% incidence of all grade events. And again, the majority of these events were, of course, mild or moderate Grade 1/2 in nature. I think when you look at also the data that's been published from the Hansoh experience in China, whether it be with the ARTEMIS 3 or ARTEMIS 2 studies, these are Phase I/II trials, we do see a relatively low incidence of Grade 3 or greater ILD events as well too. Of course, ARTEMIS-008 being the exception to that with an incidence of 4% of Grade 3 or greater ILD. Next slide, please. This was, of course, all presented on a poster at ESMO that included, of course, the ILD data for [indiscernible]. Next slide, please. And then, of course, data that was presented just yesterday, in an afternoon Presidential symposia at ESMO, I would say quite a landmark result just given certainly how challenging this disease is, osteosarcoma. Quite poorly prognostic. We have not seen any advances in standard of care over the past 50 years as one leading sarcoma expert had told us. And I think that's really important to highlight and emphasize as well too. Next slide, please. So this basically was a study looking at osteosarcoma patients in an advanced metastatic second-line disease setting. So patients had received certainly greater than 1 to 2 prior lines, specifically at least 2 prior lines. Patients were randomized 2:1, either receive Ris-Rez or certainly standard-of-care gem docetaxel chemotherapy. And then the primary endpoint of the study was PFS blinded independent review. The secondary endpoints included overall survival and PFS and objective response rate. Of course, given the sample size of the study, which is 122 patients, the study is not powered for overall survival. Next slide, please. Key baseline demographics. When we look at the median age of these patients, it's ranging between 21 to 22 months. And I think that's really important to highlight just given the patients that are typically impacted by osteosarcoma. We have about maybe 1/4 of patients that were actually adolescents, between 12 to 18 years of age. So certainly, at least the incidence tends to also occur in younger patients, as evidenced by the data. I think 1 thing to probably also highlight is this is a patient population that no doubt had a relatively high disease burden as evidenced by the fact that the majority of these patients had pulmonary metastases, and, of course, is also heavily pretreated. The majority of these patients have received prior chemotherapy and targeted therapy as well too. Next slide, please. The primary endpoint, BICR-assessed PFS, was met, demonstrating a statistically significant and clinically meaningful improvement in PFS, with close to a fourfold improvement, 5.5 months versus 1.4 months, in terms of the medians. Again, you see the curves separate relatively early and certainly stay separated until that 6-month landmark. I think it's important to highlight, of course, the median duration to follow-up at this point in time is about maybe 7.1 months. Next slide, please. Tumor response assessment by BICR as well too. The objective response rate is 15% on the Ris-Rez arm and 2% on the gem-docetaxel arm. Now one thing to bear in mind and especially with this type of tumor, just given the location of the tumor itself in the bone, oftentimes one of the challenges is really getting enough exposure to be able to penetrate these lesions, especially given the thickness of the extracellular matrix that exists around the tumor and the capsule within the bone itself as well too. So I would say probably objective response rate is not necessarily the most meaningful way to assess the activity of the drug, but rather, of course, a disease control rate may be a better proxy along with PFS. And here, as you can probably see disease control rate is at 76% on the Ris-Rez arm versus 33% on the control arm. I think one other point to highlight, the dose that was used of Ris-Rez in the study was 12 mg per kg. I mentioned and alluded to the fact that higher exposure may be needed here given the need to better be able to -- better penetrate, of course, the tumor, especially given its location and site as well too. Next slide, please. Overall survival data, currently immature. It's about, I would say, 16% to 17% mature at this point in time, with about 10 events having occurred in each arm. The study did allow for crossover. So we did note that 17 patients in the control arm have already crossed over to Ris-Rez treatment following progression on gem-docetaxel. And despite that, we're still seeing certainly a very encouraging trend at this point in time on overall survival with a hazard ratio of 0.51. And again, awaiting further follow-up just given the relative immaturity of the overall survival at this point in time. Next slide, please. Safety profile, I would say, certainly as expected, given the dose that was used here, but also the typical topo-1-based payload assessed toxicities or related toxicities, all predominantly relating to myelosuppression, including, of course, neutropenia and, of course, thrombocytopenia being the key ones. I think the one point to highlight here that's really important as well too, despite certainly the higher Grade 3 event rates across the myelosuppression, discontinuation rates were quite low at 4%. Next slide, please. Moving on to our B7-H4 ADC, Mo-Rez. We did provide an update on the data that was actually presented at SGO in April. So specifically, the platinum-resistant ovarian cancer cohort with longer follow-up now, about maybe a little over 13 months of follow-up from that cohort. Just maybe a quick, I would say, brief on the design of the study, of course. So this is our Phase Ia/Ib study. There was an abbreviated dose escalation and then a movement into dose optimization and expansion across 3 different dose levels, 2.8, 4.8 and 5.8 [ Q3 W]. And that -- it will be the focus at least of the data that will be presented on the following slides and specifically the platinum-resistant ovarian cancer cohort. Baseline characteristics, maybe just to call out the fact that -- a few key elements to this. One, the majority of these patients had received certainly prior bevacizumab and more than half had received a prior PARP inhibitor as well too. The other, of course, just to note here is that the majority of patients, close to about maybe 80%, had received 2 or more prior lines of therapy, including 36% of patients that have actually received 3 or more prior lines of therapy as well too. And then a large portion of patients had tumor tissue available for expression evaluation. Next slide, please. And what you'll see on here, of course, is a waterfall plot for objective response rate. I think the one point to call out more specifically here is that these are confirmed objective response rates across all those levels. What do we see? Well, what we see is certainly an objective response rate of 36% across the 2.8 milligram dose, 57% across the 4.8 milligram dose, and 62% across the 5.8 milligram per kilogram dose, which is the registrational dose that we're taking forward in this indication. There's also a trend towards shorter times to response relative to dose, with the shortest time to response on the 5.8 mg per kg dose level. And then also a trend towards the depth of response as well too relative to dose in that respect as well too. What's probably also important to highlight is the fact that responses, as you'll see on the following slides, were irrespective of B7-H4 expression levels as well. We did have actually 4 patients that had received prior mirvetuximab treatment. 2 out of the 4 patients developed a partial response. Next slide, please. This is certainly just data specifically on duration of response. And again, what we do see is a dose response, certainly, a trend here as well too, with the median duration of response, of course, being the longest and strongest certainly on the 5.8 mg per kg dose level at 12.2 months. along with, of course, the probability of duration of response at the 6-month landmark as well too, with certainly that separation being evident from the Kaplan-Meier plot on the right-hand side of the slide. Next slide, please. The same holds true for PFS. We saw the longest PFS on the 5.8 mg per kg dose level, with a median PFS a little over 11 months, and the probability of PFS for being progression-free at 6 months of 80%. I think all of these data in the aggregate reinforce our certainly confidence in selecting the 5.8 mg per kg dose level for the platinum-resistant ovarian cancer indication as well too, along with a few of the other studies that were -- Phase III studies that we're initiating, including the second-line endometrial cancer study and the platinum-sensitive ovarian cancer study as well too. Next slide, please. This is data that was also presented at a separate oral presentation that was more focused on translational biomarkers from this Phase Ia/Ib study as well too. And again, as you can probably see, we had a range of different, I would say, on the left-hand side of the slide, B7-H4 expression levels represented in the sample size of patients that were treated. And then on the right-hand side of the slide, and again, based on the color coding, as you can probably tell, responses were observed across a range of expression levels, including depth of response as well too. Next slide. The safety profile, as expected, and based on the topoisomerase warhead, dominated by GI and also myelosuppression events. I think just a few key points to call out in this respect. First, across all dose levels, the 2.8, the 4.8 and the 5.8 milligram dose levels, the incidence of all-grade ILD was 7%. And specifically at the 5.8 mg per kg dose double, it was 2%. And the majority of these events, 8 out of the 9 events that have actually taken place, were Grade 1/2 in nature. Only 1 event was Grade 3 or greater. One thing to also call out as well too is really just in terms of the Phase I study design itself, it did not mandate the prophylactic use of growth factors to mitigate neutropenia, as evidenced by the data that we have in hand. And that is only GCSF use was only used in 8% of patients at the 5.8 mg per kg dose level. And I think for the Phase III studies, we are being much more prescriptive and strongly recommending the use of GCSF to mitigate the neutropenia from the start of treatment as well too. And this is being implemented across all 5 Phase III studies. Next slide, please. And so just a quick recap. I've mentioned, of course, that we've initiated 5 Phase III trials across platinum-resistant ovarian cancer, platinum-sensitive ovarian cancer first-line, HR-proficient maintenance ovarian cancer, and then also second line endometrial cancer and first-line MMR proficient maintenance endometrial cancer as well too. Next slide, please. Moving forward to dostarlimab, and of course, this is data from the AZUR-1 study, I think everyone is well aware, of course, that we had announced last week the regulatory approval in the U.S. and then the data followed over the weekend with an oral presentation as well to from the AZUR-1 trial in the locally advanced MMR MSI rectal cancer patient population. Next slide, please. And maybe just to provide a little bit of context, I think this is a, certainly a patient population that is typically treated with what is multimodal therapy, a combination of chemo radiotherapy and surgery. Unfortunately, of course, the tolerability challenges and comorbidities that has on patients is quite difficult, resulting in certain gastrointestinal dysfunction, certainly bowel and also urinary dysfunction, and certainly in certain cases, also impacting fertility as well too. Historical, I would say, clinical complete response rates for this patient population range between 20% to 25%. And I think that's important when we think about how to contextualize the results from the AZUR-1 study as well too. Next slide, please. Baseline characteristics for this patient population. I think probably first and foremost, the median age was about maybe 61.5 years. But I think what's probably important is actually to look at also the confidence intervals around that. The range is about maybe 23 to 92, indicating, of course, that we're seeing these cases even in younger patients as well. And I would say that it also highlights, of course, this emerging trend of younger onset disease across multiple types of cancers, including colorectal cancer as well. The majority of patients had [ bulky ] Stage III disease coming into the study at the time of entry. And one thing to point out as well too in terms of the types of tumors, about 15% of patients had a [ mucinous ] type of tumor, which tends to probably be a bit more challenging or [ skewer ] in terms of how it shows up in the MRI scans as well, making it a bit more difficult for physicians to be able to assess clinical complete response. Next slide, please. The primary endpoint of the study was clinical complete response at 12 months. Patients actually received 9 doses of dostarlimab or about maybe 6 months of treatment. The cCR12 rate by investigator assessment at this time was 68%, as evidenced by the light-blue bars, these are the patients that actually were able to achieve cCR12 and had enough follow-up for them to be [ assessable ] for that endpoint. I think the one point to highlight on the left-hand side in the black bars as well too is that there's a number of different patients that have achieved a clinical complete response but don't yet actually have enough follow-up to be assessed for cCR12 at this time. So we'll continue to be following patients moving forward as well too. Next slide, please. These are the swim lane plots certainly demonstrating the durability of responses that have been observed across the AZUR-1 patient population. I think what's probably important to highlight here is, of course, is that 98% of the cCRs were durable. And to date, no recurrences have actually occurred so far. Next slide, please. I think probably, just to provide a little bit more color around the type of benefit that patients were driving, so cCR12 is an endpoint that's typically assessed through 2 different methodologies. One, I mentioned the MRI. The other, of course, is through an endoscopic assessment. In certain instances, when there may be a bit of ambiguity around being able to declare a cCR12 or there's maybe uncertainty from the physicians around it, oftentimes what they'll do is they'll actually biopsy the patients as well too and get access to tissue. And so there is a segment of patients in the dark-blue bars that actually have what is called a pathologic complete response at the time of the biopsy and surgery as well too. Limited number of patients that had actually undergone that, just about 12. But when you look at the combined cCR12 plus PCR rate, 76%, which is certainly, again, if you're comparing it to the 20% to 25% clinical complete response rate that's historically observed, quite significant and quite clinically meaningful, especially when you think about the fact that the majority of these patients were able to not only avoid chemo-radiotherapy, but also avoid surgery as well too. Next slide, please. And then finally, I think probably just important to be able to see what this looks like. I mentioned, of course, the 2 different approaches to assessing certainly clinically -- the clinical complete response. One is through the MRI, the other is through the endoscopic exam. This is exactly what you're looking at. So basically, this is an endoscopic assessment of the tumor in the rectum. Starting first maybe on the left-hand side, what you're seeing is this is actually one of these [ mucinous ] tumors, which are typically difficult to assess on an MRI scan. And as you can see, certainly, both from the anterior and also posterior walls, significantly encroaching and causing an obstruction within the rectal canal as well too. And then basically, the baseline evaluation after getting treatment, the patient getting treatment with dostarlimab for 6 months, 9 doses. And what you can see is there is a start of maybe normalization of the rectal mucosa and epithelium. Specifically, you see that manifested through the flattening, the smoothening as well too, with probably some very residual scarring and I would probably say even slight residual evidence of the tumor. And then finally, of course, after the second follow-up assessment, complete normalization and no evidence of the tumor exists as well too. And certainly, that gives you a sense of what this looks like in terms of the assessment of cCR as well too. The safety profile, certainly very consistent with what's known about dostarlimab and the immune-mediated adverse events. Important to highlight low incidence of Grade 3 events with these 9 doses of dostarlimab as well too. And so a low tolerability burden for patients. Next slide, please. So just to conclude, certainly we've seen an evolution in what will be the standard of care for locally advanced [ DMMR MSI high ] rectal cancer patients from where it was previously, as I mentioned, in the context of the prior treatment paradigm with chemo radiotherapy and surgery, to where we now see more than 2/3 of patients achieving a cCR12, 76% of patients achieving a cCR12 plus PCR, and certainly quite strong durability of these clinical complete response rates, with a low adverse event burden for our patients as well too. Next slide, please. I think maybe just one reminder from another data set that was presented at the World Lung Conference as well too. Very exciting data from our Nuvalent acquisition, as everyone will probably recall, zidesamtinib or Jideytro was actually approved in late July in the U.S., 2 months ahead of the PDUFA date, which I think is important to highlight as well too. And here is actually data being presented from the TKI-naive cohorts in advanced metastatic ROS1-positive non-small cell lung cancer. Very quickly, I think probably the baseline characteristics, as expected, with about maybe a little over half of patients being females and certainly the same for patients being non-smokers as well too, certainly, a good portion of these patients being fit in terms of status with an [indiscernible] performance status of [ 01 ] and about 17% of patients having a baseline CNS metastases as well and the majority of patients having advanced disease and 1/4 having previously received chemotherapy or immunotherapy. Next slide, please. And just to highlight, of course, the waterfall plot from 94 patients that are TKI-naive, and an objective response rate of 94% based on independent review with a CR rate of 15%, which is actually close to doubling the CR rates that we've observed with third-generation TKIs too, which I think is important to highlight. Next slide, please. Duration of response, also extremely encouraging at this point in time, and specifically looking at the landmark duration of response at 12 months being 86% with the median duration of response not yet reached at this point in time. Next slide, please. And then the same holds true for progression-free survival, looking at the landmark PFS at 12 months of 90%, and the median PFS not reached. Now one thing that probably for us to think about and consider as well too is how this drug was actually designed. It was -- in terms of the medicinal design of the drug, it was really designed to have this brain penetrate activity will also being [indiscernible] sparing as well too, to minimize any CNS effects or side effects that is, while also making sure that it addresses intracranial or brain metastases as well. And that was certainly evident in the [ EROS 1 ] study in this TKI-naive cohort. In the subset of patients that did have brain metastases at baseline, intracranial directive response rate was 100%. And certainly, the intracranial CR rate, complete response rate was 70%, which is quite profound. And then, of course, the median duration of response in these intracranial metastases is not -- at least duration response in the brain metastases has not been reached. Tolerability wise, I would say certainly a very good tolerability profile. Low incidence of Grade 3 events. I think probably I'll call your attention to the right-hand side of the slide, where we did see a really low discontinuation rate, only at 4%. And specifically that related to treatment-related adverse events at 1%. Dose reductions also an infrequent at 11% and 12% as well too. With that, I think what I'd probably do is hand it over to Nina for closing remarks.

Thank you, Hesham. And I'm reflecting all the data and amazing data that were presented, but also on Hesham's ability to present all of this in such a short period of time. So thank you, I think it's quite impressive. Okay. Before we go into Q&A, this slide is trying to capture the importance and the impact of the data. So to focus first on the first 2 boxes, so Ris-Rez in second-line small cell lung cancer. Why are these 2 data points important? The first one, you have seen that in the Western cohort, so Western population of second-line small cell lung cancer, we are seeing 61% response rate. And that correlates very well with 58% response rate that has been observed in the Chinese Phase III study, ARTEMIS-008. And that study has shown unprecedented, the longest median overall survival that has been seen in the second-line small cell lung cancer. And I think this data give us confidence in the activity and the promise of Ris-Rez in second-line small cell as we are going to witness from the Phase III study, which is ongoing at the moment. So very high confidence in second-line small cell for Ris-Rez. Another set of data, Ris-Rez in relapsed refractory osteosarcoma. For anyone of you who were there yesterday at the session and listening to the discussion, I think you get the full picture of what that disease is and how devastating it is and the lack of progress over the last decades. For Ris-Rez specific, it's an illustration of this asset being a pipeline in an asset with yet another indication, very difficult to treat indication, successfully tackled. Jemperli, over the last few years, we have heard repeatedly the magic of Jemperli in the MMR locally advanced rectal cancer. Now pivotal data in a study that on its own is quite unique have confirmed the efficacy, and we are actually just in the process of launching following the approval in the U.S. Jideytro, ROS1 inhibitor in TKI-naive, was presented at WCLC a couple of weeks ago, again demonstrating best-in-class efficacy. And based on this data, FDA is going to review the first-line label, resulting, hopefully, very quickly in the approval for indication in TKI -- for TKI-naive patients. Then last but not least, Mo-Rez, actually Mo-Rez had very good ESMO, with data presented in PROC or platinum-resistant ovarian cancer. Looking at the data, response rates plus duration of response and PFS that has been observed indicate that this asset is at the top end, if not the best, in efficacy in this setting. Or more specifically, in ovarian cancer, obviously, [indiscernible] indication is the beginning, ADCs are very intense -- have intense development programs in ovarian cancer. And the question is going to be where is -- which asset position either in platinum-sensitive ovarian cancer or eventually in newly diagnosed, so first-line ovarian cancer. So with this, again, I'm just going to thank Hesham for an amazing presentation and the read-through. I think we are going to open the questions, and Jeff is going to manage that.

Yes. Thank you for those of you who have not raised your hand and have a question. Please feel free to raise your hand, and we'll try to get through as many of you as we possibly can. I see James Gordon is up first, from Barclays.

One on Ris-Rez and one on Mo-Rez, please. So in Ris-Rez, so the efficacy looks good, but I think there's a 42% Grade 3 AE rate in the Phase III. So that does look challenging. And it doesn't look like it's lots of ILD, that looks all right. But it looks like these 42% of patients had to have dose interruptions or delays. So might it be a bit too high dose? And is that something you think you can improve in terms of tolerability in Phase III? Would you want to try and improve it before taking something that challenging into Phase III? That's the first question, please. And the second question was on Mo-Rez, so the B7-H4 where the data looks strong in ovarian and endo. But then on Friday, Genmab had also a very strong Phase III efficacy data for Rina-S, so its folate ADC, and there's a few other ones of those in development from other people as well. So how do you think about folate ADCs versus B7-H4 for gynecological cancer? Because it looks like at best, Mo-Rez is probably about the same, but they'll already be on the market and quite well established. Is it going to come down to some sort of subgroups or something like that? Or might it be you do a folate, then a B7-H4?

James, thank you very much for the question. I'll start off first maybe just addressing the question around Ris-Rez. And I think probably 42% that you might be referring to is coming from the osteosarcoma study. And I think maybe as I've just highlighted as well too, the dose that was used in that trial was actually the 12 mg per kg Q3W dose. That is not the dose that's currently being used across a number of key tumor types that we're exploring. Specifically, we're actually using the 8 mg per kg dose level Q3W across both small cell and prostate cancer as well too. And I think from our perspective, again, most of the, I would say, safety and tolerability at least profile is very much being driven by the myelosuppression and the neutropenia. And from our perspective, certainly, the use of growth factors in the Phase III studies should certainly help mitigate that. But then at the same point in time, we're not using the high dose, the 12-milligram per kilogram dose, that Hansoh used in their osteosarcoma Phase III trial. We're actually using the 8 mg per kg dose level. In terms of the second question that you actually had as well too and specifically regarding Mo-Rez. I think, first and foremost, of course, I think we're all well aware that we saw that the announcement from Genmab around the RAINFALL study as well too, and announcing positive results. From my perspective, first and foremost, I think it's important for patients, important for patients to be able to have treatment options, especially with this emerging class of antibody drug conjugates. With that in mind, I think we have to look at the data that we have at hand. There's things that we know and things that we don't know. The things that we know are the hazard ratios for that trial for PFS and overall survival. The things that we don't know are the medians. However, I think, again, acknowledging the caveats that exist with cross-study comparisons, what we do have is actually Phase I data from across both programs. And when we look at the Phase I data, specifically with Mo-Rez, which we just presented over the weekend in [indiscernible] we saw a confirmed objective response rate of 62% from the Phase I renez study, it was 46%. So that's one. And then second, when we looked at also PFS as well too, I think as you probably saw, at the 5.8 dose level, the median PFS was 11.1 months from Mo-Rez. And then for renez, it's about maybe 9.5 months. So I think we just have to keep in mind that, at this stage, we have to wait and see what the data looks like from their Phase III trial. But certainly, I think what's probably become evident is that there is some level of relationship between clinical activity in the context of response rates and depth of response. But also, certainly at least with these ADCs, the duration of response and the PFS as well too. And at this stage, we certainly feel pretty comfortable with the level of clinical activity that we're observing and then how that's manifesting in duration of response at a little over 12 months and then PFS a little over 11 months as well too. Now in the context of subgroups, again, I think for us, when we looked at expression levels, as you probably saw from the data itself, we see no correlation between clinical activity and expression levels. Broad activity across whether it be B7-H4 expression low or high, I think that's data to be weighted from their Phase III trial as well too, is see what, if any, relationships may or may not exist with FR alpha expression levels as well too.

And I would just add for PROC, PROC is the first step for all of these ADCs in ovarian cancer. Eventually, hopefully, the efficacy is going to confirm for many of these to be moved into earlier line of therapy. And this is probably where the more important competition is going to happen. And as you know, studies are only starting in these settings as we speak.

Excellent. Let's move to next question from Shyam Kotadia from Goldman Sachs.

So there's a lot of focus on novel-novel combinations in oncology with ADCs and new IO backbones. How do you think about this potential in gyno. We've seen activity with VEGF in ovarian cancer. So could B7-H4 be a potential partner for VEGF PD-1 bispecifics?

Yes. Shyam, thank you very much for the question. I think we'll start off first by saying no doubt that the standard of care has evolved in endometrial cancer, and we've seen that first with the advent of checkpoints. As you may probably be aware, our first-line endometrial study in the MMRP segment of patients, it's a maintenance trial, but it's also looking at to combine Mo-Rez or B7-H3 with the existing standard of care PD-1 agents. And so that's probably one component of it. The second probably is getting directly to your question, which relates to, could combining with bispecifics in this space be an opportunity? I mean certainly, we've seen some preliminary data from other competitors, including Pfizer as well too. There seems to, at least again, given the single-arm nature uncontrolled nature of the study, but there seems to be a signal of additive effects between PD-1 VEGF and chemotherapy. So it's something that we certainly take into account. Maybe the one thing that I would just highlight for us is that we do have an existing collaboration with Summit Therapeutics. And specifically, that is at this time directed more towards the Ris-Rez program and exploring combinations of Ris-Rez with [ ivenoscomab ] in lung cancer across both small cell and non-small cell lung cancer as well too. So I think it's something that we would take into account, take into consideration and maybe think about.

Excellent. We'll go next up for a question from Peter Verdult from BNP Paribas.

Just a couple for Hesham, please. Lots of doc excitement around the B7-H3 ADCs, but docs saying it's too early to differentiate and perhaps pointing to some of your competitors having stronger data in patients with brain and liver met. So would love to hear where you agree and disagree with the idea of there being a lack of differentiation right now amongst the B7-H3 players. And then secondly, on development plans for Mo-Rez, just to follow on from James' question earlier on, not on [indiscernible] itself, but look, anyone who was at Madrid, and I'm sure you guys were, it was a tidal wave of ADC data. Lots of different targets, but a lot of them are topo-1 payload. So the idea of, are you really going to do sequential therapy if you failed on topo-1 payload and the idea of acquired resistance? So I would love to get a little bit of thoughts there in terms of how that shapes your development plans.

Yes. Peter, thank you very much. Let me start off first with the question around Ris-Rez and B7-H3 and the class of agents and differentiation as well too. I think first and foremost, we probably need to rebaseline in kind of where we are today. And where we are today is we've dosed more than 1,100 patients across our development program, the GSK global development program. And then Hansoh has 2 positive Phase III studies out of 2 Phase III trials that have read out data across second-line small cell lung cancer and across osteosarcoma. So those are facts that we could start with. I think, certainly, the data that we've seen at least from our own small cell lung cancer experience, seems to also give us confidence in the translatability of those results moving forward as well too. With regards to differentiation, I think probably maybe just it's helpful, because I called it out during the data presentation as well too, I think it's helpful that maybe if we can go back to the slide specifically with the subgroups. Because I know you touched on, for example, patients with either brain mets or liver mets. I think it's a good one to maybe just look at in the context of the data itself from across the ARTEMIS-008 trial. And specifically, in one of the defined subgroups, about maybe 17% of patients that were actually recruited into the study had brain metastases at baseline. And the hazard ratio for overall survival in that segment of patients was 0.36. So I think from that standpoint, certainly, we feel pretty comfortable in terms of the drug's effects, not only systemically, but also in patients with brain mets at baseline. So I think that's probably important to touch on. With regards to differentiation relative to other agents in the class, I think really when you think about -- and we'll touch on this with Mo-Rez as well too, when you think about physicians, physicians always think about 2 things. They think about efficacy and the type of benefit patients are experiencing, but also tolerability and safety as well too. We've touched on ILD, which I think certainly across the class has been variable, including with other types of platforms. So I think maybe that's something that we have to take into account is, maybe not all linker payloads, topo-1 payload platforms, are created equal. I think it's one thing that we need to consider. And when you look at, for example, the incidence of ILD across our own global development program that was presented at ESMO, 4% all grades, 0.9% Grade 3 or greater. So that's the safety side of it. In terms of efficacy, I think we've also touched on at least the data from the second-line small cell ARTEMIS-008 study. Median OS, 18.5 months, when it's benchmarked either to other competitor trials or existing standard of care in that setting with immune cell engagers as well too. So I think probably certainly the data, the clinical data will be a key driver of decision-making for physicians. And I think that at least as you look at the class as well too, safety will become another key differentiator. And I think over time, no doubt, as we continue to evaluate and assess biomarkers, translational endpoints in other tumor types, this is something that will no doubt become a key part of how physicians make choices, along with combinations, combination partners. A good example of that, for example, is as we're moving into front-line small cell lung cancer, we're considering 3 different opportunities. One, which is the now, combinations with PD-L1; two, looking at combinations with bispecifics; and then three, of course, looking at combinations with immune cell engagers. And I think that will be equally important for physicians as they make choices moving forward. In regards to Mo-Rez, I think you touched on, I think, effect, which is there's been an explosion of antibody drug conjugates in gynecologic malignancies. I think we have to all acknowledge that and be grounded in it. And again, like I said, I actually think that that's a good thing for patients from that standpoint. I think at the end of the day, I think physicians are going to use the same criteria. They're going to use [indiscernible] and efficacy. I think when we look at across a number of different classes of agents, whether it be Trop2, whether it be looking at other B7-H4s, whether it be the CDH 6 class or others, certainly, safety is going to be a question. It's going to be a question whether or not there is, for example, some that come with ocular toxicity, some that come with ILD, some that come with stomatitis. Those are all key variables that we'll take into account, and that's what they tell me when I speak to them. The second really will be the efficacy. And I think we've seen a variation in the efficacy as well too in the performance. Now we don't know if that's related to internalization of the target or the antigen itself. We don't know if there are maybe some slight differences in the topo 1-based payloads or not. But I think one of the things that we saw over the weekend was, no doubt, these ADCs are certainly evolving the environment within the tumor. You probably saw the data that was presented from the Mo-Rez Phase I study. What you saw in that certainly is it was inducing some immunological changes within the tumor microenvironment as well too. We'll continue to learn about that. But I guess, probably what I'm saying is typically across the entire ADC class, we've seen response rates range between 40% to 60% or 65%. Mo-Rez is delivering a 62% objective response rate. It is in the upper tier of that class. And I think that's something that's important to anchor to as well too, at least in platinum-resistant ovarian cancer. And I think for us, again, continued work on biomarkers, translational endpoints over time to continue to better assess whether or not there's any additional ways to optimize benefit-risk, is something that we're going to continue to evaluate and look at.

From Seamus Fernandez at Guggenheim.