Incyte Corporation (INCY) Earnings Call Transcript & Summary

We're going to get started. Thank you, everyone, for joining us here in Berlin. And there are many more of you that are online and welcome to the solid tumor update that we're having at ESMO 2025. We're very excited about -- 2 programs that we're going to talk about today. We're going to focus on 2 solid tumor programs. Our TGF-beta receptor II, PD-1 bispecific and our KRAS G12D inhibitor. Data for both programs was presented here at ESMO. One of them was presented on Friday. The other one was peresneted earlier today. We will be making forward-looking statements and let me walk you through the agenda that we have from today. We have 3 members of our team that will walk you through the biologic rationale for our bispecific. Patrick Mayes, our CSO, will do that. Ekaterine Asatiani, Head of Early Development. Will talk about the 2 programs of the 2 data sets for TGF-beta and G12D and Steven Stein, our Chief Medical Officer, will walk here about the future plans for these 2 programs. We'll have plenty of time for questions, and we'll be able to address as many of those as you have. So we're going to focus on 2 programs, but equally important is we're going to focus on 2 tumor types today for the purpose of this update. For our TGF-beta receptor II, PD 1, we're going to focus on MSS colorectal cancer. As you know, this is 80%, 85%, maybe sometimes 90% of the patients with colorectal cancer continues to be an acute medical need because it doesn't respond to PD-1 inhibitors through checkpoint inhibitors. In fact, 4 trials were done in the early days of checkpoint inhibitor development in these patients and the response rate was [ 0 in 3 ] of the trials and 2% in another one of the studies. This patients present very frequently with liver metastases, like it happens with metastatic colorectal cancer. And the biology, and Patrick will walk you through some of this is heavily enriched for TGF-beta. In addition, some of the more recent immunotherapies that have been tried in this patient population have also been largely successful, particularly, and I bring your attention to this and Eka will talk about it, particularly for patients that have liver metastases, which are, of course, more than half the patients. The second tumor of interest for today is pancreatic adenocarcinoma, PDAC for our G12D program. We recognize this remains a very competitive area of drug development is increasingly competitive. G12D is the most common mutation in this patient population. And importantly, these patients do have a worse prognosis than wild-type patients, and that's becoming very clear now as we're focusing on the development in this population. Now I would highlight that there is no [ therapy 12D ], not only none of them are approved, but there's no G12D inhibitor in pivotal trials in pancreatic cancer today. There's a window of opportunity for us to move in an accelerated way for this disease with a G12D inhibitor. Very important, as you think about first-line therapy in patients with pancreatic cancer is the ability to combine a G12D inhibitor with chemotherapy. This is not just about the activity of the molecule as a single agent, but the combinability with both main types of chemotherapy in this disease, nab-paclitaxel and modified FOLFIRINOX. You need to be able to cover both in order to address the entire PDAC population in first-line therapy. And we're moving in that space and Eka will give you an update there. Just to walk you real quick about the framework that we use to make decisions for this 2 program and other programs, but for the 2 programs we're talking about today. The first part is obviously to establish single-agent activity. You've seen during this meeting, and you'll get more data today about the single-agent activity of TGF-beta bispecific and the KRAS G12D inhibitor. So that part, and you've seen the safety profile, we're very pleased with. So that part is almost done. These are single agent. They have single-agent activity and they're tolerable at the recommended doses for expansion. We need to demonstrate earlier response. We have that data for TGF-beta bispecific and Eka will show it. We are following the patients in the 12D program to establish what the durability of the responses are. The third part is to combine, and as I mentioned, standard of care in both cases, that would be chemotherapy of the TGF-beta receptor 2 bispecific will be FOLFOX-bevacizumab. We've done that work. Eka will walk you through it. And for our G12D inhibitor, I mentioned 2 types of chemotherapy. That work is being completed as we speak. So we're moving this in that direction. And the fourth thing we did is, okay, where is the most acute medical need? Where can we have the biggest impact for patients and over time for the business, and that is in first-line in combination with chemotherapy. So that's the area of focus for us for these 2 programs. We're not ruling out other investments in other areas, but those are the 2 areas that we're really going to have a more intense focus. So with that, I'm going to stop here. Patrick Mayes can come up and walk us through the biology and how we designed our bispecific and why is a unique approach to address TGF-beta biology, which arguably is the second most important mechanism ofmune tolerance from tumors other than PD-1/PD-L1 assays. Eka will follow with the updates on the clinical data for both the TGF-beta program and the 12D.

Okay. So I'm going to overview our first-in-class bispecific antibody targeting TGF-beta R2 and PD-1. We'll refer to this as [ INCA33890 ]. So this is what we're going to discuss. I'll take you through a bit of the importance of TGF-beta in the solid tumor microenvironment, why it is such a potent immunosuppressive factor and why we believe targeting this factor is going to be so important in these tumor types. And then I'll tell you a bit about the fundamentally different approach we've taken at Incyte in targeting this biology, why what we're doing is distinct from what others have tried in this space before. I'll show you a bit of preclinical data, but I'll refer you back to a presentation we made at AACR 2023, which is a much more comprehensive characterization of the molecule. So we prefer there to the full profile of the molecule, and then Eka will walk you through the clinical data. So TGF-beta is a potent immunosuppressive factor in solid tumors. It acts directly on T cells. It binds to T cells and it inhibits their function and their proliferation. You can see this in the graph on the left-hand part of the slide here in blue is T cells that have been induced to proliferate, increasing concentration of TGF-beta blunt that proliferation and inhibit that from happening. We can take T cells and we can treat them with a PD-1 antibody, as shown in red, PD-1 induces proliferation of T cells, induces their activation. TGF-beta is a dominant factor, right? Even in the presence of a PD-1 antibody, TGF-beta inhibits the proliferation of those cells. So it speaks to the importance of TGF-beta and even in the setting of a PD-1 antibody. In the solid tumor microenvironment, high levels of TGF-beta are associated with an immune excluded phenotype. This is where immune cells are present in the tumor, but they're excluded from direct contact with tumor cells. Instead they're stuck in the tumor stroma, they're unable to form productive synapses with tumor cells and elicit that antitumor immunity. So what we know is that the immune-excluded phenotype in addition to high levels of TGF-beta are associated with PD-1 nonresponse in the solid tumor microenvironment. So together with [ Tempus ], we looked at TGF-beta biology across solid tumors. This is an analysis of 16 different solid tumor types that we looked at. We looked at 2 different factors in this particular plot that we're showing here on the bottom right. First, TGF-beta R2 expression on the X-axis. And then we looked at a TGF-beta gene signature that's associated with T cells. This is on the Y-axis. And these 2 factors we looked at in various solid tumors, we can see a high enrichment score for TGF-beta across solid tumors, in particular, MSS colorectal is highly enriched for TGF-beta biology. So because of the importance of this biology, multiple attempts have been made at targeting this pathway in solid tumors. None has yet to be successful clinically. And you can bucket these approaches into 2 broad categories as to how they've been engineered. First is agents which target the receptors directly. So you have TGF-beta R2. It forms a hetero complex of TGF-beta R1, and that's how the signaling occurs intracellular. Antibody approaches have been attempted targeting TGF-beta R2, monoclonal antibodies have failed toxicity. Likewise, small molecule inhibitors of TGF-beta R1inhibiting the kinase domain, which signals downstream have been tried and have failed because of toxicity associated with the approach. TGF-beta is an important factor in normal tissues around the body and it's, I think, the narrow therapeutic index associated with broad potent inhibition systemically. So more recent approaches have worked upstream of the receptor to try to minimize the toxicity associated with broad inhibition. These approaches can be characterized as agents which target the processing of ligand -- or the engagement of ligand with receptor, either using a track or a monoclonal antibody. These approaches can be characterized as being partial inhibitors of TGF-beta. This is what gives them the therapeutic index necessary to be able to dose in humans, but this partial inhibition profile has yet to be successful in terms of eliciting efficacy in cancer. So the approach we've taken is different. It's distinct from what others have tried here. We're taking a cell-targeted approach where we are targeting TGF-beta R2 on tumor-infiltrating lymphocytes and potently and completely inhibiting that signal on those cells, thus having full activity on the cell type of interest and avoiding the systemic toxicity associated with pathway inhibition. So how have we achieved this cell-targeted approach? We have generated a 1-by-1 bispecific antibody, and we're utilizing a dock and block mechanism of action here. So the first thing we did was to engineer a very high affinity PD-1 binding arm for this antibody. This binds to and inhibits PD-1 and all PD-1 positive cells in the body. We then engineered and tuned the TGF-beta R2 arm in a way that it allows for potent and complete inhibition of TGF-beta R2 only in the context when the PD-1 arm of the antibody is read out. No inhibition of TGF-beta signaling is -- occurs on cells that do not have PD-1 expression, thus avoiding the toxicity associated with broad TGF-beta inhibition in the body. An example of this selectivity shown here on the graph on the left, this is an example of a cell line that has TGF-beta R2 expression but no PD-1 expression. The control for this experiment is in blue. This is a monoclonal antibody targeting TGF-beta R2. It inhibits completely the signaling through TGF-beta pathway via phospho SMAD, whereas the bispecific shown in red has almost no signaling inhibition in this context. If you look then, this is an isogenic system. The only change being made in this cell is the introduction of PD-1 expression on the right. And the control looks the same. You see potent complete inhibition of TGF-beta signaling, whereas in this context, the bispecific antibody has complete inhibition of the pathway even to a greater extent than the monoclonal. So in summary, we have a potential first-in-class bispecific here. This is a context-dependent inhibitor of TGF-beta signaling in tumor-infiltrating lymphocytes. We believe there's strong rationale for this agent in tumor types where TGF-beta is highly enriched. This includes a number of tumor types where immune checkpoint inhibitors have not been approved and are not used, such as ovarian cancer and MSS colorectal cancer, which we'll talk about today. But we believe this also has a PD-1 better approach and potential in tumor types where ICI is approved, PD-1 is used, and this provides the opportunity to expand the responsiveness in those tumor types as well. So I will stop here and pass it over to Eka.

Thank you, Patrick. So I'll now switch to clinical data that was presented on Friday, as Pablo mentioned. So this is a schematic of a Phase I trial that we presented. Dose escalation was done in selected tumor types from 100 milligram to 1,500 milligram given every 2 weeks IV. We also tested 900 milligram every 4 weeks. We arrived at 3 recommended doses for extension and randomized patients with selected tumor types. Those were selected based on the TGF-beta signature that Patrick mentioned. The biggest enrichment was for colorectal cancer, the biggest group was patients with MSS colorectal cancer in this expansion. In parallel, we also tested selected tumor types in combination regimens with focus with standard of care relevant for colorectal cancer, such as FOLFOX-bevacizumab, FOLFIRI bevacizumab, bevacizumab and cetuximab. Now dose escalation with 900 milligram has been completed, and now we are enriching and enrolling more patients in expansion cohorts, particularly with FOLFOX and bevacizumab to support the safety database Phase III trial. So this is baseline demographics and characteristics of 260 patients that were treated in monotherapy cohort as of July 25. This is pretty mature data set. 52 patients are still ongoing. Majority have discontinued. It should be noted that discontinuations due to treatment-related adverse events were extremely rare, only 4.6% of patients discontinued due to adverse events. The other thing I want to note here is that it's a very advanced patient population. As you can see on the bottom of the slide, there is 35 months from initial diagnosis, multiple lines of therapies were given to these patients is median of 3 and range of 1 to 9. Again, biggest set is in MSS colorectal with 114 patients treated with this trial. Safety summary. So we escalated doses up until 1,500 milligrams without DLTs, 1,500 milligram exceeded maximum tolerated dose. There was 1 DLT of myocarditis, but there are also other severe immune-related adverse events of those endocrine and CNS events in later cycles at this dose level, and we stopped enrolling patients at the dose level and extended dose levels below. So 300, 600 and 900 were extended, and that's the data set I want to focus and present now. It should be noted that treatment-related adverse events and Grade 3 events were very rare. This compares very favorably to approved checkpoint inhibitors. There were especially 900-milligram group, large group, 110 patients, we had very few grade 3 events in single-digit percentages, very few serious treatment-related adverse events. There were few treatment delays and only 2 patients discontinued due to adverse events. When we look at the immune-related adverse events as reported by investigators, again, 5% Grade 3 events. We also looked at infusion reactions. There were some infusion reactions of Grade 4, 2 events, one leading to discontinuation, other one with rechallenge. Those happened at lower doses. Once we evolve training of the sites on infusion rates and pre-medications, secondary prophylaxis for premedication, those events reduced, and there were no Grade 3 or higher events at 900 milligram. A bit more granular view of safety profile with treatment-related adverse events with decreasing frequency and 5% cut. Again, few events. Grade 3 treatment-related adverse events are mostly to skin toxicities in rash and [ floridus ]. Also one transient transferase increase in 900 milligram. Here, we have a slide describing pharmacokinetics and antidrug antibodies. Very favorable and typical, I would say, for bispecific antibody. There is some treatment-mediated drug distribution at the lower doses. We did have antidrug antibodies in 78% of patients, but that did not affect PK. So it did not affect concentration at 900 milligram in large cohorts of patients that we have. We also did analysis of ADA versus adverse events and ADA versus efficacy, and there was no correlation there. It did not also correlate with infusional reactions. We did paired biopsies and evaluated, among other things, CD8 cells, and there was increase in cycle to day 15 on treatment and this extent of this increase correlated with the efficacy -- in reached for the efficacy in responders versus nonresponders. And finally, efficacy data. So here, we focus on MSS colorectal cancer. We have 105 patients treated and evaluable at [ RPDs ] at those 3 dose levels that I listed before. Now this was heavily pretreated patient population. So 93% of those patients received this treatment as third line and beyond. So they had 2 prior lines of therapy. 70% had active liver metastases, and those were large active metastases. I will show a couple of representative cases. 16 of those patients responded. And most surprisingly, I must say for myself personally as that has never been reported before that those patients with liver metastases also had responses. So 9 out of 16 had active liver metastases and 7 had no liver metastases. There was no correlation of dose versus efficacy that we could tease out from here, which is, again, not surprising for immunotherapy. Duration of treatment was 7.3 months. And I'll show you on the next slide, swimmer plots for patients for responders basically. And you can see that these are confirmed responses in majority of the patients. The bottom swimmer plot is not confirmed, but ongoing, so confirmable. And there is another one that discontinued before confirmation, but the rest of them are confirmed responses. Now I should note here also that there is one patient that discontinued early due to actually low-grade troponin increase and continue to have response for 1 year, so 8 months beyond discontinuation. But quite striking response in this patient. This is a 72-year-old gentleman with Stage IV MSS colorectal cancer with multiple visceral metastases, liver, lung, also bone metastases. This patient had prior FOLFOX-bev and FOLFIRI treatment, was treated at low dose at 300 milligram and achieved PR at 28 weeks and confirmed at 32 weeks and remained on treatment for another year. And you can see how big these liver mets are. These are not small liver lesions. These are clinically relevant but clinically active big lesions that show shrinkage. So we have this target lesion measured and also their nontarget bigger lesions, which also shown. Another case, again, a patient with prior 2 lines or actually 4 lines of therapy here, FOLFOX-bev and FOLFIRI and some additional, including investigational agents treated at 900 milligram, achieved PR at 8 weeks and confirmed at 16 weeks and currently still on treatment 10 months plus. Again, big liver lesion shrinking. I think it's very illustrative of what we have observed in those patients. Now we also saw responses and efficacy in other tumor types where we would not expect immunotherapies to work. Among them in patients that have been previously treated with immunotherapies. As you can see here in blue, we have patients that have received prior checkpoint inhibitors, we have responders among head and neck patients and as well as non-small cell lung cancer patients, pretty impressive responses in ovarian cancer patients. And we have also marked the patients here that have very low PD-L1 staining of less than 1 CPS score. And amongst those patients as well, we have some responders. So this data kind of increases our confidence that this biology that Patrick described has proof of concept -- strong proof of concept with clinical efficacy in tumor types that would otherwise not respond to immunotherapy and also coupled with very favorable safety profile. So based on this, we started combinations relevant for earlier lines of therapy in colorectal cancer. So we have now cleared in dose escalation cohort of patients for bevacizumab and FOLFOX-bevacizumab, bevacizumab and cetuximab. We are currently enrolling a larger cohort, focusing on FOLFOX and bevacizumab in preparation of supporting Phase III trial with additional safety data. Combination looks good. There is no overlapping toxicity that we could tease out from patients treated so far. So to conclude, 900 milligram is selected as a recommended dose. It has favorable PK profile. There is very little effect of ADA or actually no effect of ADA on PK at this dose level. There are responses observed in MSS colorectal cancer patients, including ones with active liver metastases. And currently, we are preparing a Phase III trials that Steven is going to describe in [indiscernible]. I will switch now to KRAS G12D inhibitor. The key takeaways here, so we all know that KRAS is one of the most common driver ontigenes relevant in solid tumors. And G12D is the most relevant one and most common one, isoform [indiscernible] . We have the inhibitor, which is potent and selective. It's on and off inhibitor. And hopefully, today, I'll be able to convince you that we have a potential to be the first selective G12D selective therapy for G12D mutated pancreatic cancer. So KRAS G12D in cancer, again, it's a molecular that belongs to KRAS proteins, molecular switches that control multiple signaling cascades that promotes cell proliferation and survival. This isoform, G12D is most common mutation, more relevant in pancreatic cancer with close to 40% of patients having G12D mutation, also in non-small cell lung cancer and 15% of colorectal cancer. Now G12D converts poor prognosis. In terms of response to chemotherapy, also overall survival and when compared to wild-type -- KRAS wild type, but also other G12 isoforms. But compared to other KRAS mutations, it converts to prognosis. So this is a data that was presented by Patrick's Group in 2024. We have G12D inhibitor, 734, which binds KRAS protein in inactive and active forms as they switch to pocket. And it's a picomolar concentration, so it is potent. It is also selective with more than 80-fold selectivity in different assays. And you can see some of them on the right side of the slide. We have presented a number of preclinical data in xenograft in syngeneic tumor models, and this was all in the poster at AACR in 2024. So I will today present clinical data that was actually presented from scientific podium this afternoon. So this is from this Phase I trial where we conducted dose escalation in G12D mutated tumors from 200 milligram to 1,600 milligram QD. We also tested twice a day regimen with 600 milligram twice a day. In parallel, we did additional exploration in PD cohort at 2 dose levels, 601,000 with cleared biopsies. We did some effect work, which enabled us to administer drug now with food. And we selected 2 dose levels, 600-milligram and 1,200 milligram and randomized patients with these 2 dose levels in the patients, the largest cohort we have is in pancreatic cancer and also colorectal cancer and additional work is ongoing in other tumor types. And then we further enriched 1,200 milligram, which we selected out of those 2 RD expansions and focusing on second-line pancreatic cancer now. We also tested combinations with chemotherapy regimens for pancreatic cancer, both commonly used chemotherapy regimens, Gem Abraxane and FOLFIRINOX. We also actually combined with TGF-beta receptor 2 PD-1 bispecific and currently, the first dose level is enrolling. So this is a patient disposition and baseline characteristic as of August 1 cutoff. We have enrolled 138 patients on monotherapy. The largest group here, again, is pancreatic cancer with 83 patients. followed by colorectal cancer. Now this is less mature data set. So more than half of the patients are still ongoing. 75 patients are still on treatment. I should note here that there are no toxicity-induced dose discontinuations. So no patient has discontinued treatment due to adverse events. Very heavily pretreated population with multiple prior lines of therapy. So focus here again is on pancreatic cancer. And as you can see in this data set in these 83 patients treated at various dose levels, only 13 were second-line patients, majority were third line and plus. Safety profile. No DLTs were observed. We arrived at all the way up to 1,600 milligrams without any DLT. MTD was never reached. However, we stopped dose escalation and decided to expand 600 and 1,200 milligrams based on emerging PK and PD data that I will dose here in a minute. So once again, I would like to mention that no patients discontinued treatment due to adverse events. The most common treatment-related adverse events leading to dose reductions were nausea, decreased appetite and fatigue. Majority of adverse events were Grade 1 and Grade 2, and I will show it on the next slide in a little more granular way. So these are treatment-related adverse events with frequency of 5% and above in decreasing incidents. As you can see, the [indiscernible] toxicity is on top of the list, but majority of those cases are Grade 1. So half of them are Grade 1. Very few Grade 2 and Grade 3 events, including nausea, diarrhea and vomiting and fatigue, which are the common ones. We also looked actually at our database, looking for myelosuppression, skin toxicity, et cetera. They are isolated cases, but there is no signal. We do not observe it in long term. Here, there is a PK profile, focusing on 2 dose levels, 600 and 1,200. So both dose levels at steady state cover IC95, more consistently at the 1,200-milligram higher dose. And also when we looked at ctDNA change from baseline in pancreatic cancer patients, there was deeper and quicker reduction at higher dose. So that's why we selected 1,200 milligram, the dose to move forward. And these deep reductions in ctDNA also correlated with clinical response. We actually did this, which we were complemented today. We did it real time during the dose escalation, and it really helped us with the dose escalation and selection of the dose. And here is efficacy slide, so waterfall plots. And I'm going to take time to walk through this slide slowly, so indulge for a minute. So it's a busy slide, and we show a lot of things here to be as transparent as possible. So we have waterfall plot with scans in 50 patients. But we include in our denominator all patients that were treated and discontinued treatment or had at least 1 scan. So 54 patients included in the denominator. Second, majority of those patients received treatment as third line plus. There are only 9 patients that were treated as a second line in this data set in these 54 patients. And third point I want to make is that majority of those patients only had one scan and many of them are still ongoing. 27 out of those 54 only had one scan. And we know from other G12X or G12C and D inhibitors that actually responses can take place on a second and subsequent scans. So with all of this said, we have 34% response rate and high disease control rate of 86%. Illustrative case here. So this 69-year-old gentlemen with Stage IV pancreatic cancer was diagnosed in last year 2024, extensive mets, liver, lung peritoneal, which usually do worse, previously progressed on FOLFIRINOX and received this treatment at 1200 milligram, received treatment without interruptions, have deep reduction of disease, including the primary tumor, which is actually harder to treat. Usually, the primary pancreatic lesions do not respond as well. So this patient has a large reduction of pancreatic mass and was achieved on -- was assessed then on 2 subsequent scans and had a confirmation of PR on 20 to 24 weeks and as of treatment still continues on treatment as of today, still continues on treatment. So in conclusion, we have a molecule that has manageable toxicity profile quite tolerable. We have selected a dose now based on ctDNA, PK coverage of the target. And we have very promising early clinical efficacy still confirming durability of responses. We have combined with 2 different chemotherapy regimens. Gem Abraxane and modified FOLFIRINOX. Gem Abraxane has finished dose escalation. We're expanding. And for FOLFIRINOX, we are still waiting for completion of the DLT evaluation period for the last couple of patients, and we plan to expand this as well. With this, I will pass on to Steven to discuss next one.

Thank you, Eka, Patrick, Pablo. The reason I'm standing here, it's important in that you can see we're about to go into the next phase of development. So I'll outline the why behind that, and then we'll invite everybody up here for Q&A. So just to go back to the framework that Pablo gave you upfront and reset it based on the data you just saw. So if you look at the framework in terms of establishing single-agent activity and a safety profile, both for TGF-beta and for KRAS G12D, you saw the efficacy signals given to you in the monotherapy data safety profile. For the TGF-beta, you saw mostly IR-related as and a DLT at 1,500, which is not the dose we'll be taken forward. And for the 12D profile, you saw the GI safety profile. In terms of monotherapy, single-agent activity for both, you saw what is striking single-agent activity for TGF-beta in microsatellite colorectal cancer, particularly for the liver metastasis, which is unprecedented in terms of IO therapies and for 12D, I'll just paraphrase to discuss them today at the session, we said remarkable activity and potentially the best single-agent activity seen in PDAC with a 12D directed agent to date. Durability of response demonstrated with TGF-beta R2 was becoming common with biotherapies is once patients respond, those responses are very long, and you saw duration of therapy for the majority of patients greater than 24 weeks. One could argue that for the KRAS 12D, we still have to wait a bit longer to see durability of response, which is obviously what we will be doing before triggering a registration program. The profile in compliance with standard of care is ongoing now, as Eka alluded to, but we cleared the initial safety hurdles in terms of DLTs and very importantly, for the 12D compound, we've demonstrated that both for Gem Abraxane and for modified FOLFIRINOX. Why is that important? If you look at real-world use of these regimens in first-line pancreatic ductal adenocarcinoma, it's about 50-50. So we feel it's very important to be able to combine potentially with both chemotherapy regimens. And then lastly, this is a clear medical need in very large tumor types, quantitative. These are enormous problems across the world in massive unmet need in terms of microsatellite colorectal cancer and pancreatic ductal costs in them. Let's go back to microsatellite stable colorectal cancer. It is one of the most common cancers seen worldwide. It's a leading cause of cancer there. In fact, if you look at the United States, Western Europe, Japan, there's nearly 2 million people diagnosed with colorectal cancer and about 400-mile north of 100,000 of those of Stage 4 metastatic patients. Unfortunately, the long-term survival for patients with Stage 4 metastatic microsatellite stable colorectal cancer, dismal, 16% 5-year survival rate. And as both Pablo and Eka pointed out, immunotherapies in microsatellite colorectal cancer little to no activity and particularly in patients with liver metastasis that's become almost a clinical marker of the lap of irresponsive. Hence, that very important signals seen in patients with liver metastasis. The standard of care in the first-line setting in terms of chemotherapy is FOLFOX-bev or FOLFOX EGFR but the FOLFOX-bev regimen is used regardless of RAS status, whether you're mutant or wild-type, regardless of the sidedness of the tumor, whether you left or right sided. The EGFR combo use mostly elected tumors and is more commonly used in Europe. FOLFOX response rates for the chemotherapy regimens of the 50% to 60% range, PFS, 8 months, top end 11 months and overall survival 30 months. Speaking to the massive unmet medical need in population. As Patrick showed you, TGF-beta expression is extremely high in the tumor microenvironment to microsatellite colorectal cancer and is probably outside of PD-L1 expression, the dominant marker of T cell and responsiveness. So there's an opportunity here to establish a novel regimen in first-line microsatellite colorectal cancer that build on the current most common standard of care, which is VEGF combined with the chemotherapy, FOLFOX-bev. It's a broad population, independent of a status independent of sidedness and reminder that about 70% of patients have liver metastasis. In terms of by diagnosis, this covers 85% of the population with the other 15% made up of the microsatellite high, some BRAF mutant tumors and then obviously, other biomarkers like HER2. But 85% would be covered by this regimen potentially. So where are we? We are durable single-agent activity, a manageable target profile demonstrated by Eka's data set in late-line microsatellite patients. The responses are observed both in patients with and without liver metastasis. And the profile thus far provides an opportunity for a combination in first-line microsatellite colorectal cancer with the standard care chemotherapy with some ongoing safety work going. To be clear, we're planning the initiation of it's peak now of a Phase III registrational program in early 2026, in first-line microsatellite metastatic colorectal patients in combination with standard of care. We're aligned with regulators on the schema and the primary endpoint of progression-free survival. So turning to pancreatic ductal adenocarcinoma. This is probably the most RAS-addicted cancer with no targeted therapies for a specific mutation, KRAS mutant 12D patients with a rapidly progressive disease with extremely high mortality, less than a 10% 5-year survival. Again, in Western Europe, North America and Japan, 210,000 patients of which greater than 90% carrier expectation of which 40% of those had a 12D mutation. First and second line metastatic treatment is limited to combination of single-agent hemotherapy. But because of the severity of the disease and the lack of tolerability of the regimens upfront in these stations, most patients do not make it to second line regimens. Chemotherapy is associated with many Grade 3 and 4 toxicities, particularly minor suppression as well as neuropathies. And the care standard, as I said upfront, is argued between Gem Abraxane versus modified FOLFIRINOX probably split 50-50 with some regional differentiation there. Response rates in the 20% to 40% range, medium PFS 5.5 to 8 months and an overall survival of 8.5 to 11.7 months with those chemotherapy regimens. So where are we with our KRAS 12D in pancreatic ductal adenocarcinoma. Again, a solid proof of concept as speakers said today, remarkable activity and maybe probably the best data seen in the 12D mutated patients to date. 12D mutations are known to carry worse prognosis in other patients with a manageable safety profile in the heavily pretreated population and an ongoing enabling work with the chemotherapy combinations that are important. And again, both Gem Abraxane, as modified FOLFIRINOX. We feel we have the first potential target therapy for KRAS-mutated PDAC patients. We'll continue to do the enabling safety work and continue to evaluate the durability of response with this immature based on the data set that Eka showed you today. And we'll be aligning the regulators on the registrational program pending those will be going into registration in first-line PDAC in combination of both chemotherapy regimens also in 2026. I'll summarize again, large patient population by size significant unmet need, certainly in the cancer setting, probably the most significant unmet need in terms of microsatellite colorectal cancer and pancreatic adenocarcinoma. And again, to reiterate the importance, for us to go into first line to make the most difference for patients in this condition, and we feel that's an important strategic choice that we've made. The TGF-beta bispecific, the efficacy and safety data support that advancements the novel regimen in the broadest population in combination with FOLFOX and bev. And to reiterate, we will be initiating a Phase III program in early 2026. The 12D, probably a little behind, but single-agent activity demonstrated a manageable safety profile, the ongoing enabling work with safety and then the durability that needs to be finally assessed before we trigger the program, but the intent is to start that program as soon as those milestones are achieved and to be the first potential targeted therapy with KRAS mutated 12D patients in pancreatic carcinoma. With that, I'll ask Pablo come up and the other 2 speakers to join us all on the program. Up here, there are about 100 people online. We will first take questions in the room and then move to the online.

Thank you. Patrick, Eka, Steven. Mr. Evan, please.

Hi there. Evan Seigerman, BMO Capital Markets. So -- and as of last year the focus of bureaucrat was really on the CDK2 inhibitor, gynecological cancers. This year you're talking about G12D and TGFb. And these data are fantastic. I don't want to deny that. But it seems that the effort is a bit inconsistent. How should I square how you're thinking more broadly about solid tumor development in that 1 year, we're talking about 1 topic next year, we're focused on G12D in pancreatic cancer.

So you're correct. Last year our focus was CDK2. CDK2 inhibitor program was obviously -- and we generated efficacy data in ovarian cancer. That program, I would say, is today the most advanced CDK2 inhibitor in development. And we're developing, as we pointed out, in the ovarian cancer. I think that the approach that we're taking with these 3 programs just follow the science, quite honestly. In CDK2, we generated data, some baby breast cancer, the work hasn't stopped, but it hasn't been the main focus. Early on, it was obvious that we had responses in a lot of stable disease with CDK2 in platinum-resistant ovarian cancer. So we agreed to chase that signal, which is what we're doing. We've got another combination with bevacizumab, and our goal in the long run is plug-in sensor going harsh. So basically maintenance up to first line. We think in patients post-chemo bed that need maintenance, which is long duration of therapy for 12, 15, 18 months, in oral molecularly targeted therapy with an extension, people could have a big advantage over the intense competition that continues to emerge in our implant cell. Now on these 2 programs, we once again follow science. For TGFb, as Patrick explained, we had a hint that the biology gave us about the imports of the TGFb pathway in particular MSS colorectal in others. But early on, we saw responses in MSS colorectal. We accelerated development there. We enrolled more than 100 patients. We have a very strong efficacy signal and we've done the combination. I think where the KRASG12D inhibitor was the most straightforward, right? We knew where to go from the beginning. In fact, even though it was clear which patients to go after, the pancreatic signal emerge faster than the others. We are doing some work in colorectal. I think we have a unique advantage in EGFR treated colorectal cancer because the ability to combine with cetuximab, which I think some of our competitors facing a difficulty. So I gave you a very long answer. I think what we're doing with these programs is, we start with some scientific principles at the beginning. And then in a disciplined and thorough way, we chase science-driven signals and we make decisions based on the emerging data, and we'll continue to do that. We're now going to go everywhere all at once. We are being deliberate in how we take these opportunities in order to use -- to have disciplined use of capital, but at the same time, trying to address some medical needs. Michael?

Michael Schlitt with Guggenheim. On the TPOR, you programmed, I know, discussed and today talked about the GI portability on new molecule and one of the others. And just wondering if you could share your insights -- or your insights from new combination work, but if you're doing chemotherapy.

So let's focus on GI, and there was a comment today, the discussion about trispecific, I'm not sure why you focus on that, but maybe you can talk about a little bit more granular on what we're seeing in one.

1,200 milligram is what we're moving forward and enriching with additional patients. We have systemic toxicity, majority grade-1 cases are manageable with Incyte REA and [indiscernible]. There are very few grade-2 cases, no discontinuations due to this.

Combination with chemo.

Combination with chemo is ongoing. We spoke during our general statement, colorectal result and new deals are severe. We don't have to dose reduce. We don't have to dose reduce chemo, and we do not have the dose revenue, both of these chose [indiscernible].

We have to remember, right, when you look at a certain percentage with a certain grade, toxicity with diarrhea, that person has one day of that grade, we think gets counted automatically there. I think when you go, I think you more granularities and what I always look for is just a continuation in terms of dose interruptions. And from that perspective, we're comfortable that this has proven to be a well tolerated driver in these doses and the combination with chemo, as we pointed out in the presentation, we're about to clear the dose escalation period whether for fair enough team.

Salveen Richter, Goldman Sachs. Could you speak to competitive positioning around your KRAS G12D program. As you noted, there's not much of a second line opportunity versus first line that you have revolution medicine with 2 assets here. So maybe put that in context for us, especially as you think about combining with standard of care.

So KRAS in general with PDAC and KRAS are so far specific inhibitors, obviously, become competitive over the past couple of years. When we look at all the data available, we put in 2 or 3 of the presentations today in the last couple of days. We are convinced that when you look for 12D specific patients, 12D mutated patients, the balance of efficacy and safety that we have is best-in-class. If there's somebody that is comparable, perhaps. But we are very comfortable with the tumor reductions that we're seeing in tolerability and now a second tolerability in combination with chemotherapy. We can combine with both main types of chemotherapy for pancreatic cancer. Let's remember, the GEMNabP and FOLFIRINOX used the 50-50 procedural patients. So if you can cover the entire chemotherapy spectrum with a precisely targeted G12D inhibitor, we think that's going to be an advantage. Now second line, we think that train has left the station. That second line study is ongoing. They're going to have rolling to file next year. We expect that to be positive. But as Stephen pointed out, patient with pancratic cancer, the opportunity really is reduced dramatically in second line. We think that the big opportunity here for patients and for the business is the first line in combination with chemotherapy. So our goal now, as we continue to live to the emerging data, to make sure we're making the right decisions is to move to implement those study, the first-line study as quickly as possible. Now if the data changes over the next 6 months, we will act accordingly. But right now, the plan based on what we have today, is to move as quick as possible to first-line pancreatic therapy. And we think we can be very, very competitive there.

Reni Benjamin from Citizens. Just a question on your framework. When I'm thinking about a listing, I was -- the comparison of other drugs in development, whether it's drugs currently in development or the ones that are already centered. So kind of curious as to when does that get factored in to that one. And then the other is that, I think, Eka, you were mentioning that the MSS, the gene symmetry that we use, they're not just sitting up on CRC. I think you said is utilized in the clinical trial as well. I'm kind of curious how heterogeneous is that gene signature, but was there a correlation response? And could you use it for patients election and reaching patients?

Yes, there is the first one, then Eka and Patrick can answered gene signature. We are constantly monitoring our competitors. And when we look at, let's take the 2 more, I think I explained our positioning is every competitors for G12D pancreatic cancer. Obviously, we're fully aware of witnessing the raise in second line. And we have a chance to compete in first line, and we take out a very competitive profile. And nothing that I saw in the last couple of days changes in my mind, our competitive positioning for G12D inhibitor feedback. I think for first-line MSS colorectal, there's less activity. The way we look at it is we have unprecedented single-agent response in third, fourth line in metastatic colorectal therapy. There's 4 trials in historical evopembo, et cetera. 3 of them had a 0% response rate, 1 of a 2% response rate. We showed 15% response rate to that. Newer immunotherapies in the same context have shown no responses in patients with liver mets. Nick I'll walk you through the data in patients with liver met. So we think relative to other immunotherapies in development in MSS colorectal, we think right now, we have unprecedented single-rig activity. And the combined with chemotherapy has now been standard. When I look at the broader landscape outside of that, there's other entrants in this space. But I think, again, looking at the single agent activity that we've shown in third, fourth line, I would argue we have a best in the disease right now or comparable to some of the best interventions in the disease. And the goal is to execute as fast as possible to go into first line colorectal in combination with chemotherapy. Do you want to address...

That in same definition of MSS colorectal to the question, Andy?

No. It's about the TGF-beta...

So Patrick showed this data, have to elaborate that MSS colorectal, which is basically MSI negative, right? So microsatellite stable colorectal cancer. Both high in TGF-beta signature based on the states that we understands the future as well. So we selected patients with MSS colorectal, extension cohorts based on this data. We have not strained patients for TGFb, which is central computing their MSS stands.

Yes. The question is, can we enrich for any markers that would be associated with response? I think, we're looking at a number of exploratory measures included in that is the TGF Gene Signature. We've got Gene signers associated with T cells specifically, other signatures, other factors within TGF-beta pathway, the blue ligans, the receptor itself. So we're looking at those measures. Data that was shown on Friday in the presentation was also PDL1. So we saw correlation with response in PL1 greater than 1%. So I think that is another marker. Obviously, that's an asset that used. It's there. That was the association of that, something we compete. We just completed far. We may decide to incorporate some of this in some analysis and is tele to be clear, the study will be no e-commerce other than, obviously, patients with certain mutations, wild type right to the left side in MSS colorectal.

Following up on this years equivalent day 90. So just you did see some kind of activity across new KRAS mutant patients and other things that you wouldn't want to exclude those in the Phase III. And then are you continuing to explore some of the other tour types that you showed here or did you haven't shown yet?

Let me take the second part and then we can talk about whether we have across a range of indications. We saw the data that we generated so far. I think it's partly said, it's very intriguing, particularly the ovarian cancer data. I mean, the sponsor is rending about 28% in cancer population, interesting results in head and neck, not unexpected interesting results in non-small cell lung cancer. At this point, we're being very deliberate in how we continue to expand this program. MSS colorectal is an intense focus. We will generate additional data on the tumor types, and we'll make decisions based on that emerging data. But those programs have not been accelerated right now. The second part.

So we have looked at various mutations website right side is clinical and molecular for those responses is novalty responders. What we presented was PDL1 as has to be obviously a significant correlation. We are not excluding any patients that gave us mutation, and that's not planned. We will explain that alternative first-line therapies, which is anything DRAM at the right now this is very small cell.

Eric Schmidt from Cantor. Two questions quickly on the G12D. Maybe you can dive a little bit deeper into Salveen's question. What actually are you trying to solve for with regard to the front-line pancreatic cancer trial out of a world where we do have the KRAS multi-antibiotic is looking to it. You can look for better safety, better efficacy, better convenience, what happening. And then two, maybe I missed it, was there a PFS data from the chief royalty and pancreatic, is that not yet true.

The second real quick. No, the data held mature. We'll have the PFS data over time, and we'll update you all on those results as they emerge. But as Eka mentioned, half the case is only at 1 scan. So we can tell you confident in this period is a tumor shrinkage, the PRs, but we need time to establish durability and that could conceivably, I think it's unlikely based on what we've seen so far. You can see the change our decision-making. What are we trying to solve in first line? So look, I think what our colleagues, as you mentioned, that have done is impressive. However, when you look at the second and third-line data, and as Eka mentioned, we had a very advanced patient population with a very small number of second-line patients in that lateral plot. Their data in third class line was 22% responsive. So we'll see where our response rate lands, but we think we're going to be very competitive and perhaps numerically significantly better than that. So that's point number one. The second is, I think, in part because with the profile of the panRAF inhibitor, when you look at the most recent update, the dose intensive chemotherapy in that combination was 63%, which tells you the compromise in the just of a chemo and they haven't combined with [indiscernible] which as I mentioned, is used by back math population and credit. That's what we're trying to solve. We're trying to develop a G12D inhibitor that can be used for all patients with G12D mutated PDAC, with any chemotherapy and by maintaining the intensive chemotherapy, we expect to overcome resistance, which obviously they try to overcome by the fanout coverage, we drive overcome resistance and maybe get better results. Good turn out to both ideas we're working very well. And then, in my experience, and I think, Arun probably shares this, is that molecular precisely targeted therapies tend to react. But we'll see. I think that's something we'll be following.

Stephen Willey with Stifel. 33890, can you just talk about the levels of TGF beta inhibition that you're achieving at the doses that you move forward for the purposes of expansion? And then maybe just quickly on like KRAS asset. When would we -- when should we be thinking about next update from a timing perspective? And principally, that accretes to single-agent duration of response data, but should we also expect some chemo accompanying that -- at that point of time.