Incyte at ESMO Congress 2025: Strategic Focus on Tumor Programs

On Sunday, 19 October 2025, Incyte Corporation (NASDAQ:INCY) presented its strategic initiatives at the ESMO Congress 2025. The company highlighted its focus on two solid tumor programs, emphasizing innovative treatments and combinations to address unmet medical needs. While promising data was shared, challenges remain in navigating competitive landscapes and regulatory pathways.

Key Takeaways

• Incyte is advancing two major tumor programs: a TGF beta receptor two by PD-one bispecific antibody and a KRAS G12D inhibitor.
• The company plans to initiate Phase 3 trials for both programs in early 2026, focusing on first-line treatments.
• Promising early data for the TGF beta bispecific in MSS colorectal cancer was presented, especially in patients with liver metastases.
• The KRAS G12D inhibitor shows potential as a first-in-class therapy for pancreatic cancer, with a manageable safety profile.
• Incyte is strategically focusing on first-line treatments to maximize patient impact and is monitoring competitive developments closely.

Operational Updates

• TGF Beta Bispecific:

- Completed dose escalation, selecting 900 mg as the recommended dose.

- Ongoing enrollment in expansion cohorts with FOLFOX and bevacizumab.

- Preparing for Phase 3 trials to start in early 2026.

• KRAS G12D Inhibitor:

- Dose escalation conducted, with MTD not reached.

- Exploring 600 mg and 1,200 mg doses based on pharmacokinetic and pharmacodynamic data.

- Testing combinations with gemcitabine/abraxane and modified FOLFIRINOX.

- Phase 3 program in first-line pancreatic cancer scheduled for 2026.

Future Outlook

• TGF Beta Bispecific:

- Phase 3 registrational program to start in 2026 for first-line MSS colorectal cancer, focusing on progression-free survival.

• KRAS G12D Inhibitor:

- Aligning with regulators for a registrational program in first-line pancreatic cancer, targeting 2026.

- Potential to be the first targeted therapy for KRAS mutated 12b pancreatic carcinoma patients.

Q&A Highlights

• Strategic Direction:

- Incyte is committed to following scientific data, accelerating development in promising areas such as MSS colorectal cancer and KRAS G12D mutations.

• Competitive Positioning:

- Management believes their KRAS G12D inhibitor offers a best-in-class balance of efficacy and safety.

• Combination Therapies:

- Ongoing trials combining therapies with chemotherapy show promise, with no dose-limiting toxicities observed.

Incyte’s presentation at the ESMO Congress 2025 underscores its commitment to addressing critical medical needs through innovative therapies. For further details, readers are encouraged to refer to the full transcript below.

Full transcript - ESMO Congress 2025:

Pablo: We’re gonna get started. Thank you everyone for joining us here in Berlin, and, there are many more of you that are online. Welcome to this phone tumor update that we’re having at s one twenty twenty five. We’re very excited about, two programs that we’re going to talk about today. We’re going to focus on two solid tumor programs, our TGF beta receptor two by PD-one bispecific and our KRAS D12P inhibitor.

Data for both programs was presented here at ESMO. One of them was presented on Friday. The other one was presented earlier today. We will be making forward looking statements, and let me walk you through the agenda that we have for today. We have three members of our team that will walk you through the biology rationale for a bispecific.

Patrick Mayes, our CSO, will do that. Then Eka Satyen, our head of early development, will talk about the two programs of the two datasets for, TGF beta and for g 12 d. And Steven Stein, our chief medical officer, will work here on the future plans for this, for these two 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 focus on two programs, but equally important is we’re going to focus on two tumor types today for the for the purpose of this update.

For our TGF beta receptor two by PD-one, we’re going focus on MSS colorectal cancer. As you know, this is, eighty, eighty five percent, maybe sometimes ninety percent of the patients with colorectal cancer, continues to be an acute medical need because it doesn’t respond to PD-one inhibitors through checkpoint inhibitors. In fact, four trials were done, in the early days of checkpoint inhibitor developing in these patients, and the response rate was zero in three of the trials and two percent in another one of the studies. These patients present very frequently with liver metastases like it happens with metastatic colorectal cancer, and the biology and and the patchwork will walk you through some of this is heavily enriched for TGF beta. In addition, some of the more recent immunotherapies have been tried in this patient population have also been largely unsuccessful, particularly and and I bring your attention to this, and then Edgar will talk about it, particularly for patients that have liver metastasis, which are, of course, more than half the patients.

The second tumor of interest for today is pancreatic adenocarcinoma, PDAC, for our g 12 d program. We recognize this remains a very competitive area of drug development. It’s increasingly competitive. C12D is the most common mutation in this patient population. And importantly, these patients do have a worse prognosis than wild type patients.

So that’s becoming very clear now, and we’re focusing on the development in this population. Now I would highlight that there is no fair C12D, not only none of them are approved, but there’s no C12D inhibitor in pivotal trials in pancreatic cancer today. There’s a window of opportunity for us to move, in an accelerated way in this, for this disease, with a G12B inhibitor. Very important as you think about first line therapy in patients with pancreatic cancer is the ability to combine a G12B inhibitor with chemotherapy. This is not just about the activity of the molecule or single agent, but the combined ability with both main types of chemotherapy in this disease, nab paclitaxel and modified for ferranox.

You need to be able to cover both in order to address the entire peanut population in first line therapy, and we’re moving in that space. Anika will give you an update there. Just to, walk you real quick about the framework that we use to make decisions for this two program and other programs, but for the two programs we’re talking about today. The first part is only to establish single agent activity. You’ve seen, during this meeting, and you’ll get more data today about the single agent activity about TGF beta bispecific in the KRAS g twelve beta.

So that part, and you’ve seen the safety profile. We’ve we’ve we’re very we’re very pleased with. So that part is almost done. These are single agents. They have single agent activity, and they’re tolerable at their recommended doses for expansion.

We need to demonstrate our earlier response. We have that data for TGF beta bispecific, and ECA will show it. We are following the patients in the 12T 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 will be chemotherapy and the TGF beta receptor two. By specific, will be falafelix, bevacizumab.

We’ve done that work. Rebecca will walk you through it. And for our detailed being, I mentioned two 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, what 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 other focus for us for these two programs. We’re not ruling out other investments in other areas, but those are the two areas that we’re really gonna have a more intense focus. So with that, I’m gonna stop here.

Patrick Mays, can come up and walk us through the biology and how we designed our bispecific and why is it unique approach to address TGF beta biology, which arguably is the second most important mechanism to resume tolerance from tumors other than PD-one, PD-one access? Edgar will follow with the updates on the clinical data for both TGF beta program and the.

Patrick Mayes, CSO, Incyte: So I’m going to overview our first in class, bispecific antibody targeting TGF beta r2 and PD-one. We’ll refer to this as INCA-eight 90 for now. So this is what we’re gonna discuss. I’ll take you through a bit of the importance of TGF beta in the solvent tumor microenvironment, why it is such a potent immunosuppressive factor and why we believe targeting this factor is is gonna be so important in these tumor types. And then I’ll 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 twenty twenty three, which is a much more comprehensive, characterization of the molecule. So refer there to the full profile of the molecule, and then Ecky 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 inhibits their function and their proliferation.

You can see this in the graph on the left hand of the slide here. In blue is T cells that have been induced to proliferate, increasing concentration of TGF beta blunt that proliferation, inhibit that from happening. We can take T cells and we can we can treat them with a PD one antibody as shown in red. PD one induces proliferation of T cells, induces their activation. TGF beta is a dominant factor, right?

Even in the presence of a PD-one 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-one antibody. Within 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 and and elicit that antitumor immunity. So, what we know is that the immune exfoliated phenotype in addition to high levels of TGF beta are associated with PD-one nonresponse in the solid tumor microenvironment. So together with TEGF beta, 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 two different factors in this particular plot that we’re showing here on the bottom right.

First TGF beta r two 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 two factors we looked at in various solid tumors. You can see a high enrichment score for TGF beta for all solid tumors.

In particular, MSS colorectal is is highly enriched for TGF beta biology. And 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 two broad categories as to how they’ve been engineered. First is agents which target the receptors directly.

So we have TGF beta r two. It it forms a hetero complex with beta r one, and that’s about how the signaling occurs in each of the cellular. Antibody approaches have been attempted targeting TGF beta r two monoclonal antibodies that failed due to toxicity. Likewise, small molecule inhibitors of TGF beta r one inhibiting 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 and vicious systemic.

So more recent approaches have worked upstream of the receptor, to try to minimize the the toxicity associated with broad inhibition. These approaches can be can be characterized as agents which target the processing of ligand or the engagement of ligands, with receptor, either using a trap or monoclonal antibody. These approaches can be characterized as being partial inhibitors of TGF beta-six. This is what gives them the therapeutic index necessary to be able to dose in humans, but 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 one by one bispecific antibody, and we’re utilizing a docking block, mechanism of action here. So the first thing we did was engineer a very high affinity p d one binding arm for this antibody.

This binds to and inhibits p d one and all p d one positive cells in the body. We then engineered and tuned the TGF beta r two arm in a way that it allows for potent and complete inhibition of TGF beta r2 only in the context when the PD-one arm of the antibody is prebiotic. No inhibition of TGF beta signaling occurs on cells that do not have PD-one expression, thus avoiding the toxicity associated with broad TGF beta inhibition environment. 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 with no PD-one 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 SNAT. 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 line expression on the right.

The control looks the same. You see potent and complete inhibition of TGF beta signaling, whereas in this context, the bispecific antibody has complete inhibition to pathway even to a greater extent than the monoclonal antibody. 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-one better approach and potential in tumor types where ICI is approved. PD-one 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 Edgar.

Eka Satyen, Head of Early Development: 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 one trial that we presented. Dose escalation was done in selected tumor types from one hundred milligram to fifteen hundred milligram given every two weeks IV. We also tested nine hundred milligram every four weeks.

We arrived at three recommended doses for extension and randomized patients with selected tumor types. Those were selected based on the TGF beta signatures that Patrick mentioned. The biggest, enrichment was for colorectal cancer. The biggest group was, patients with MSS colorectal cancer in this extension. 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, porphyribevacizumab, bevacizumab and cetuximab.

Now dose escalation with nine hundred milligram has been completed, and now we are enriching and enrolling more patients in expansion cohorts, particularly with Tolpox and bevacizumab to support the safety data base Phase three trial. So this is baseline demographics and characteristics of two sixty patients that were treated in monotherapy cohort as of July 25. This is pretty mature dataset. Fifty two patients are still ongoing. Majority have discontinued.

It should be noted that discontinuations due to treatment related adverse events were extremely rare. Only four point six percent 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 thirty five months from initial diagnosis. Multiple lines of therapies were given to these patients with median of three and range of one to one.

Again, biggest set is in MSS colorectal with hundred and fourteen patients treated with this one. Safety summary. So we escalated doses up until fifteen hundred milligrams result, DLTs. Fifteen hundred milligram exceeded maximum tolerated dose. There was one DLT of myocarditis, but there were 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 that dose level and expanded dose levels below.

So three hundred, six hundred, and 900 were extended, and that’s the dataset I want to focus and present now. It should be noted that treatment related adverse events and grade three events were very rare. This compares compares very favorably to approved checkpoint inhibitors. There were, in especially nine hundred milligram group, large group, 110 patients, we had very few grade three events in single digit percentages, very few serious treatment related adverse events. There were few treatment delays, and only two patients discontinued due to adverse events.

When we look at the immune related adverse events as reported by investigators, again, five percent rates to events. We also looked at infusion reactions. There were some infusion reactions of grade four, two events, one leading to discontinuation, other one with rechallenge. Those happened at lower doses. Once the above training of the sites on infusion rates and pre medications, secondary prophylaxis for pre medications, those events reduced, and there were no grade three or higher events at nine hundred milligram.

A bit more granular view of safety profile with treatment related adverse events is decreasing frequency and five percent. Again, few events. Rates with treatment related adverse events are mostly skin toxicities, in rash and pruritus. Also, one trends in alan alanotransferase increase in nine hundred milligram. Here we have a slide describing, pharmacokinetics and anti drug antibodies.

Very favorable and typical, I would say, for bispecific antibody. There is some treatment mediated distribution. At the lower doses, we did have anti drug antibodies in seventy eight percent of patients, but that did not affect PK. So it did not affect concentration at nine hundred 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 nutritional reactions. We did paired biopsies and evaluated among other things CD eight cells, and there was re increase in cycle two day fifteen on treatment. And this extent of this increase correlated with the efficacy enriched for the efficacy, in responders versus nonresponders. And finally, efficacy data. So here we focus on MSS colorectal cancer.

We have hundred and five patients treated and available at RPDs at those three dose levels that I listed before. Now this was heavily pretreated for patient population. So ninety three percent of those patients received this treatment as third line and beyond. So they had two prior lines of therapy. Seventy percent had active liver metastases, and those were large active metastases.

I will show a couple of representative cases. Sixteen 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 nine out of sixteen had active liver metastases and seven 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 seven point three months, And I’ll show you on next slide, swimmer plots for patients is for responders, basically.

And you can see that these are confirmed responses in major rotiflu 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 this one patient that discontinued early due to, actually low grade, troponin increase, and continue to have response for one year, so eight months beyond, discontinuation. But quite striking response in this patient, this is a 73 year old gentleman with stage four MSS colorectal cancer with multiple visceral metastasis, liver, lung, also bone metastasis.

This patient had prior FOLFOX bed and for theory treatment, was treated at low dose at three hundred milligram and achieved PR at twenty eight weeks and confirmed at thirty two 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, that show show shrinkage. So we have this, target lesion measured, and also there are non target bigger lesions which also shown.

Another case, again, a patient with prior two lines actually, lines of therapy here, FOLFOX BEV and FOLFIRi and, some additional, including investigational agents, treated at nine hundred milligram, achieved PR of eight weeks, and confirmed at sixteen weeks, and currently is still on treatment ten 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. Amongst them, in patients that have been previously treated with immunotherapies, as you can see here in in blue, we have patients that have received prior checkpoint inhibitors.

We have responders among, head and neck patient and as well as non small cell lung cancer patient. Pretty, intensive responses in ovarian cancer patients. And we have also marked the patients here that have very low PD L1 staining of less than one, CPS score. And amongst those patients as well, we have some responders. So this data kind of increases our, confidence that these biologists 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, for puribetuzumab, bevacizumab, and cetuximab. We are currently enrolling a larger cohort, focusing on FOLFOX and bevacizumab in preparation of supporting phase three trial with additional safety data. The combination looks good. There is no overlapping toxicities that we could tease out from patients treated so far.

So to conclude, nine hundred 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 metastasis. And currently, we are preparing, phase three trials that, Steven’s gonna describe in them.

I will switch now to KRAS g twelve d inhibitor. The key takeaways here, so we all know that KRAS is one of the most common driver oncogenes, relevant in solid tumors, and g four b is the most relevant one and, and most common one, from an isopoine n one c. We have, 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 g twelve d selective therapy for g twelve d mutated pancreatic cancer.

So KRAS g twelve d in cancer, again, it’s a molecular it belongs to KRAS proteins, molecular switches that control multiple signaling cascades, that promote cellular proliferation and survival. This isoform g twelve d is, most common, mutation, more relevant in pancreatic cancer. It’s close to forty percent of patients having, g twelve d mutation, also in non small cell lung cancer, and fifteen percent of colorectal cancer. Now g four d confirms full prognosis. In terms of response to chemotherapy, also overall survival, and when compared to wild type, KRAS wild type, but also other g twelve, g twelve isopoams.

When compared to other KRAS mutations, it confers for for prognosis. So this is a data that was presented by Patrick’s group in, 2024. We have G12D inhibitor seven thirty four, which binds KRAS protein, in inactive and active, forms as they switch to pocket. And it’s it’s a it’s high comolar 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 number of preclinical data in xenografts and chimps syngenic 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 one trial where we, conducted dose escalation in g 12 d mutated tumors from two hundred milligram to sixteen hundred milligram q d. We also tested twice a day regimen with 600. In parallel, we did, additional exploration in PD cohort at two dose levels, six hundred and, 1,000 with tiered biopsies.

We did some food effect, work, which enabled us to administer drug now with food. And we selected two dose levels, six hundred milligram and twelve hundred milligram, and randomized patients with these two dose levels. In these 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 with FARSOR enriched twelve hundred milligram, which we selected out of those two RDE extensions and focusing on second line pancreatic cancer now. We also tested combinations with, chemotherapy regimens for pancreatic cancer, both commonly used chemotherapy regimens, gemmaprexane and porphyrinops.

We also actually combined with TGF beta receptor two PD-one bispecific, and currently, the first dose level is enrolling. So this is a patient disposition and baseline baseline characteristics as of August 1, couple. We have enrolled a hundred and thirty eight patients on monotherapy. The largest group here, again, is pancreatic cancer with eighty three patients, followed by colorectal cancer. Now this is less mature data set, so more than half of the patients are still ongoing.

Seventy five patients are still on treatment. I should note here that there are no toxicity induced dose discontinuation. So no patient has discontinued treatment due to other adverse events. Very heavily, pretreated population with multiple prior prior lines of therapy. So focus here, again, is on pancreatic cancer.

And as you can see in this dataset, in these eighty three patients, treated at various dose levels, Only thirteen were second line patients. Majority were third line and plus. Safety profile. No DLTs were observed. We arrived at, holds rate up to, 1,500 sixteen hundred milligrams without any DLT.

MTD was never reached. However, we stopped dose escalation and decided to, extend six hundred and twelve hundred milligrams based on emergent PK and PD data that I will pose you in a minute. So once again, I would like to mention that no patients discontinued treatment due to treat, adverse events. The most common treatment related adverse events leading to those distinct, reductions were, nausea, decreased appetite, and fatigue. Majority of adverse events were, grade one and grade two, and I will show it on the next slide in a bit more granular way.

So these are treatment related adverse events with a frequency of five percent and above in decreasing, in decreasing, incidence. As you can see, GI toxicity is on top of the list, but majority of those cases are grade one. So half of them are grade one. Very few grade two and grade three events, nausea, diarrhea, vomiting, and fatigue, which was a common one. We also looked actually at our database, looking for myelosuppression, skin toxicity, etcetera.

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 two dose levels, six hundred and twelve hundred. So those dose levels at steady state cover I c 95, more consistently at twelve hundred 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 twelve hundred milligram, the dose to move forward. And this deep reduction in ctDNA also correlated to this clinical response. We actually did this, which we 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 slides of waterfall plots, and I’m gonna take time to walk through this slide, slowly.

So indulge me for a minute. So it it’s a it’s a busy slide, and we show a lot of things here that should 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 one scan. So 54 patients included in the denominator. Second, majority of those patients received treatment and as third line plus.

There are only nine patients that were treated as a second line in this dataset, in this fifty four 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. Twenty seven out of those fifty four only had one scan. And we know from other g twelve x or g twelve c and d inhibitors that actually responses can take place on a second and subsequent scans. So with all of this said, we have thirty four percent response rate and high disease control rate of eighty six percent.

Illustrated case here. So this 69 year old gentleman with stage four pancreatic cancer was diagnosed in last year, 2024, extensive NASH, liver lump peritoneal, which usually do worse, previously progressed on Fofrinox and received this treatment at twelve hundred milligram. Received treatment result 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 this patient has a large reduction of pancreatic mass, and was achieved then on two subs was assessed then on two sub subsequent scans and had a confirmation of PR on twenty twenty four weeks and as of treatment still continues on 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 two different chemotherapy regimens, gemabraxane and, modified fopirinox. Gemabraxane has finished dose escalation we’re extending.

And for fulpironolx, we are still waiting for completion of the DLT evaluation period for the last couple of patients, and we plan to extend this as well. With this, I will pass on to Steven to discuss next ones.

Steven Stein, Chief Medical Officer: Yeah. Thank you, Edgar, Patrick, Pablo. Reason I’m standing here is 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 and a. So just to go back to the framework that Pablo gave you upfront and and reset it based on the data you just saw.

So if you look at the framework in terms of establishing single single agent activity and the safety profile, both for TGF beta and for KRAS12D, you saw the efficacy signals given to you and the monotherapy data safety profile. For the TGF beta, you saw mostly IR related AEs and a DLT at fifteen hundred, which is not the dose we’ll be taking forward. And for the twelve d profile, saw the GI safety profile. In terms of monotherapy single agent activity for both, you saw what is striking single agent activity for for TGF beta in microsatellite colorectal cancer, particularly for the liver metastasis, which is unprecedented in terms of IO therapies. And for twelve d, I’ll just paraphrase the discussion today at the session, you said, you know, remarkable activity and potentially the best single agent activity seen in PDAT with the 12 directed agent to date.

Durability of response demonstrated with TGF beta r two must become common with IO therapies is once patients respond, those responses are very long and you saw duration of therapy for the majority of patients greater than twenty four weeks. One could argue that for the KRAS12D, we still have to wait a bit longer to see durability of response, which is obviously what we will be doing before triggering the registration program. The profile when combined with standard of care is ongoing now as I alluded to, but we cleared the initial safety hurdles in terms of DLTs. And very importantly, for the twelve d compound, we’ve demonstrated that both for gemmobraxane and for modified for foreigners. Why is that important?

If you look at real world use of the regimens in first line pancreatic ductal adenocarcinoma, it’s about fifty fifty. 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 quantitatively. These are enormous problems across the world and massive unmet need in terms of microsatellite colorectal cancer and pancreatic ductal carcinoma. 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 death. In fact, if you look at, The United States, Western Europe, Japan, there’s nearly two million people diagnosed with colorectal cancer and about four hundred little north of one hundred thousand of those are stage four metastatic patients. Unfortunately, the long term survival for patients with stage four metastatic microsatellite stable colorectal cancer is dismal sixteen percent five year survival rate. And as both, Pablo and Echo pointed out, immunotherapies in microsatellite colorectal cancer have little to no activity and particularly in patients with liver metastasis that’s become almost a clinical marker of the lack of IR responsiveness, hence that very important signal seen in patients with liver metastasis.

The standard of care in the first line setting in terms of chemotherapy is FOLFOX PIV or FOLFOX EGFR. But the FOLFOX PIV regimen is used regardless of RAS status, whether you’re mutant or wild type, regardless of the sardines of the tumor, whether you’re left or right sided. The EGFR combo is used mostly for left sided tumors and is more commonly used in Europe. Ballpark response rates for these chemotherapy regimens of the fifty percent to sixty percent range, PFS eight months, top end eleven months and overall survival thirty months, speaking to the massive unmet medical need in this population. As Patrick showed you, TGF beta expression is extremely high in the tumor microenvironment and microsatellite colorectal cancer and is probably outside of PD L1 expression, the dominant marker of, you know, T cell, unresponsiveness.

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, BolfoxFib. It’s a broad population independent of RAS status, independent of sardines, and reminded that about seventy percent of patients have liver metastasis. In terms of by diagnosis, this covers eighty five percent of the population with the other fifteen percent made up of the microsatellite high, some BRAF mutant tumors and then obviously other biomarkers like HER2. But eighty five percent would be covered by this regimen potentially. So where are we?

We have durable single agent activity, a manageable tolerability profile demonstrated by ECA’s dataset 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 combination in first line microstabilized colorectal cancer with the standard of care chemotherapy with some ongoing safety work going. To be clear, we’re planning the initiation of the SPEEP NOW of a Phase three registrational program in early twenty twenty six with first line microsatellite metastatic colorectal patients in combination with standard of care. We’ve aligned with regulators on the schema and the primary endpoint of progression free survival.

So turning to pancreatic ductal endocarcinoma. This is probably the most RAS addictive cancer with no targeted therapies for the specific mutation KRAS mutant 12b patients. It’s a rapidly progressive disease with extremely high mortality, less than a ten percent five year survival rate. Again in Western Europe, North America and Japan, two hundred and ten thousand patients of which greater than ninety percent carrier RAS mutation, of which forty percent of those have a 12b mutation. First and second line metastatic treatment is limited to combination of single agent chemotherapy.

And because of the severity of the disease and the, lack of tolerability of the regimens upfront in these patients, most patients do not make it to second line regimens. Chemotherapy is associated with many grade three and

Pablo: four

Steven Stein, Chief Medical Officer: toxicities, particularly myelosuppression as well as neuropathies. And the case standard as I said upfront is argued between gemobraxane versus modified fulphuronate probably split fifty-fifty with some regional differentiation there. Response rates in the twenty percent to forty percent range, median PFS 5.5 to eight months and overall survival of eight point five to eleven point seven months with those chemotherapy regimens. So where are we with our KRAS12D in pancreatic ductal adenocarcinoma? Again, a solid proof of concept, as the speaker said today, remarkable activity and maybe probably the best, data seen in the 12D mutated patients to date.

12D mutations are known to carry a worse prognosis than other patients with a manageable safety profile in the heavily pretreated population and then ongoing enabling work with the chemotherapy combinations that are important and again both gemmobraxane plus modified porphyrinos. We feel we have the first potential targeted 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 dataset Echo showed you today. And we’ll be aligning with regulators on the registrational program, pending those will be ongoing into registration in first line PDAC in combination with 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 needs in terms of microsatellite colorectal cancer and pancreatic carcinoma.

And again, to reiterate the importance for us to go into first line to make the most difference for patients in this condition. We feel that’s an important strategic choice that we’ve made. The TGF beta bispecific, the efficacy and safety data support that advancement, the novel regimen in the broadest population in combination with FOLFOX and BEV. And to reiterate, we will be initiating a Phase three program in early twenty twenty six. The 12D probably a little behind, but single agent activity demonstrated 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 for KRAS mutated 12b patients with pancreatic carcinoma. With that, I’ll ask Pablo to come up and the other two speakers to join us on the program. Up here, there are about 100 people online. We’ll first take questions in the room and then move to the online.

Pablo: Thank you, Patrick, Edgar, Steven. Starting the wrong place.

Evan Seigerman, BMO Capital Markets: Hi there. Evan Seigerman, BMO Capital Markets. So at ESMO last year, the focus of your event was really on your CDK two inhibitor, the gynecological cancers. This year, you’re talking about g twelve d and TGF beta. And these data are fantastic.

I don’t wanna, you know, deny that. But it seems that the effort’s a bit inconsistent. How should I swear how you’re thinking more broadly about solid tumor development in that one year, we’re talking about one topic. The next year, we’re focused on g twelve d in pancreatic cancer.

Pablo: So you’re correct. Last year, our focus was CDK two. CDK two inhibitor program was obviously ahead and we generated efficacy data in ovarian cancer. That program, I would say, is today the most advanced CDK two inhibitor in development, and we’re developing, as we as you pointed out, in ovarian cancer. I think that the approach that we’re taking with these three programs is follow the science, quite honestly.

In CDK two, we generated data, some data in breast cancer, That 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 CDK two in platinum resistant ovarian cancer. So we agreed to chase that signal, which is what we’re doing. We’ve done another combination with bevacizumab, and our goal in the long run is platinum sensor. Maintenance up to first line.

We’re thinking patients post chemo bed that need maintenance, which is long duration of therapy for twelve, fifteen, fifteen, eighteen months, an oral molecularly targeted therapy, with an excellent safety profile could have a big advantage over, the intense competition that continues to emerge in ovarian cancer. Now with these two programs, we, once again, follow science. For TGF beta, as Patrick explained, we had the hints that the biology gave us about the importance of the TGF beta pathway, in particular, MSS colorectal and others. Early on, we saw responses in MSS colorectal. We accelerated development there.

We enrolled more than a 100 patients. We have a very strong efficacy signal, and we’ve done the combination one. I think for the KRAS two twelve, the inhibitor was most straightforward. Right? We knew where to go from the beginning.

Know, in fact, even though it was clear which patients to go after, the pancreatic signal emerged 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 are things on rectal fibrosis may have difficulty. So I’ll give you a very long answer. I think what we’re doing with these programs is we establish some scientific principles in the beginning, and then in a discipline and far away, we chase science driven signals, and we make decisions based on the emerging data.

And we’ll continue to do that. We’re not gonna 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 the medical need. Michael?

Evan Seigerman, BMO Capital Markets: Thanks. Michael Schmidt with Rubinstein. On the t 12 b program, I know you discussed and today talked about the GI probability on on the molecule and and one of the others. And just wondering if you could share any insights or insights from your combination work that you’ve been doing with chemotherapy. So

Pablo: let’s focus on GI, and there was a comment too there discussing about diarrhea specifically. I’m not sure why they focused on that, but maybe you can talk about a little bit more granular what we’re seeing in the Twelve

Eka Satyen, Head of Early Development: milligram is yeah. Twelve hundred milligram is what we’re moving forward and enriching with additional patients. We have seen GI toxicity, majority grade one cases, manageable with antidiarrhea and antiemetics. There are very few breakthrough cases. No discontinuations due to this.

Pablo: Combination with chemo?

Eka Satyen, Head of Early Development: Combination with chemo is ongoing. We spoke during oxymoraxin was tolerated without any DLTs or severe. We don’t have the dose reduced. We don’t have the dose reduced chemo, and we do not have the dose reduced the the the those that we chose both in.

Pablo: We have to remember. Right? When you look at a certain percentage with a certain grade toxicity that’s diarrhea, that person has one day of that great diarrhea that gets counted automatically there. I think, Radhika, I think, gave you more granularity is and what I always look for is dose discontinuations, dose reductions, dose interruptions. And from that perspective, we’re comfortable that this is proven to be a well tolerated drug at this doses.

And the combination with chemo, as we pointed out on the presentation, we’re about to clear the dose escalation period for the forfeitinof geminatazone.

Salveen Richter, Goldman Sachs: 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, but you have Revolution Medicine with two assets here. So maybe put that in context for us, especially as you think about combining with standard of Keva.

Pablo: So KRAS in general with pan RAS, pan KRAS and and, you know, so far specific inhibitors, obviously, have become extraordinarily competitive over the past couple of years. When I when we look at all the data available, including two or two or three of the presentations today in the last couple of days, we are convinced that when you look for 12 d specific patients, 12 d 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, the tolerability, and now, as Zika pointed out, the tolerability combination with chemotherapy. We can combine with both main types of chemotherapy and pancreatic cancer.

Let’s remember that GenNav and Lofrinox are used in about fifty fifty percent of the patients. So if you can cover the entire chemotherapy spectrum with a precisely targeted g twelve b 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 gonna have probably on file next year.

We expect that to be positive. But as Steven pointed out, patients with pancreatic cancer, the opportunity really is reduced dramatically in second line. We think that the big opportunity here for patients and for the business is in first line and commercial team up with. So our goal now, as we continue to monitor 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 six 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 pediatric combination with pediatric. And we think we can be very, very competitive there.

Ren Benjamin, Citizens: Ren Benjamin from Citizens. Here’s a question. One, in your framework, one thing that thought was missing is the comparison of other drugs in development, whether it’s drugs, you know, currently, in development or the ones that are already established. So I’m kind of curious as to when does that get factored in to that breakdown. And then the others, I think, Edgar, you were mentioning that the MSS gene signature that was used to not just identify and assess CRC.

I think you said it is utilized in clinical trials. But I’m kind of curious, you know, how heterogeneous is that gene signature represent a correlation with response, and could you use it

Pablo: for patient selection or in reaching patient selection? Let me address the first one, then echo Andrew or Patrick in regards to GeneSignature. We are constantly monitoring our competitors. And and when we look at let’s take this two more times. I think I explained our positioning is a big competitor for G12P pancreatic cancer.

Obviously, we’re fully aware of who’s leading the race in second line. We have a chance to compete in first line, and we figured out a very competitive profile. And nothing that I saw in the last couple of days changes, in my mind, our competitive positioning, for t 12 t to inhibit our MPD back. I think for a first line, MSS colorectal, there’s less activity. The way we look at it is we have unprecedented single agent response in third or fourth line in the test for rectal therapy.

There’s four trials, the historic of Neva, Pembroke, etcetera. Three of them had a 0% response rate, one had a 2% response rate. We showed fifteen percent response rate to that. Newer immunotherapies in the same context have shown no responses in patients with liver mets. Nick, I walked you through the data in patients with liver mets.

So we think relative to other immunotherapies in development in the sense for erectile, we think right now we have unprecedented single agent activity, and the combined ability with chemotherapy has not been established. 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 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 and combination of the chemotherapy. Chemotherapy.

He wants to address the gene signal problems.

Eka Satyen, Head of Early Development: Definition of MSS colorectal is that’s what the question was, Andy.

Pablo: No. It’s about the TGF beta

Eka Satyen, Head of Early Development: You give it. No. So Patrick showed this data. Have to elaborate on that that MS is colorectal, which is basically MSI negative. Right?

So microsite microsatellite stable colorectal cancer falls high in TGF beta signature based on the assays that we used and they they published literature as well. So we selected patients with MSS colorectal extension cohorts based on this data. We have not screened patients for TGF data signature in clinical trial. We just centrally confirm their MSS studies.

Patrick Mayes, CSO, Incyte: Yes. The question is, can we enrich for any markers that would be associated with response? Think We’re looking at a number of exploratory measures included in that is the TGF beta gene signature. We’ve got gene signatures associated with T cells specifically, other gene signatures, other factors within TGF beta pathway, the ligands, the receptor itself. So we’re looking at those measures.

Data that was shown on Friday in the presentation was also PD L1 levels. So we we saw correlation with response in PD L1 greater than 1%. So I think that is another marker. Obviously, that that’s an asset that’s used. It’s there.

That was an association that we saw in some particular problem.

Pablo: Let me just complete the thought. We may decide to incorporate some of this in such analysis in the study. But to be clear, the study will be no homers other than, obviously, patients with certain mutations. Wild type, right and left side, MSS colorectal.

Evan Seigerman, BMO Capital Markets: Right. That’s absolutely good. Thanks for having us on all the data. Following up on the the CRC program with

Pablo: eight

Evan Seigerman, BMO Capital Markets: ninety. So just to confirm, you did see some kind of activity across maybe patients and other things that we wouldn’t wanna exclude those in the phase three. And then are you continuing to explore some

Pablo: of those tumor types that you showed here or maybe

Mark Graham, TD Cowen: you haven’t shown yet?

Pablo: Let me take the second part, and then we can talk about whether we have across a range of mutations. We show the data that we generated so far. I think it’s it’s it’s fair to say it’s very intriguing, particularly the ovarian cancer data. I think the response rate is ranging about twenty eight percent, in the heavily pituitary ovarian 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’ll 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 map. But those programs are not being accelerated right now. The second part.

Eka Satyen, Head of Early Development: So we we have looked at various mutations, left sided, right sided, clinical, and molecular characteristics of those responders versus nonresponders. What we presented was and the system validation. We do not see any significant clinical otherwise. We are not excluding any patients with KRAS mutation, and that’s not planned. We will exclude patients that have alternative first line therapies, which is NSI, and this is a very small cell phone.

Pablo: Eric. Thank you. Pablo, Eric Schmidt from Cantor. Two questions quickly on the g twelve d. Maybe to 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 in a world where we do have the KRAS multi inhibitor that seemingly is looking terrific.

You can look for better safety, better efficacy, better convenience, what have you. And then two, maybe I missed it. Was there PFS data from the g twelve d in pancreatic? Is that not yet mature? So second, real quick.

No. The data, I’m not sure. We’ll have the PFS data over time, and we’ll we’ll update you all with those results as they emerge. But as as Ezekah mentioned, half the patients only have one scan. So we can tell you’re confident in the experience of tumor shrinkage.

There’s PRs, but we need time to establish durability. And and, you know, that could conceivably I think it’s unlikely based on what we’ve seen so far, but you conceivably changed our decision making. Why are we doing so on first line? So look. We I think what what our colleagues, as you mentioned, have done is impressive.

However, when you look at the second and third line data, and as Vikram mentioned, we had a very advanced patient population. You know, there was a very small number of second line patients in that waterfall plot. Their data in third plus line was twenty two percent response rate. 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 of the profile of the pan RAS inhibitor, when you look at the most recent update, the dose intensive chemotherapy in that combination was sixty three percent, which tells you they’re compromised in the dose of the chemo, and they haven’t combined with fulphirinox, which as I mentioned, is used by about half the population of pancreatic cancer. That’s what we’re trying to solve. We’re trying to develop a g twelve b inhibitor that can be used for all patients with with g twelve b mutated PDAC, with any chemotherapy. And by maintaining the intensity of the chemotherapy, we expect to overcome resistance, which obviously they try to overcome by the panelist coverage. We try to overcome resistance and maybe get better results.

Good turnout that both ideas were working really well. And then in my experience, and I think the room probably shares this, the molecular precisely targeted therapies tend to wean out. But we’ll see. I think that’s something we’ll we’ll be following.

Ren Benjamin, Citizens: Yeah. Hi, thanks. It’s from Stifel. For eight ninety, 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 the KRAS asset.

When would we when should we be thinking about next update from a timing perspective? And presumably, includes the single agent duration of response data, but should we also expect some chemo coming data at that point as well? Thanks.

Pablo: Yeah. Let me take the second one real quick, and then Edgar Patrick can address the TGF beta target engagement question. Honestly, we haven’t decided. It will be over the next few months. And and as we accelerate these decisions and and implement these studies, we’ll give you clarity where we are with the data.

But, you know, looking at the next few months, I can’t come up with the right venue. So it may have to be a stand alone update to tell you where we’re with the response rate, what’s the duration of response, and, obviously, over time, we’ll have efficacy with the chemotherapy. I think the safety of the chemotherapy does pretty much clear. I think we need a week or two to make sure the FOLFIRINOX combination clears the official DLT period, but then, obviously, we’ll we’ll generate longer term follow-up. And we’ll we’ll provide updates in a timely fashion over the next few months.

You want to address the TK?

Patrick Mayes, CSO, Incyte: Yeah. The target occupancy, I mean, I guess a couple of things. One, we were achieving full occupancy of both on even the three hundred milligram dose. So I think the dose response you saw there were saturated early. The 900, I think, is the PK, is the lag of ADA effects at the nine hundred dose.

So I think it’s part of the rationale there. Because of the precise mechanism here, it’s challenging, right, to get a real definitive measure of inhibition in tumor infiltrating lymphocytes into a microenvironment where there’s high level of TGF beta, high levels of shirmer cells which have the same factors. So we’re measuring it. It’s I would say it’s a qualitative assessment. It’s tough to get numbers on that.

But I’ll refer you back to the PK plot where we had a line there. It was EC90 for an MLR assay and very well above that MLR EC90 coverage at the dose selection going forward. So based upon our preclinical measures and the modeling that we did, we think we’re more than enough in giving both PD-one and TGF beta at these sales goals.

Mark Graham, TD Cowen: Mark Graham from TD Cowen. Maybe as you’re clearing safety shortly for the G12D combo, is that really all you need to finalize this design and we can start the process of finalizing the regulators and initiating the Phase 3s? Or do do you think you need a a pretty good sense of, you know, what the efficacy looks like of that combination and the patient number that, you know, might be needed to get to there?

Pablo: So let me let me see if I can clarify this because I think it’s a very important point, right, because of the competitive intensity in this case. We’re not standing still waiting for this data. Okay? The team is preparing protocols, preparing interaction with FDA. We are moving forward.

What we’re doing is tracking the data and see where the air falls out and see if we need to change that decision. It’s possible. So the planning for first line pancreatic cancer study is ongoing. The interaction with FDA will happen in the near term. We’ll show the data, show the design.

The thesis that combining a twelve t inhibitor with chemotherapy in pancreatic cancer, frozen on pancreatic cancer, I I don’t need a lot of data to follow that signal. Right? I mean, it’s a it’s a it’s a relatively obvious thing to do when you think about it. But, obviously, we want safety. We want a good number of patients.

We wanna show the FDA that we’ve done our diligence, and we wanna see the durability of the cohort that Eka showed to confirm that we have indeed a good durability of of those responses. All that is going in parallel. And once we have the green light, we’ll accelerate the process.

Mark Graham, TD Cowen: And and then maybe on the, TGF beta program, you know, as the slides mentioned, you with full box and for theory, are you it depends on center preferences. But I think the slide said you’re moving forward with full box combination in first line. Is that am I over interpreting that you’re not going to do first line full period? And then is there some sort of synergistic or safety reason that’s driving that that decision?

Eka Satyen, Head of Early Development: So we we we tested both combinations just in in planning. Both were combinable. Both were tolerable. We chose the as its most commonly used regimen in first line. You don’t think?

Yeah.

Pablo: It was just to keep the study simple, to be honest with you. But we could do both if necessary. And, you know, if we decide to go on second line, obviously, as you know, you switched. I wasn’t used in first line. We used in second line, so we could have we will have that data if necessary.

Okay. Anyone in the room?

Eka Satyen, Head of Early Development: Anyone online? Okay. Great. So we will switch to some of

Salveen Richter, Goldman Sachs: the online question. So the first is regarding the d twelve b program, specifically. Can you remind me can you

Eka Satyen, Head of Early Development: remind us of how many

Salveen Richter, Goldman Sachs: of the responses for d twelve b program at six hundred and twelve hundred doses were confirmed versus unconfirmed? We’ve gotten this question a couple times online.

Pablo: So it’s it’s an excellent question. Let me let me point out a couple of things before I give you the the exact number. So one of the challenges with the dataset, and we’re it covered very transparency presented data, was it’s a relatively mature dataset. Half the patients had only one scan. In other words, you’ve had one scan.

There’s no way you can be confirmed by definition, no matter how good the response is. So we looked at the subset of patients that had two scans or discontinued due to progression or any other factor. So that’s the truly evaluable patient population. Right? Either two scans or discontinued before the second scan.

Those are confirmed responses, two are confirmable, meaning there are PRs that are still on therapy to be confirmed, and there are three stable diseases, two at twenty nine percent, one at twenty two percent tumor shrinkage, but obviously it can become PRs. What it tells you is the response rate that we presented and all the information is in the waterfall chart. We have the number of scans at the bottom. We have the hours telling you which one is ongoing. All the information is presented clearly, but obviously, an immature dataset needs time for the confirmations to come in.

And that’s part of the data we’ll continue to follow to continue the decision making process that I described earlier.

Salveen Richter, Goldman Sachs: Great. I know, Akhay, you spoke about this briefly during the presentation, but given the high ADA rate with, eight nine zero, what gets you confident that this

Eka Satyen, Head of Early Development: will not impact long term efficacy? Well, confidence comes from the number of patients we treated at nine hundred milligram, and we have assessed PK in after several cycles of treatment, and there was no effect on. At nine hundred milligrams, that’s how we chose.

Patrick Mayes, CSO, Incyte: We we also characterize bathing’s non neutralizing, so it doesn’t have any effect on the binding of the antibody and no effect on activity as we’ve mentioned.

Salveen Richter, Goldman Sachs: Our next question is, would you consider combining ANZero with seven three seven three four and MSF CRC patients who also have a g twelve d mutation? Seems like a new opportunity, specifically at.

Pablo: No. Organs already started. That combination has already started. We’re doing dose escalation. We will have that data just a few months if we can clear the first dose cohort.

So we agree it’s an excellent idea, and we’re the only we we’re the only company that has both programs in in the same place, so that work is taking place right now.

Salveen Richter, Goldman Sachs: Great. Now related to eight times zero, can you talk about your plan to advance the nine hundred milligram dose of the bispecific given it’s on the higher end of the RDE levels? Can you comment on the efficacy and safety profile you observed at twelve hundred milligrams? Was at the MTD, and how does that shape the level of confidence in the therapeutic window?

Eka Satyen, Head of Early Development: So at 1,500, we exceeded MTD. We treated few patients at 1,200, but then we chose 900 based on the emerging data, and there were no DLTs at 1,200. But because of the ongoing events at twelve hundred milligram, there were some severe adverse events that described in in the presentation. We deescalated, and we went forward with nine hundred milligram. Also, at that time, the ADA and PK data came in at nine hundred.

There was no efficacy associated with higher dose, so there was no exposure response indicating that we have to go higher. So we basically decided to move

Salveen Richter, Goldman Sachs: that forward nine hundred milligram.

Pablo: I mean, more likely than not, or I think it’s pretty clear. This is a p d it’s a p d one better. It’s a p d one inhibitor with EGF beta receptor two antibody, and the dose response for efficacy is likely to be flat. As Patrick mentioned, we have full target engagement at lower doses. The reason to push the dose was to make sure that ADAs did not impact the PK as a result of the efficacy of the drug.

So that’s why the nine hundred doses selected. This, again, and I think the discussant said it very well today due to KRAS section, was a multi part decision making for the dose selection, including efficacy, safety, PK, and PD, and the understanding of the target engagement that we needed.

Salveen Richter, Goldman Sachs: For the g twelve d inhibitor, will you prioritize chemo combination versus monotherapy, and in what setting would you pursue? Would you consider bringing this one as a monotherapy in pDAF?

Pablo: Not at this time. Not at this time. And and the reason is we want to focus laser focus on the first line program. Appending some of the data points that we just discussed, we’re going to go fast in the first line PDAC and population with two types of chemotherapy. Within second line, our competitors are far ahead of us, And the market opportunity is much smaller because a lot of the patients with pancreatic never progressed, unfortunately, never progressed to second line therapy.

So at this point, we’ll continue to generate the data that you heard, Erica, and we’ll update you on those results, but we have no plans to initiate the second line registrational trial with the g twelve p and everything like that.

Salveen Richter, Goldman Sachs: Great. And just wanna also check if there’s additional questions in the room. Okay. We have about two more online. So for the so for our CDF data bispecific, I wanna understand your perspective, how does that be compared to Niris’ as shown seven percent partial response and forty three percent stable disease with either cardiac or liver or AVs.

Pablo: Yeah. The first point I would make on the back end of that question, which is the safety, we have not seen cardiac events of the recommended dose for expansion. That was seen at the fifteen hundred million dose. So I don’t think that makes a difference, really. I think we have twice the single agent activity that they showed in terms of responses, which I think positions us very well to be competitive.

So at this point, while the data continues to emerge, we think that the fact that we have a high single agent activity, the combinability of the chemotherapy and the safety profile that I can detail, I think we have a very good opportunity for Slybdenum, as vis a vis some of our competitors have been pointing out.

Salveen Richter, Goldman Sachs: And I know we, this question was asked earlier, which has come up a couple times for the food quality specifically. So maybe we could, talk again about her confidence in the twelve hundred milligram dose moving forward and how we think this compares to RevMeds that have shown 22% lower.

Pablo: Well, let’s start let’s start with the the safety side. So there’s there’s two datasets from RevMed, and and we should just focus on RevMed. I mean, there’s a lot of competitors in this page. RevMed is obviously one that’s ahead, and everyone’s mind seems to be. Their pan RAS has shown twenty two and twenty five percent in third and second line PDAC.

That is in all, RAS mutations. I have not seen recently a breakdown by 12 d versus 12 d, the two most common cardiac cancer mutations. So let’s keep that in mind. The data for the 12D, selective inhibitor is better. I have not seen what plans they have for that molecule.

The pan RAS is moving. Obviously, the the second line trial is almost done in terms of enrollment. The first line, we’ve said openly, we’re not going to combine They’re combining with Gemnab. I pointed out the dosing since with Gemnab seems to be compromised in the regimen, and I don’t think it’s the case with adults. And the fact that we can provide the full prenups in a tolerable manner, we’ll have that confirmation in a couple of weeks.

But it looks to be that way, we think opens that entire door for us. We basically make this a broadly applicable intervention in patients with first nineteen five percent.

Salveen Richter, Goldman Sachs: And then also related to some of this today, can you compare and contrast your g twelve b data with the GFH three seven five monotherapy data for the g twelve b inhibitor and data, and what key differences do you see if it’s within the respective patient populations? Yeah. Gently. Yeah.

Pablo: I can’t comment on the patient population. I think my first reaction with that is the mild suppression. Clearly, the activity was really interesting. I mean, the the response rate was high. I mean, it was forty, forty one percent was reported today, but there was quite a bit of neutropenia.

And it may not be high grade neutropenia, but when you combine with a regimen that’s mild suppressive like Geminiab or cofirinox, I think that could be complicated. So I see I have no idea what the plans are, but I see that as a strong plan in second line. Whether you can combine with full dose chemotherapy in first line, you know, we look forward to seeing that data.

Salveen Richter, Goldman Sachs: Great. And any final questions in the room? All right. Back to you, Pablo, for closing our questions.

Pablo: Thank you very much, everyone, for coming. Thank you to the 100 plus people that were online. We look forward to continue to update you in those those exciting programs, and have a great rest of the meeting and safe travel home. Thank you.

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