Incyte Corporation (INCY) Earnings Call Transcript & Summary

Okay. Good evening, everybody. Those of you here in Madrid. It's been a wonderful ESMO for us at Incyte, and we're really excited about telling you a lot of the progress we're making in solid tumors. So thank you very much for joining us here today. We will be making forward-looking statements that you can see here. We have a great set of speakers today. You can see them here, our own Steven Stein, Chief Medical Officer and Head of late development at Incyte. Dr. Elena Garralda, who's Co-Director of the Vall d'Hebron Clinical Research Program and group leader for the Vall d'Hebron Early Clinical Drug Development Group as among many other titles, and Dr. Manuel Hidalgo, Professor of Medicine Director of Gastrointestinal Cancer Center at the Perlmutter Cancer Center at NYU. So we're really pleased, and we're very grateful that they agreed to join us here today. We have a great agenda. I'm going to make a very -- a couple of very quick comments to get us started, and then we're going to shift to reviewing the data for 2 key programs, 890 and 734. Our speakers will review the data for you, and we'll give you an overview of how we're developing these programs going forward. I'm going to make some closing remarks, and then we'll have plenty of time for Q&A. So please prepare your questions. All our speakers will be available for the Q&A. The focus today is a solid tumor development strategy at Incyte. I think over the last couple of years, we've been busy at work to build what I would consider a world-class solid tumor franchise. The focus today will be more on GI oncology, but we're building a broader solid tumor franchise within the organization. We have focused on 3 basic principles to build that strategy to build that franchise. One, we're trying to go out to novel targeted therapies, whether we are to novel biology, then in the case of TGF-beta by PD-1 or we approach a particular target of G12D with a different mechanism for what was there before. Instead of an on-off inhibitor, in this case, on inhibitor in this case, we go with an on-off inhibitor, for example. We are focused on cancers of high incidents. We're trying to address large medical needs in patients that have limited treatment options. And what I think that we've done pretty consistency in both programs as well as in our CDK2 program is go as quickly as possible to frontline. We believe that, that is what largest patient benefit resides and obviously, the largest commercial opportunity as well. So that's something that has been a consistent pattern in these programs, and you'll see it as we review the data. This is our portfolio today. We have one approved medicine, Zynyz, we shouldn't forget about that. It's approved for patients with anal cancer. The first PD-1 approved in combination with chemotherapy for frontline anal cancer as well as merkel cell carcinoma. 890 and 734 will be the bulk of the presentation today. And of course, on the right side of the slide, 667, our CDK2 inhibitor, which is in pivotal trials for patients with ovarian cancer and will continue to progress in the clinic. The 3 programs address approximately 0.25 million new patients per year. You can see the numbers here. taking into account only the indications that we've listed in the slides, which are the initial approvals for these programs. For 734 pancreatic cancer with 12D mutations, for 890, MSS colorectal cancer and for 667, CCNE1 over expressing ovarian cancer over 0.25 million -- or almost 0.25 million patients with very poor outcomes today. So now this is a very large opportunity for us as a business, but it's a very important medical need that needs to be addressed with better medicines for these patients. The programs have grown and will continue to expand. And this slide gives you an idea of what we're doing. And Steven, after Dr. Garralda and Dr. Hidalgo showed the data, Stephen will give you an idea how we're deploying our resources in this program. So for 890, our first indication in pivotal trials is colorectal cancer. We'll talk more about that. But let's not forget that we've shown evidence of efficacy in head and neck cancer, ovarian cancer and non-small cell lung cancer. All in patients that most of which had poor likelihood of response to PD-1 inhibitors. We moved initially in first-line colorectal. We are already implementing an adjuvant proof of concept studying colorectal cancer very important, and we've generated data that we've seen in this meeting as well in late lines. Very important for both programs is to expand into novel combinations. With 890, we've done chemotherapy, FOLFOX that is the bulk of the data you're going to see today. But recently, we announced a collaboration with the next-generation anti-CTLA-4 antibody. We think that's an important approach to be tested with what believe is a better PD-1. And we are in conversations to collaborate with an EGFR antibody as well as a novel ADC and you'll hear more about those in the next few weeks. For 734, our lead indication is pancreatic cancer. However, as you saw today, we presented data over the weekend, we presented data in colorectal cancer as well in late line in combination with cetuximab, that is going to be implemented as a pivotal trial. In first-line pancreatic we're well underway. The enrollment is going on globally and accelerating as we speak, and we're moving into the adjuvant setting in pancreatic cancer as well. In addition to the combinations with chemotherapy and cetuximab, we announced today and on Friday, 3 very important collaborations to continue to expand the scope of this program. Those are with navlimetostat, PRMT5inhibitor with SNV1521, a PARP1 inhibitor. And on Friday, we announced a collaboration with petosemtamab with a focus in colorectal cancer. So this novel, novel combinations will allow us to continue to expand and improve, hopefully, the results that we're seeing with combinations with chemotherapy and existing EGFR inhibitors. Highlighting one more time, the importance of the breadth of these programs that we're trying to address a number of patients across 2 core indications to begin with, colorectal cancer and pancreatic cancer, so a very strong focus for us initially in gastrointestinal Oncology. But as I mentioned, we have interest and continue to expand and grow within GI oncology as well as other therapeutic areas. So with that, I'm going to hand it over to Steven Stein. He's going to walk you through elements of the development strategy for these 2 programs. Dr. Garralda and Dr. Hidalgo will then walk us through the data, and we'll come back with more details. Thank you.

Thanks, Pablo. So as Pablo said, we're going to focus on the solid tumor side of our development at Incyte just to start to offer now our brilliant logic on our numbering systems, INCA and the ASD antibody, 33890 is our TGFBR anybody. I will -- and it gives you some sense of the number of compounds that are screened before these things get into the clinic. I'll refer to as 890 going forward. And then INCB in this case, a small molecule 161734, I'll refer to 734 going forward, our 12D mutant specific small molecule, and I'll take you through some of the development highlights related to this. We had 4 rapid oral presentations at ESMO, and I hope most of you saw them, but in case you didn't will go through the data in them tonight. Firstly, 890 in first-line microsatellite colorectal cancer in combination with standard of care chemotherapies very importantly, the ability to show you data with FOLFOX bev in the setting, both in terms of response rates and some evidence of durability. In terms of 734 presentations in pancreatic ductal adenocarcinoma and again, very importantly with standard of care chemotherapies in both Gem/Abraxane and modified Folfirinox which is somewhat of a differentiator for this compound. And then 734 in second-line colorectal cancer in combination with the EGFR inhibitors, cetuximab was also an oral presentation. And then lastly, not the focus of tonight. But as Pablo mentioned, 667, our CDK2 inhibitor in CCNE1 overexpress in this setting, platinum-resistant ovarian cancer with bevacizumab, but it's a very good setup for going forward, our maintenance study in platinum-sensitive ovarian cancer, but not the focus of tonight's presentation. So let's talk about TGR by PD-1. And we think, and as Pablo alluded to, this has the potential to be a next-generation immunotherapy backbone. So go beyond PD-1 alone and addressing probably the 2 most important tumor mechanisms in terms of invading the immune system in PD-1 and TGF beta R2. Broadly speaking, the takeaways we'd like you to get from what we're going to show you tonight is the ongoing development of this bispecific antibody, microsatellite colorectal cancer being the lead indication, and as Pablo said, well underway and enrolling very well but with expansion opportunities in additional solid tumors. The first line activity that will take you through the night, we think is enabling in a large way for the ongoing first-line study. I will show you the FOLFOX BEV response rates and way above historical benchmarks for standard care chemotherapies. And then the durability thereof is a read-through to potential down the line, both progression-free survival and an overall survival signal. And then in keeping with the rationale of the bispecific they're really encouraging and notable activity in liver metastasis, which themselves a TGF-beta R2 high expressing and supportive of the rationale in its entirety for developing this construct in terms of the bispecific antibody. And then expanding again with a Phase II study, but an elegantly designed proof-of-concept in patients with microsat like holorectal cancer who have had curative resection attempted adjuvant chemotherapy but [indiscernible] ctDNA positive and they are treated with 890 for up to 12 months, and I'll show you that schema. High TGF-beta tumors RPDL or PD-1 inhibitor-resistant. The pathway is hyperactivated in immune-excluded tumors that are resistant to these anti-PD-1 inhibitors, bindingto the TGFBR receptor leads to suppression of CD8-positive T cells. And then as a consequence, immune exclusion of those cells. And additionally, high TGF beta R2 expression is shown to be significantly associated with nonresponse to checkpoint inhibitors and reduce survival overall. In terms of the biology behind us, this schematic shows on the Y-axis T cell TGF-beta gene expression and then uses a Pearson correlation coefficient on the X axis to look at TGF beta R2 protein expression in solid tumors. And you can see circle for you both microsatike colorectal cancer itself. And then the liver mets are high scoring in terms of regard and enrich for the biology that's addressed by the bispecific antibody. In terms of the construct here, it's again, a very cleverly designed bispecific -- given the history with TGF-beta biology where toxicity was largely limited over the last couple of decades with different mechanisms trying to address the biology. This is a high affinity PD-1 arm. It's more than tenfold higher affinity if you compare it to the TGF beta R2 arm. By -- the mechanism is sort of docking in terms of the PD-1 and then blocking on the immune cells, the TGF beta R2 signal and thus sparinormal tissues, which enables normal function to continue and then avoid the known toxicity of the broad pathway blockade. So a smart construct that we've taken forward. Pablo alluded to it, the highlighted in dark blue are the ongoing efforts. First, in the middle, the first-line Phase III [ NCR-303 ] study is well underway. It uses the care standards of FOLFOX bev, plus/minus the 890 antibody. And then on the left of that, the adjuvant study is also starting as we speak in patients who have been resected, have had adjuvant chemotherapy and are then in window of up to a year ctDNA-positive and then treated with [indiscernible] with the proof of concept being ctDNA clearance and document in that. There's ongoing work with the mask CTLA-4 antibody, there on the right, a [indiscernible] combo alone, some of the data shown at this meeting, in ovarian cancer combinations with chemotherapy and then an ADC that will be announced shortly, a novel EFR antibody in head and neck cancer that will also be announced in chemotherapy combinations in lung cancer but not addressed to night. With that, I'm going to hand it over to Dr. Garralda to present the data further. As Pablo said, she is the Co-Director of the Vall d'Hebron Clinical Research Program, the group leader of the early clinical drug development group and the Director of the Research unit for molecular therapy of cancer, Dr. Garralda.

Thank you very much. It's really a pleasure to be here and walk you through the data that has been presented in 890 during ESMO. So let me see if I manage to -- very good. So I think you've seen already the need that there is for therapies in colorectal, but I'll just walk a bit through perhaps a concept that has not been stressed. So the 85% of cases of colorectal are going to be MSS. For these cases, still immunotherapy has not really managed to provide any substantial benefit to these patients. It's only the 15% that are going to be MSI high. that really have obtained benefit from immunotherapy. So just to put the things in context, it's also important to understand what is still the current first-line treatment, and this is still the chemotherapy with FOLFOX and BEV. And what would be the benchmark would be a response rate of around 45%, 50% median PFS of around 10 months and 25, 30 months for median OS in Phase III trials. So this would be the numbers that we would be benchmarking the results today. So INKA33890 is really a big Phase I study. We did the dose exploration that explore different doses. And really we export and reach that 900 milligrams IV every 2 weeks was the recommended Phase II dose, and this led to several expansions. We have done expansions with different chemotherapies based in the different settings. So you see that it's all patients with advanced colorectal and then depending on the chemotherapy, there were different lines of treatment. So I'm going to focus on the combination with FOLFOX Bev for frontline, but you can see in general, the patient situation for all treatment indicates. So the median age was 56%. It was a good prognosis that most of the patients, all of the patients were at Cox 0 or 10. What it would be important to highlight is in the frontline, first-line 67% had liver metastases. So this is, I guess, like the normal pattern of colorectal. But as you've heard in previous presentation, liver metastasis is worse prognostic factor for colorectal cancer and also has been proven to be a predictive factor for immunotherapy with those patients that liver metastasis responding with the immune checkpoint inhibition. Also regarding PD-L1, you can see that 61% of patients are PD-L1 above 1%, and as you know, in colorectal, there's also importance about the sites. So just to say that 65% were less sided versus 30% right sided. This is the normal prevalence of left and right. 63% were [indiscernible] mutants. This have slightly worked prognosis, but in general, a representative population of what we see in clinical trials in global Phase III clinical trials. So it's a Phase I study. What did we see in the combination? Well, when we are combining drugs of course, one of the first things is to see if we can actually give this combination. The combination safe. We didn't observe any DLTs. And it's important to stress that we did manage to maintain the relative dose intensity of the standard of care. That would be one of the concerns when you are combining in frontline with standard of care. So there were some adverse events leading to those delays or discontinuations, but you can see the numbers are low, so 9% for 8 and what would be expected from the combination of around 67%. You need to remember that FOLFOX is given in a long term, but there's normally reductions of the oxaliplatin because of the toxicities. Important to mention that we did see some immune rated adverse events. These are similar to the proportion that would be seen with regular checkpoint inhibition with only 14% having more than a grade 3 event. And as I've mentioned, we didn't observe any fatal events or Grade 5 events. So if we dive a bit deeper in which were the most common treatment-emergent adverse events, you can see that they are really well-established adverse events due to chemotherapy. So you're going to be seeing the neuropathy of oxaliplatin. That was mainly low grade. We did see 2% only of Grade 3 neuropathy. And then the GI toxicities that would be expected due to the FOLFOX criteria -- FOLFOX toxicity, sorry. We did see some infusion-related reactions, but they were mainly due to the oxaliplatin. So also the standard of care, a very few infusion-related reactions due to 890. So in general, an adverse events that would be consistent with what is known of FOLFOX chemotherapy and also of immune-related adverse events due to the checkpoint inhibition. Also perhaps important to mention the hypertention, only 28% of cases had hypertention, also similar to what we would expect with treatment with bet. Here, you can see the waterfall plot. So we did have 42 patients were evaluable for efficacy in this first-line MSS colorectal cohort with a median follow-up of nearly 6 months. So we did see 71% response rate, and this was confirmed in 67% of the cases with a 6-month PFS of 81% and a disease control rate of 100%. You can see with the arrows that most of the patients are still on treatment. So it's still early times to actually understand the durability of the response. But as mentioned, it is promising in the stage that we are. If we go to subgroup analysis, it's also important to highlight different patient characteristics. So as I've mentioned, liver met is still a big area of need in colorectal. You can see in patients with liver metastasis that are actually drawn in blue in the presentation. The response rate is 83%. Peritoneal invasion, also a hard case to reach metastatic sites, 62% then also important to mention that in those patients that were PD-L1 high that we already have seen in the monotherapy that we're enriching for response. Actually, the response rate reaches 81% versus 50% in those patients that were be DL1 less than 1%. The response is in the right side is 92%, and the left side, it's 64%, but these are smaller numbers. So to conclude, I think that the data has shown that there is a tolerable to combine FOLFOX BEV with 890. We haven't seen any DLTs still early times. But for now, no safety concern. There's no notable preliminary efficacy in this frontline MSS with the 890 FOLFOX/BEV. The response rate has reached 71% disease control rate of 100% and 6-month PFS of 81%. We have seen responses in patients that are hard to get responses such as patients with liver metastases with a response rate of 83% in patients with peritoneal metastasis 62%. And also this is enriched in patients with PD-L1 positive reaching up to responses of 81%. And this data support the Phase III NAXETA study that you have heard in the previous presentation. So thank you very much for listening.

Thank you, Dr. Garralda . So to reiterate a few points in terms of where we are when the efforts in microsatellite colorectal cancer and then expansion beyond that. It's a high incidence tumor, as you saw from Pablo's data. And currently, to date has not been sensitive to checkpoint inhibition in any way. The Phase III study in NEXERA-303 is ongoing, and as Pablo said, is enrolling very well. Beyond that, we'll be starting a proof-of-concept study or is starting, as I speak, in colorectal cancer resected, post adjuvant chemotherapy that is ctDNA positive. And I'll show you that study schema in a moment and then the novel combinations that we mentioned to you as well, are underway. In terms of -- there's a few important disclosures on this slide, I'll highlight them. One is that the top line data is expected in 2029, right at the top there. This is histologically confirmed metastatic colorectal cancer no prior treatment for the metastatic disease, patients if they have received either neo or adjuvant therapy were allowed to enroll if they didn't have a recurrence within 12 months of the end of that therapy. They could not be MSI high, obviously, no BRAF mutation and no immune checkpoint inhibitor within the prior 3 years and an ECOG of 0 to 1, the goal N is 700. It's a standard 1:1 randomization of 890 at a 900-milligram Q2 week IV dose with standard FOLFOX chemotherapy versus placebo. The primary endpoint is progression-free survival and then an important disclosure just after that, based on the data Dr. Garralda showed you that the hierarchical analysis tests the PD-L1 positive group first, which is based on the data we have has a much higher chance of success in terms of at least the response rate data. the key secondary, obviously, in this disease is overall survival and then other secondary endpoints listed there for you. In terms of the adjuvant setting, there is obviously a significant unmet need for patients with colorectal cancer who have documented MRD by ctDNA post-surgery. About 15% of Stage 2 patients and double that 30% of Stage 3 will experience recurrence. The curve show you in for stage 2 and stage 3, median disease-free survival if you're ctDNA positive. For Stage 2, if you're positive in this particular data set, which is large 1,100-plus patients a median DFS of 12.7 months, if you're positive, and for stage 3, 16.2 months. Overall, that's about a 1-year median DFS, if you see DNA positive post adjuvant chemotherapy. There is also evidence from other work that if you are able to clear the ctDNA and that's the POC for this particular effort, that would alone would be a biological surrogate for disease-free survival, hence, the design of the proof-of-concept study. Here it is for you, you have to have microsatellite colorectal cancer, a curative resection prior adjuvant chemotherapy, be stage 2 or 3 ctDNA positive with a much larger window that's typically used in the setting up to 12 months and have no evaluable disease on PET CT screening. And it actually needs quite a low number to get there, 40 patients overall. You can see the schema above, we treat for up to 12 months and the primary endpoint is CTDNA clearance at 3 months without the end points below, including disease-free survival and some exploratory biomarker work. So just to reiterate, a potential immunotherapy backbone that goes beyond CPI alone by destined TGF beta R2 biology, top line data for the registration study in 700 patients in 2029 based on enrollment currently. The efficacy measures that were shown tonight, we think 0.2, as we said, notable clinical activity and overall response of 71%, disease control rate of 100% and 6-month landmark PFS of 81%. And hopefully, over next year in 2027, we're able to update the PFS data as data matures. Including, as was shown to activity and difficult to treat subgroups, liver mats being a clinical marker of checkpoint resistance, an 83% response rate there. Peritoneal met 62%. And the response rate in the PD-L1 positive by TAP scoring of 81%. And then the move into the adjuvant setting, which we think is really important for the program in that ctDNA positive population. And then ongoing work which will be the subject of later updates, ovarian, head and neck and lung cancer. Turning to 12. The idea is to build a franchise across 12 mutated tumors. And that's where we are with 734, and we're very proud of the data at this meeting but also where we're going with the compound beyond that. So again, the key takeaways that we want to show you here tonight that this itself has the potential to be a backbone for a G12D mutated gastrointestinal cancers. The Phase III in PDX ongoing and enrolling very well, a planned registration study, which I'll show you in a minute, in second and third-line colorectal cancer in the first half of 2027.ndthen the adjuvant PDAC study. The first-line PDAC activity in Phase I supports ongoing Phase III development. We were able to show you activity with both standard of care chemotherapies modified Folfirinox or Gem/Abraxane. And again, what we think are historical benchmarks above standard of care. The promising colorectal cancer activity that supports expansion across lines of therapy with the cetuximab response rate above a historical benchmark for second, third line standard of care chemotherapies. And then combinations that Pablo alluded to with a PRMT5, a PARP 1 inhibitor and an eGFR LGR5 bispecific. It will all begin in 2027. 734 itself is a highly selective G12D on and OFF inhibitor. It's a scaffold that binds at the switch to pocket with Picamola affinity. That translates to a GDP on bond in affinity of 0.38 nanomolar and a GTP off-bound Infinity of 0.32 nanomolar. The selectivity of a wild type is greater than fold. And we think that the construct of an on-off inhibitor may translate to more durable efficacy as seen with either only or only of inhibitors, and we can talk about that more in Q&A. It is, to our knowledge, currently the only KRAS12D on/off in Phase III development. Again, the entirety of the program is listed here for you in the middle, the Phase III DAWN 303 study ongoing with both standard of care chemotherapies. An adjuvant study on a chemotherapy backbone to chemotherapy plus/minus 734 that will begin in 2027 with curative intent and then the novel combination work on the far right there in PDAC. In colorectal cancer, the most established data we have is with cetuximab in which we'll show you at this meeting, but then ongoing work within EGFR, LGR5 bispecific, a PARP 1 inhibitor and that Phase III. That data with cetuximab will enable a registration study to start in the first half of 2027. And we're obviously interested in other 12D mutated tumors as listed below, including non-small cell lung cancer. With that, I'll hand the podium over to Professor Hidalgo, who, as Pablo said, is the Director of the GI Cancer Center at the Perlmutter Cancer Center NYU, Professor Hidalgo.

Good evening, and thank you very much for inviting me to discuss these exciting data. I think most of what I will be presenting today was already discussed or presented at ESMO will be a nice opportunity to summarize some of the data. So pancreatic cancer, very, very serious little disease. It's very commonly RAS mutated, the majority of patients have a mutation in the KRAS oncogene and 12 alleles the most commonly mutated up to 40%. Management of patients with advanced disease with metastatic disease, which is basically half of the patients at presentation and another 60% of those of the patients who present with earlier disease will progress a few years after resection and adjuvant chemotherapy. It's with the systemic multi-agent chemotherapy not very effective in Phase III trials, response rates in the 20%, 30% range, median survival around 1 year in the best case. For that reason, the overall survival for the entire pancreatic cancer population is about 5 years, 10% for stage 4 disease is very dismal only 3%. So a very, very significant medical need will never get this point right. It's the other way around. So the data that I will be presented today is the part of the Phase I trial, the combination of the novel agent with both of the standard of care chemotherapy in patients with untreated advanced adenocarcinoma of the pancreas locally advanced or metastatic disease, of course, they needed to have a confirmed 12D mutation, good performance status, no prior treatment with any of those RAS inhibitors. And the study proceed in 2 steps. First, dose escalation from 600 milligram to 1,200 milligram of the 734 with either gemcitabine, Abraxane, or modify for Folfirinox at standard of care dosages using this disease. And then the selective recommended dose was expanded. So in aggregate, if you look at the patients who were treated at the recommended dose, we have 26 patients for GA and 28 patients for modified Folfirinox. And the primary endpoints were safety and tolerability and then ORR disease control rate and PFS. So these are the patient disposition. Let's look at the tables, very common population for this type of first-line advanced disease pancreatic cancer clinical trial. The only noticeable difference is that in the Gemcitabine/Abraxane group, if you can see, there are significant number of patients, 38% who have received prior chemotherapy. Those patients likely have received prior modified fulfilinox in the adjuvant setting, and then they progress and we're entering to the study. The majority of patients 85%, 86% with liver metastases, which is the most important prognostic factor. So this is a very standard population for patients with advanced pancreatic cancer. The -- these are the safety data for the gemcitabine and nab paclitaxel combination in general, as expected with chemotherapy for this particular chemotherapy very low rate of grade 3 events, perhaps a little bit more neutropenia. But as I said, a large proportion of these patients had been likely pretreated with modified for Folfirinox. And then the GI toxicity nausea and vomiting that we see with 734, which is grade 1, 2 is easily manageable. If you look at the relative dose intensity, is about 85% for the 734 and then about 70% for the first few cycles, 4 cycles for chemotherapy, which is very similar to what you would be expecting in the standard of care. So no really major concerns or concerns at all from the safety perspective. This is the data for safety with modified Folfirinox similar. Actually, the incidence of neutropenia is lower here, which is rare compared to tencytabine ABRAXANE, probably because very few patients have been pretreated, I think, only 11%. And probably most of these patients would modify Folfirinox at least in the U.S. will get growth factor support, expected safety profile of the modified Folfirinox backbone with, again, higher incidence of mild easily manageable GI toxicity nausea and vomiting. And again, the dose intensity, very high in the 70% range for chemotherapy, which is what you would be essentially expecting. This is the combined response rate for the 2 groups. The ORR for gemcitabine and nab-paclitaxel is 69% and for modified Folfirinox 89% and the confirmed upending is 58% and 81% with close to 100% disease control rate and a few patients with complete responses, which is totally unheard of. in this particular disease. Now this data is maturing. We don't have yet fully analyzed PFS and, of course, OS. But when you look at the a swimmer plot for PFS, the 6 months landmark analysis for PFS, which with chemotherapy is around 50% for standard of care chemotherapy. With this regimen is 80%, 90% for the 2 regimens. So compared in this noncomparative trial I think very well with what is expected based on standard of care chemotherapy. So responses seems to be durable, which is very important, of course, we need more the data to mature to analyze this in more detail. So the conclusions for the pancreatic cancer component of the presentation is that there is a favorable safety and tolerability profile in combination with both standard of care GA and modify Folfirinox, very consistent with what is expected for this standard of care chemotherapy regimens with only perhaps a higher incident of easily manageable GI toxicity Nathan vomiting, which was observed in the single agent Phase I trial as well. Very deep and appears to be durable responses with both regimens, responses in the 70%, 80% range for this 70% to 90% range for these 2 regimens with 6 months progression-free survival of around 80% and 90% expected it's about 50% for those in those chemotherapy regimens. So this supports the ongoing Phase III trial comparing 734 with gencitabine/ABRAXANE and/or modified Folfirinox in combination in this patient population. So we go now to colorectal cancer, which there is less data but also very, very interesting. Colorectal cancer is, of course, more common than pancreatic cancer, but the frequency of RAS mutation is lower. It's about only 50% of the patients. And if you look at the RAS 12, the allele is only 15%. As discussed before, patients receive combination chemotherapies, cituximab, bevacizumab patients with the mutant KRAS do not benefit from cetuximab. So basically, they're managed with FOLFIRI, FOLFOX, bracizumab. And then the standard of care second or third-line regimen depending if they got triple chemotherapy or doublet chemotherapy is lone or with regorafenib, very low response rate, less than 5% and median PFS of 5.6 months with median less of a year. So very significant medical need as well in patients with late-stage colorectal cancer metastatic disease with a 12D mutant allele. I said before, many years ago, it was established that EGFR inhibitors don't work in this particular situation and for some reason, they are not used. But there is preclinical and early clinical data that the combination of the RAS 1D inhibitor with cetuximab synergistic and that has been explored in this trial. This synergy, which probably is also applicable to other diseases, pancreatic cancer, less data, lung cancer, some data as well. But where we think is more relevant in colorectal cancer. So this is the clinical trial in combination with cetuximab in patients with metastatic colorectal cancer. Locally advanced or metastatic disease with 12D mutation good performing status who have progressed to standard of care chemotherapy. There was a single agent, those expansion. The dose evaluation from 200 to 1,600 milligrams. The drug is active as per se, a single agent. But most of the activity, as you will see, is in combination with cetuximab and it's very well tolerated at both 600 and 1,200 milligram, the recommended dose for the clinical trial moving forward is the 120, but it's very well tolerated. These are the characteristics of the patient population, really nothing very special majority of patients with liver metastases. And I said before, all of them have received a significant number of prior chemotherapy regimens and bevacizumab or similar inhibitors, which is the standard of care for this population. Nothing really too special in these 2 populations, very, very classic second, third line patients for clinic trial. This is the safety data on the left in blue or the left in blue, you have the single agent safety data that as mentioned before, basically, the only important side effect is GI toxicity, nausea, vomitting. But as you can see, the majority of them is rig. Then on the right, in green, you have the safety for the combination with cetuximab, which the major difference is in the acne, the rash. Cetuximab causes rash. This is well known. It is manageable. There is a areflexia mechanism and with time it goes away. Patients in general, can take cetuximab without problem. But because this RAS inhibitor alone has very little rush, as you can see in the slide, can be combined with cetuximab, which other agents, as you know, have more scheme toxicity, and these combinations are simply just not feasible. So here, I think this is the only real opportunity to test this combination in clinical trials. And again, most of the patients were able to stay on trial with very dose -- very little or very few dose modifications or interruptions. This is the data of the combination. It's a small cohort, but the ORR is 36%. Remember, with the standard of care is less than 5%. Actually, it's close to 0%. There is basically no responses. And this is a controlled rate of about basically 100%, no patient had disease progression in this cohort. The single-agent monotherapy is -- there's some activity. Actually, it's more than with the standard of care, it's 8% and 79%. But for this reason, because of the tolerability and the higher efficacy of the combination, it makes sense to move this 1 forward into more definitive clinical trial. And as I said, these responses are durable. Median PFS is already 7.2 months. It's about 5 months with the standard of care. So it's a very, very interesting the said and in a population for whom there is no very effective treatments. This is biological data. Cell-free DNA tumor biopsies collected in the context of trial. Two pieces of information. The first one is the changes in the G12D valve, which as you can see, is very, very profound. We are seeing this across different diseases with the majority of patients in this particular trial have been more than 90% controlled or elimination of the mutant allele and it's becoming clear that this correlates with outcome. You will see data down the road yet published that patients with stable disease who have this clearance of the mutant alleles also derive substantial benefit. So I think this surrogate or intermediate or biological endpoint, whatever you want to call it, will be progressively incorporated into clinical trials. And on the right, you have the baseline genomic characteristics and more detail mutational analysis beyond the 12 as expected for colorectal cancer, but nothing that really correlates on the left, the responders on the right, the stable disease, nothing that really correlates baseline with outcome. So for this reason, the only selection criteria should be 2D mutation for this trial. Now I'll be very interesting in this trial as we move forward to repeat these post-treatment biopsies and see where at the escape mechanism of patients when they progress. Similarly to the profound correlation between allele the VAF decrement for response when patients start to progress in some patients, we see that going up, not necessarily the Russia deal, but some other mutations start to emerge. So that's a very interesting translational field that we will navigate as we go. So for colorectal cancer, these are the conclusions, very manageable toxicity profile as monotherapy and in combination with cetuximab with only the rush, but because the single agent doesn't have a skin toxicity or has very little scheme toxicity. This makes this combination feasible. No DLTs in the escalation and low rate of side effects leading to discontinuation. Very interesting preliminary activity all cohort at 36% response rate, universal disease control and PFS 7.2 months, and this supports clearly the continuation of this clinical trial in patients with RAS 12D mutant colorectal cancer. And I think this is my last slide. Thank you very much.

Three visits to the podium. It's testing my ability with flash in light and not experiencing a seizure. We'll see how we go here. So 734 mutants specific small molecule in pancreatic ductal adenocarcinoma is ongoing in the Phase III DAWN-303 study enrolling really well in the adjuvant study to begin early 2027. The colorectal data, just shown to you, leveraging the synergy with eGFR blockade a Phase III second third-line colorectal study planned in the first half of 2027 and enabling work in first-line setting is ongoing as well as potential going forward, and then the novel combination work has shown to you as well. Another important takeaway here, the top line data for the Phase III study, given the enrollment characteristic to date is expected in 2028. And study eligibility is histologically confirmed metastatic PDAC with a KRAS 12D mutation, no prior therapy for metastatic disease, ECOG performance status of 0 to 1. And very importantly, measurable disease by RECIST is needed with an [ N 590 ]. I'll come back to the why behind the RECIST criteria in a second. Randomization is one-to-one. Chemotherapy plus 734 versus chemotherapy plus placebo. Stratification factors are there for you, the chemotherapy regimen, ECOG status, the presence of liver mets and geographic regions. In terms of the endpoint, the primary are 3 oral survival, progression-free survival by a blinded independent review committee and an overall response rate, which you noted in the clinicaltrials.gov listing. And that's why the measurable disease by resist is required and gives a potential opportunity to take that forward at a regulatory level should deliver the data that's encouraging in that regard, standard secondary endpoints. The adjuvant setting beginning in 2027 in PDAC, we think the best way forward is to hit early and hard with the chemotherapy plus/minus 734 combination study been a likely study that we do there enabled by the data shown tonight. The rationale is obviously to use as an [indiscernible] to eliminate micrometastatic disease and extend disease-free survival study deals, broadly speaking, a post-resection PDAC chemotherapy backbone with a planned Phase III start in 2027. In colorectal cancer as shown by professional Hidalgo. Again, a Phase III start first half of 2027 enabled data you've seen here tonight. Study is cetuximab plus 734 in second, third-line colorectal cancer. Again, a high incidence tumor with significant G12D mutated disease, aiming to take advantage of the synergy with EGFR antibodies. Study details, broadly speaking, second, third line colorectal cancer that bevacizumab experienced and that helped give you the control arm to beat likely PFS. The regimen again is cetuximab plus 734 start first half of next year. I hope this illustrates for you why we think this will be a multi-combination franchise. The pancreatic combinations are obviously both chemotherapy regimens, gemoraxane-modified Folfirinox then a PRMT5 with BMS nablematostat, the PARP 1 from Sinivasan. Colorectal combinations, you just saw cetuximab data. ongoing enabling work in earlier settings with FOLFIRI and FOLFOX with cetuximab and then for FOLFIRI and FOLFOX with [indiscernible] as well will be ongoing. The next steps, establishing it in first-line pancreatic. First and ductal carcinoma top line data 2028 into adjuvant 2027. A new tumor type with colorectal cancer vital initiation first half of next year, ongoing work in the first-line setting, and that's up and going, and then the novel combinations as elucidated for you earlier. With that, I'll hand the podium back to Pablo.

Thank you, Steven, Dr. Garralda, Dr. Hidalgo. Let me close emphasizing a few key points here. You heard data and the development plans for these 2 programs, 734 and 890. And I should add here that we're very proud that both programs were entirely discovered and developed at Incyte, in fact, by the team led by our CSO, Patrick Mayes, who's sitting right here. So we're very proud of that fact that we are really delivering on our promise of discovering and developing novel therapeutics. Both are in Phase III, as we discussed and Steven reviewed in great detail, based on the data that has been presented at this meeting, we remain convinced that [indiscernible] is very competitive in the space, but that we have shown data that substantially derisks the ongoing pivotal trials. I think that to our eyes, is becoming increasingly clear. Both programs have relatively near-term milestones. As Steven described, the 734 credit cancer study will deliver top line data in 2028, which is test around the corner and the TGF-beta PD-1 in colorectal cancer 229 will provide more details on the other pivotal trials as they get initiated. As I mentioned in my introduction, we think what the greatest patient benefit is, is the earliest we can -- the early we intervene in this diseases. Hence, the important push in the direction of adjuvant therapy, proof-of-concept with 890 in the adjuvant setting in colorectal and we're initiating adjuvant in pancreatic cancer next year. As we described at the beginning, not only these are very large medical needs, but they provide substantial commercial opportunities for Incyte in what is a growing franchise around GI Oncology as a focus that we'll continue to expand as we described over the past hour. So with that, concludes our remarks. Thank you, everybody, for listening. We can now open for questions here or online. We can start it Alexis. There's a lot of questions. We want to give a minute. Eric, Michael, Evan, 1 sec.

Okay. Eric -- Michael grabs the mic, go ahead.

[indiscernible], just curious how you think about that in the competitive environment? And then the second question I had was on the DAWN-303 study. Just to clarify, if overall survival is necessary to hit to declare success. And if you think there is -- if that's possible, just given possible post-progression treatment with other KRAS inhibitors now in PDAC.

I'm going to ask Dr. Hidalgo to comment. One point I would make is the data has been reported for [indiscernible] combination with the same 2 chemotherapy regimens and ours, our duration of exposure is longer. It's between 1.5 and 1.7x longer duration of exposure. You treat patients for a longer period of time, you have more time to develop adverse events. Therefore, those rates of adverse events you need to keep that into account. We're not presenting exposure adjusted event rate, which we could do, but that's not the way we ended there. We presented all the data, so you have it all but the exposure is different. Therefore, the numbers are different. Let me ask Dr. Hidalgo to comment on how he sees the profile here, and then we'll go to Steven with the question on DAWN-303.

The question was [indiscernible] plus chemo.

Chemo combo.

I guess any differences between that and the 734-plus chemo.

I don't -- no. I think they are -- it's very early to say. I think there appears to be very effective, which is good. But I think we need to look at the full data set, more follow-up. The duration of the responses, the timing of the side effects, the molecular analysis of the cell 3 DNA. So at this moment, I think they are both very interesting combinations, but time will tell.

The median dose intensity for [indiscernible] is 72 and 59 of the 2 regimens. For us is 67 and 69. I mean I don't find those numbers to be different. -- the rate of events, as I discussed, has to be -- you have to keep the duration of exposure to account. Steven on DAWN-303.

Michael, thanks. The primary endpoints are 3. [indiscernible] free survival overall response rate and overall survival. The overall -- the response rate on was disclosed in the clinical trials to listing we'll able to do that analysis at an earlier time point, but likely when the study is fully accrued, given how well it's accrued. It has the potential to be an accelerated approval strategy, but they will be determined at the time based on the data plus the durability. The good thing is the confirmatory part of it is inbuilt in the study itself. So given that the PFS is in that study, that could serve as confirmatory and accrual is very likely to being completed. So we're only dealing with that issue in that regard. The meat of your question is, is always actually required? It's -- given the short duration historically, we're likely to have all 3 endpoints, probably PFS with overall response rate in the right direction on OS would be adequate. But we are likely to achieve all 3 based on the data we have to date.

Evan Seigerman with BMO. Congrats on the data. So 2 for me, One, as you think about kind of the benefit of targeting on and off with 734 versus the competition, when do you think that will start to play out in the data that we actually see. And then my second question is, I want to just discuss a little more about your partnership with Genmab, but looking at 734 in combination with petosemtamab, what did you see kind of in their data set or kind of in the biology that had you want to partner with them?

Why don't you address the on-off question, I'll come back to the petosemtamab question, Steven.

And then our Chief Scientific Officer is here as well, Patrick Mayes, if he wants to add anything to I'm about to say. So obviously, we have an on-off inhibitor with Picomolar affinity on the switch 2 pocket for both the GTP and GDP states, that was intentional in what we do. We think there's potentially signaling through both the on and off state and that may translate to a benefit. It may also be the reason, by the way, in colorectal cancer, that they didn't achieve ultimate PFS benefits, but that will be determined, obviously by the final efficacy data. I'll just see Patrick wants to add anything in terms of the construct.

So the nuance here is that the mutant KRAS sits in 2 different states to sell, right? The Allstate GDP bound and the [indiscernible] GTP bound. The off-state is more predominant. So 60% to 70% of mutant KRAS in a mutant cell is off at any given time. So if you think about a once-daily drug, which these are, you have a peak to trough profile of that drug over time, for on/off, you're maximally inhibiting all mutant KRAS in the cell across the dose interval. For an on only you're inhibiting a small fraction of the total KRAS pool and then that pool increases over time as you reach trough. So the theoretical advantage is you're getting more maximal inhibition, which you know is very important for these mutant proteins. We're getting target coverage above IC95, we see that as important to drive these DAF responses. So that's the nuance on the on-off.

On the petosemtamab question. So the discussion at very eloquently in KRAS mutated colorectal cancer, EGFR is always a driver Always. And that's why we -- very early on, we did the combination with cetuximab and you saw the data, which we think it's actually quite compelling considering the background response rate you expect with cetuximab in this population, which is single digits at best. So we accelerated that combination. We are entering a pivotal trial early 2027. In parallel with that, I think Steven mentioned it, but there were so many new pieces of data in the presentation, just to emphasize it, we have done work income we fall FOLFOX-CETUXIMAB and FOLFIRI-CETUXIMAB that those cohorts have been enrolled. They need longer follow-up, which is why we haven't presented them, but they will enable potentially frontline. As we started to think about the bracelet it became clear to us that there's a next generation of EGFR inhibitors that deserve attention. Of those, we decided perasanimab based on the data summer which was presented here at ESMO was the most compelling data set, and that's why we put in place that combination. I can't tell you today what the frontline colorectal study will be with 734. I can tell you that we're going to conduct one, whether it's with the backbone of cetuximab or petosentamab, I think the data will determine that. Eric, I don't know where the mic went. Eric has been waiting, sorry, and we'll go to the back there. Yes, then we're going to the back.

Maybe for Dr. Hidalgo or the company, what is the role of chemotherapy first-line setting going forward if you do have a chance or a choice of using a G12D with a pan RAS or with an EGFR or even with a PRMT5 inhibitor. Where do you think the patients are going to want to go and how has that been on the data, of course. And then for the company, are you doing any prophylax, GI prophylaxis on 734.

So the chemo question. all is going to be, of course, data-driven. I won't be surprised and actually, I hope that not too far from now, there are no chemo combinations that in selected populations or in larger populations at the PLN5 results in substantial responses and duration of responses that can displace chemotherapy from the front line. But I think that chemotherapy still will remain part of the standard of care for later lines no patient is being cured, unfortunately with these combinations. We delayed the progression. But eventually, we're seeing that with that action, we're seeing that in all the studies that will be a point that we treat them with chemotherapy. So one question would be a more sensitive or differentially sensitive to chemotherapy. But as we speak today, I think the chemotherapy is the standard of care in the first-line setting. So the combos with chemo that are well tolerated, I think are going to get there sooner than the targeted, targeted combinations. And then we will see how the impact on OS is going to be also important. Probably, these are killing different sell-up types. So do you want to kill them all at the beginning or kill a few and then kill the others. What is the impact of that in survival will be important. So it's interesting questions for the future, but I don't think chemotherapy is going to move from the front line in the next few years.

Steven on the geoprophylaxis, please.

Eric, yes, thanks for the question. So obviously, in terms of nausea, vomiting and diarrhea, learning as we went through the Phase I program is to very proactively manage them. So both at the antiemetics and antidiarrheals, and then train in, in that regard. And I think you saw it play out in the data sets in terms of very low discontinuation rates despite the relative amount of those different adverse events. And then certainly, in terms of and proves algo alluded to this, sort of patients getting used to on how to manage themselves in terms of when to the therapy is how because you see amelioration of those toxicities as the cycles progress. Second and third cycle and beyond rates actually get much, much lower. So I think the combination of training, appropriate use of treatments and then patient adaption to the regimens is what's happening there.

Andy Berens, Leerink Partners. Congrats on the data and the very extensive programs. And maybe to follow up on Eric's question. When I look at 734, it's obviously very extensive. A lot of different combination partners, but there's 1 that's conspicuously missing and that is a pan-RAS inhibitor. Why would you not want to do that trial now just to protect yourself in case that's the direction that the clinical paradigm evolves to. I mean that we're hearing a lot of enthusiasm amongst clinicians. And then also for 734, is it brain-penetrant? And if it is, what kind of side effects do you see from that?

The second [indiscernible] is not. So that's pretty clear from the preclinical data. On the first part of your question, Andrew, look, we are not done established combinations. As we made clear in the slides, both for 734 and 890, we have ongoing discussions for additional combinations. I agree with you on the potential merit of a combination with the pan-RAS inhibitor. We haven't selected 1 at this point, which is 1 -- we haven't put that in place, but we're not rolling out doing that as well. We thought other commissions were more urgent because we have, particularly in PRMT5, I think we need to accelerate that collaboration, which is one of the reasons why we selected the compound that is in the lead. It's in pivotal trials already. But stay tuned as more collaborations will be announced in the future and what could very well be with the Pan RAS inhibitor.

Combinations -- it's that there are now -- every day, there is a paper a preclinical paper that -- show synergy, right? And there are, I don't know, 20, 30 very cool combinations that everyone is kind of -- so I think it's going to be quite crowded space, what are the right combinations and which 1 of those we need to advance to the clinic, but there are many, many others that are in preclinical studies look very, very interesting. So how do we -- which ones we select, which one do we pick, it's going to be a challenge.

Matt Phipps, William Blair. Thanks for all the details. First of all, if you think about some of these conversations, any thoughts on an EGFR combo in PINK, maybe even pitosyntomab? Is that a possibility under the current agreement? And then as you look at agree, this might be also a question for Dr. Garralda if EGFR biospecifics become kind of left-sided KRAS wild type standard of care and then some KRAS combo moves into the KRAS mutant across these different variants. Do you need to try to fit 890 into those? You're running this 890 bev combo, like is that patient population going to shrink as these others kind of come up?