Hello, my name is Sarah, and I will be your conference facilitator today for Amgen conference call, following the 2023 European Society for Medical Oncology Congress. All lines have been placed on mute to prevent any background noise. There will be a question and answer session at the conclusion of the last speaker's prepared remarks. In order to ensure that everyone has a chance to participate, we would like to request that you limit yourself to asking one question during the Q&A session.
To ask a question, please press Star, then the number one on your telephone keypad. To withdraw your question, please press Star one again. I would now like to introduce Mr. David Reese, Executive Vice President of Research and Development. Mr. Reese, you may now begin.
Thanks, Sarah, and good morning and good afternoon, everyone, depending on where you're joining us from. We're very happy today to give an update on our oncology pipeline after the ESMO meeting, where we had some major data presentations.
We have a lot of material, so we're going to jump right in, in just a moment. I would note that all of the slides that we're presenting today will be posted on our website immediately following the call. On the next slide is our standard safe harbor statement. If we move to the next slide, you'll see the agenda today. I'll give an introduction to our strategy, just as a reminder, very briefly.
I do want to say a few words about BLINCYTO, because we continue to generate very nice data with that molecule, and reach more patients who can benefit from it. We're very happy to be joined by Dr. Taofeek K. Owonikoko from the University of Pittsburgh Medical Center, to talk about Tarlatamab, and Dr. Kevin Kelly from the Sidney Kimmel Medical College, where he's the Chair of the Department of Medical Oncology, to talk about Xaluritamig . Both of these investigators have extensive experience with these particular bispecifics, and I'm sure you'll have questions for them.
Then Jean-Charles Soria, whom you all know, will take you through some of our precision oncology drugs, with updates there, as well. So just to remind you of our general approach to oncology, it is split between immuno-oncology and precision oncology approaches.
Today, we're going to talk about updated data from our T-cell engager platform, which I think is showing now real maturation and has reached some watershed moments with demonstration of efficacy in solid tumors, more than one solid tumors. We will also talk about updates on targeting cell-intrinsic targets, in particular, AMG 193 and some additional LUMAKRAS data.
The oncology portfolio in the 18 years that I've been at Amgen, I think now is broader and actually more heterogeneous than it's ever been. And to me, the one real takeaway is that I think we have the opportunity to really change the natural history of some of these diseases, where there is tremendous unmet medical need a nd that's a theme that I'm going to come back to as we move through today's event.
Now, let me start with BLINCYTO. BLINCYTO has been around now for a decade, and as you can see, it is approved, of course, initially in the relapsed refractory ALL setting. It is also FDA-approved in individuals who have minimal residual disease or MRD positive ALL after induction therapy t hat's a situation where there's a high risk of relapse. We've demonstrated curative potential in that setting. And now with the E1910 data, which I'll remind you of in a minute, which FDA filing is underway, we will be moving into the first line.
One of the things that, you know, we have learned through now a decade of development of BLINCYTO is that efficacy improves and toxicity decreases as you move into earlier lines of therapy, almost certainly related to the lower tumor burden. This makes sense biologically, it makes sense immunologically, but that's a roadmap that I'd like you to keep in mind as we begin talking about Tarlatamab and Xaluritamig .
I'd also remind you that the Golden Gate phase III study is enrolling for BLINCYTO, which is a potentially chemotherapy-sparing regimen in older adults o lder in this disease is considered 55 years or older, where the prognosis is often much more poor.
This is a trial that I'm looking forward to very much a gain, I think we can change the natural history of the disease i n fact, if you look at the next slide, what you can see from the ECOG-ACRIN NCI 1910 trial, E1910, in both patients with MRD negative disease as well as MRD positive disease, you see an improvement of overall survival when BLINCYTO is incorporated into standard consolidation regimens for ALL.
You know, this is, you know, this to me really points to the direction where this field is moving, and an ability to really enhance cure rates.... Now here again, we show E-1910 on the left, but this has been replicated in the pediatric setting, as well as against historical controls in infants with first-line ALL. So again, you're seeing a theme here. Increased cure rates when you actually administer the drug in a setting of low tumor burden.
I 'd like to leave you with a thought about BLINCYTO. Here you see on the chevron illustrated its development over time. Now, as I mentioned, the Golden Gate phase three study is enrolling, which I think could redefine the standard of care in first-line induction therapy, as well as consolidation and maintenance as part of the complex treatment regimens that these patients receive. And then I do want to put on your radar that we are developing a subcutaneous formulation of BLINCYTO w e've reported a few handfuls of patients previously at ASH.
We've accumulated a fair amount more data since then, which we're hoping to show later this year or on into next year. I think this is very, very promising, and maybe there's a possibility of enhanced efficacy, but certainly patient convenience and reach of the drug should be improved. I think there's still a ways to go with BLINCYTO as we really try to redefine the approach to ALL. Now we're gonna switch to our solid tumor bispecific, starting with Tarlatamab. And Tarlatamab targets DLL3, as you'll see in a minute, which is almost uniformly present on small cell lung cancer cells.
Just so everyone understands the disease we're talking about, small cell lung cancer, when it's staged, is divided essentially into two stages: limited stage and extensive stage. Limited stage means the disease is confined to the chest, in an area that can be encompassed by a radiation port, and chemoradiotherapy is the standard approach for those patients.
The vast majority of patients, unfortunately, at the time of diagnosis, have extensive stage disease, and there are roughly 30,000 to 35,000 patients with small cell lung cancer in the US. In the major countries in Europe, a relatively comparable epidemiology. Standards of care have not changed dramatically over the last 30 years. In fact, the same drugs that I learned as an oncology fellow in training 30 years ago are still employed in the clinic. Checkpoint inhibitors have been introduced. They have produced improvements in survival, but that has been very modest.
In the third-line setting, which we'll initially talk about today, there is no accepted standard of care, and most agents have not demonstrated very much efficacy at all. So keep in mind the BLINCYTO paradigm of moving forward to earlier lines of disease, as we talk about Tarlatamab. But let's start with the foundational data for the program, which is the Delphi 301 study. And with that, I'd like to invite Dr. Owonikoko to the stage to present the data that were just shared at ESMO a couple days ago. Dr. Owonikoko?
Thank you so much, Dr. Reese. Good afternoon, everyone, from Madrid. My pleasure to be part of this, and I want to quickly go through the data for Tarlatamab, an immunotherapy agent targeting DLL3 in small cell lung cancer. As you've heard, this is a construct that binds to CD3 on the surface of immune cells and DLL3 on the surface of cancer cells. Vast majority of small cell lung cancer cell will have DLL3 expression on their surface, more than 90% with different degrees.
W ith this binding, that this leads to activation of the T cell and T-cell mediated cell lysis. Next slide, please. The DeLLphi 301 study was designed to test two different doses of Tarlatamab in patients with extensive stage small cell lung cancer, who had received at least two lines of therapy. They have good performance status, and they have disease that we can measure and follow to estimate the efficacy of interventional agent. A lot of our patients have brain metastasis, and this was allowed in the study if it's been treated and stable.
T he two doses tested were at 10 mg and 100 mg of Tarlatamab. This was given on day one with a small dose followed by the definitive dose on day eight, and then subsequently on day 15, and thereafter, every two weeks. The primary endpoint for this study was overall response rates. And other important endpoint that we look for is duration of response, as well as other measures of activity, such as overall survival. Next slide, please.
Majority of the patients on this trial, which was more than 200 patients across the different parts of the study, were male, 70% of them. Median age is comparable to what we see in patients, and if you see here, more than a third of the patients had received at least three lines of therapy. This is a population where we currently don't have any standard of care.
Important to also note that majority, about 70% of these patients, received anti-PD-1 or PD-L1 as part of their frontline regimen before coming on trial. DLL3 expression was assessed and was present in more than 90% of the patients. Next slide, please.
L ooking at the two doses of Tarlatamab tested on this study, there was definite evidence that this agent had activity. Our objective response rate was 40% at the lower dose of 10 mg and 28% at the higher dose of 100 mg. We did see patients with complete responses with both doses, especially at the higher dose of the drug that was tested.
W ith this evidence, we, I think it's safe to conclude that we have preliminary evidence that Tarlatamab, at the 10 mg dose especially, would be efficacious in heavily pre-treated small cell lung cancer based on this objective response rate of 40%. Next slide, please. This is our waterfall plot showing individual patient on trial. What is most noticeable here is the vast majority of patients, even if they did not meet the objective response criteria, showed some reduction in tumor burden.
Now, whether you look at the 10 mg or the 100 mg dose, and this was regardless of the level of presence or absence of DLL3 expression. The red diamond signs there show those without undetectable DLL3, where we still saw evidence of tumor shrinkage, including patients treated at 10 mg who had objective response by RECIST criteria. Next slide, please.
This is what we call the Swimmer plot. It sort of tells us, for those patients who had response, how long did the response last for? Number one thing to notice there is the patient that had responses, it occurred very, very early.
The time to response was about 1.4 months in terms of median, and the duration of response when measured in terms of median, has actually not been reached. Majority of the responders continued to benefit more than six months from when they achieved response, and 56% of the responses were still ongoing at the time the data was summarized for this ESMO meeting. Next slide, next slide, please.
One thing about small cell is we've had agents in the past that would induce responses, but those responses don't last, and oftentimes they do not convert into other efficacy signals, such as progression-free survival and overall survival. What is particularly encouraging with Tarlatamab is the fact that the responses that we're seeing also converted into signal in terms of PFS at six months, with more than 40% of patients achieving progression-free survival at that median time six-month landmark time point.
M ost impressively is the overall survival. In the third line setting, where we do not have anything to really treat patients effectively, majority of the patients do not last very long. It's usually measured in matter of months. If anything, you treat the patient with works or doesn't work, and majority of our patients unfortunately do not do well at this line of therapy.
While this is still very, very early, I think this early data is quite encouraging, that 57% of patients treated at the 10 mg dose, and more than 50% of the patients treated with the 100 mg dose, were still alive by the time of the data summary for the meeting. Next slide, please. There's always concern with this immune, mediated strategy, whether or not patients can actually tolerate them. Vast majority of patients treated at both doses experienced some type of adverse events.
As would be expected, majority of these were immune-related, sort of, what we call CRS, which is more or less on-target effect that we see when we use this type of construct. Grade three or higher toxicity were much less frequent, and dose reduction or dose interruption was infrequent. If you look at the 10 mg dose, only 14% of patients had their doses reduced or interrupted, and a slightly higher proportion, at 29%, at the 100 mg dose.
Speaking specifically to the CRS, about half the patients on the 10 mg dose experienced some type of CRS, mostly grade one and two, no grade three. With the 100 mg dose, about 55% had grade one, two, and 6% experienced grade three. These were mostly easy to manage. A majority of these patients, as I highlighted before, did not have to permanently discontinue the treatment.
There is ongoing efforts to see whether or not this regimen will be amenable to our patients' use, on like what we did when we first started, where we had to admit patients into the inpatient setting to administer the drug. Next slide, please. With respect to the cytokine release syndrome or CRS, we are particularly interested in whether or not there is neurotoxicity, the ICANS t his is a subset of CRS that could be life-threatening. Two things that I want to quickly highlight here is the observation that CRS was largely confined to the first two doses that the patient got on trial.
W hen we look at the 10 mg and the 100 mg dose, a majority of the CRS was observed with the first two doses that the patients were given... once you pass the first two doses, the rate of CRS overall went down. More importantly, ICANS, which is a much more concerning type of CRS, was quite infrequent. Less than 6% of patients across all the doses and time points experienced any type of ICANS event. And when you look at those that had it, it was predominantly observed with the Tarlatamab at the much higher dose of 100 mg.
This was also reversible with the use of tocilizumab. Some of the patients had requirements in terms of additional intervention for CRS of using oxygen and vasopressor support in very rare instances with one or two patients. Next slide, please.
T o conclude, based on the aggregate data that we have now about Tarlatamab, especially the 10 mg dose, there's durable anticancer activity. The safety is very encouraging. A lot of what we saw were CRS that were easily manageable, with the overall response rate of 40%, in this third line setting or higher.
This is really, really meaningful for our patient population, and this is durable response that is lasting more than six months in more than half of the patients. The most common treatment-associated adverse events, was the CRS, occurring mostly with the first two cycles, doses in cycle one, and generally manageable with supportive care. Discontinuation was very low, at 3% with Tarlatamab.
While we continue to use inpatient monitoring for the first cycle, there is ongoing effort to study the safety profile without the need for inpatient monitoring at all, or maybe a shorter duration of inpatient monitoring as we continue to develop this agent. At this current point, Tarlatamab at the 10 mg dose has been selected for further development. I think the results overall will support the use of this agent in previously treated small cell lung cancer. I'll be happy to take questions later on. Thank you.
Great. Thank you, Dr. Owonikoko. That was great, and we'll come back to you, of course, for questions. I just want to end this section by returning to the development program for Tarlatamab. DELPHI-301, which you just saw, we actually have begun, after discussions with the FDA, a submission and, as you know, these data continue to evolve, we will update you on that potential registration pathway and what timelines may look like. But you know, that's something obviously of great interest to the field.
In addition, the DeLLphi-304 study, which is a second-line trial, head-to-head against standard of care chemotherapy, with overall survival as a primary endpoint, is now briskly enrolling. And we have studies planned in the first-line induction maintenance setting, as well as in the setting of limited stage disease. Again, returning to the BLINCYTO paradigm, and moving into earlier lines of therapy with lower tumor burden.
We anticipate with that, within the next six to eight months, we will launch the studies in earlier lines of therapy, first-line induction maintenance, and limited stage disease. So this is going to be a comprehensive, broad-based development program based on the clinical profile that we've seen to date. Now, we have a second BiTE with activity in solid tumors as well, Xaluritamig , and, you know, we'll move into that in a minute.
Unlike small cell lung cancer, the treatment landscape for advanced prostate cancer is much more complex. Patients often, when the disease progresses beyond local therapy, they receive a variety of hormonal therapies, then ultimately potentially, chemotherapy, and now, radioligand-directed therapy, as well.
There still remains substantial unmet medical need across that spectrum. The disease cannot, as of yet, be cured. And the question is how to best position Xaluritamig in this complex treatment landscape. I do believe we have the foundational data to begin thinking about that, and would now like to ask, Dr. Kelly to present, the data that he shared just a few days ago, in Madrid, at the ESMO meeting. Kevin?
Yeah. Thank you, David. Good morning, good afternoon, everybody. It's my pleasure to present some of this data that we just recently presented to ESMO. And this was in patients with advanced prostate cancer, targeting STEAP1, which is a cell surface antigen, which is highly expressed in prostate cancer, and is associated with poor survival.
Important to note, it is highly expressed in prostate cancer, but minimally expressed in other normal tissues. Often I'm asked is the differences between the PSMA expression and STEAP1. Again, it's that STEAP1 is more homogeneously expressed throughout tissue into higher levels, and it doesn't have the off-target effects that PSMA may have also. So this makes it a very good target for immunotherapy.
Xaluritamig is a 2:1 T cell engager designed to facilitate T cell-mediated lysis of STEAP1-expressing cells. It's unique because it has specificity to STEAP1 and also attracts the T cells through the CD3 component. I n preclinical studies, Xaluritamig showed a broad anti-cancer effects, both in prostate cell lines and xenograft models.
I t was moved into early phase development. Next slide, please. And, you know, this w e presented the first global first-in-human open label study in patients with advanced prostate cancer. The primary objective of this study was really understand the safety and tolerability and find the maximum tolerated dose of Xaluritamig. Secondary objectives including looking at the pharmacokinetic profile, but also look at the primary anti-tumor activity. And it's just important to note, in a phase one study like this, is that usually you see responses less than 10% of the patients.
Other exploratory objectives include progression, pharmacodynamics and immunogenicity of the drug itself. Patients that were included were patients with metastatic castration-resistant prostate cancers. These are patients who have progressed on most of the standard therapies, hormonal therapy, chemotherapy, and the novel anti-androgens, such as enzalutamide and apalutamide.
This was a dose exploration, which means that we started at a low dose and increased the dose over time. We went through 12 cohorts to really define the optimal dose for it, which actually included giving pre-medications, hydration, and also doing what we call step dosing. We finally discovered the safe dose or the tolerable dose in this population, which was 0.1 mg on day one, cycle 1, 0.3 mg on day eight. Day 15 was 1 mg, and day 22 was 1.5 mg.
These were given with pre-medications, and it was well tolerated. The patients that enrolled here was typically what we see in a phase one study like this. It's important to note these were very heavily pretreated patients. Number of prior lines of therapy was an average of 4. 27% of them had 5, 85% of them had prior chemotherapy. But most important is a large proportion of these had bone metastasis, 53%. But of those, 37% of them had liver disease, which is the most aggressive component of this advanced disease. Next slide, please.
Again, just get to the point here, this is what we call a PSA waterfall plot, which actually shows the decline of PSA, which is the marker we use to see the clinical activity in patients. We looked at it in two ways, with high dose and low dose cohorts. The high dose cohorts was above 0.7 mg, which were the therapeutic levels that we saw preclinically that we suspected versus the low dose. Important is that we saw responses in all cohorts across the board. And again, that it was high response rates was higher in the higher dose cohorts.
When we look at the PSA, less than 50, was done in the low cohorts, around 40%. In the high-dose cohort, it was 59%. But patients whose PSA went down more than 90% was 19% in the low-dose cohort and 36% in the high-dose cohort. Very impressive, PSA responses for this very advanced, population. Next slide, please.
Again, so we also looked at, patients with measurable disease on the CT scan. And again, that we looked at high dosing, low dose cohorts. And again, is that, partial responses for overall was 24%, 3% in low dose cohorts, but 41% in the, high dose cohort, which again, is very remarkable for this population. Next slide, please.
Again, it's very much like Tarlatamab. Responses occurred very quickly. If you look at the blue stars there, that's when you get the PSA 50 response, and PSA 90 is, if you can see it there, on the purple triangles. It usually occurred within the first four weeks. Again, there are patients who have been on a long time. Some patients have been a long time.
It's a little difficult in the phase one study because we are pushing some patients to toxicity. But the 19 patients from the high-dose cohort remained on treatment at data cutoff, and those 13 patients from the high-dose cohort remained on treatment for over six months. If you look at those patients who actually had measurable disease and a confirmed partial response, the median time was 9.2 months. That's also very, very encouraging data there. Next slide, please.
This is just an example of a patient who responded. On the left is a 65-year-old who was heavily pretreated with metastatic castration-resistant prostate cancer. Again, what you see in the liver, on the left, large metastatic lesions into the liver. After several cycles, these have virtually gone away. And this correlates with his PSA dropping down to less than 90%.
On the right-hand side is what we call PSMA PET scan. What you can see is diffuse disease not only all the way through the liver, but throughout the bones. And what you see on the right is, this is a complete resolution of the liver and most of the bone disease.
Again, that this was also confirmed the PSA 90 response. It's impressive here because very rarely we see responses in the bone, and here we are seeing responses in bone, which is also a very encouraging response. Next slide, please.
Toxicity was overall manageable. The major toxicity we did see was low-grade cytokine release syndrome. We did have initially early, we had some grade three, but with the adjustment of the premedications, afterwards, we did not see any grade three CRS. We did see fatigue and anemia, which was related to more to the disease. And again, that's really no grade four or five events.
We did have treatment related musculoskeletal and connective disorders reported in 14% of the patients. Again, etiology is not known since STEAP1 is not known to be expressed highly in the muscle. That's ongoing investigation to better understand these muscle skeletal and connective tissue disorders. Next slide.
Overall, Xaluritamig is the first T-cell engager for STEAP1. The MTD was established with a step-dosing premedications. The safety profile overall was manageable, with CRS generally low grade, and we saw principally only in cycle one. We saw very encouraging antitumor activity in heavily pretreated patients with metastatic castration-resistant prostate cancer. Again, PSA 90 response in the high dose, 36% with overall RECIST criteria of 41%. Ongoing is dose expansion and optimization are currently ongoing, both as a monotherapy and combination.
Again, this abstract actually really, or the study really, gave a lot of buzz around ESMO because this is really the first T-cell engager that has shown activity, and it's first in class in prostate cancer, in a tumor that most people thought would be a cold tumor and could never be targeted like this. So I think it really breaks a new barrier for immunotherapy in prostate cancer and other solid tumors also, that there is really hope that these type of therapies are gonna really be meaningful and make a great impact on patients. And I'll turn you back, Dave, and thank you for your attention. Happy to take questions later.
Great. Thank you, Dr. Kelly. I'm sure there'll be plenty of questions. So, if we look at the plans going forward for Xaluritamig , as Dr. Kelly mentioned, we're on a rolling dose expansion now to generate additional efficacy and safety data. In fact, we have relatively large cohorts, and I'm pleased to announce that we've completed enrollment very quickly in the dose expansion cohorts.
We will be examining those data in through next year to further define the development plan. But again, if you think about what I think of now as the standard BiTE paradigm of trying to move towards lower tumor burden settings. Of course, we'll start in later lines of therapy in a chemo-refractory setting, but also the chemotherapy-naive setting in patients with advanced castration-resistant prostate cancer.
We are enrolling cohorts now in combination with various hormonal therapies, and that will form a foundation for treatment in earlier lines of therapy, in combination. And then ultimately, I think, you know, the real chance for this molecule, should we continue to develop efficacy and safety data, that, you know, resemble the current clinical profile in settings like biochemical relapse, or earlier stages of disease, which can be thought almost as an analog of minimal residual disease, in ALL, or a post-induction therapy setting in small cell lung cancer, where you've got minimal tumor burden.
You know, this is where I think we really have a shot to change the natural history of the disease. So while it's, while it's a little earlier here, I think we again have the foundational data, and, and we're very eager to move this molecule forward in a broad development program. Well, now, let's turn to precision oncology. And, I will now turn things over to Jean-Charles, whom you all know, who will talk about some of the updates again that were just presented within the last week, or ten days, and then we'll open it up for Q&A. Jean-Charles?
Yes, thank you, Dave, and good morning, good afternoon to all of you. I would like to share an update on AMG 193, next slide, that we shared as an oral presentation a little over two weeks ago at the triple meeting, AACR, EORTC, NCI. AMG 193 is an oral MTA-cooperative PRMT5 inhibitor that demonstrates synthetic lethality in MTAP-deleted cancers.
PRMT5 is a master protein regulator and enzyme that is implicated in cancer development through a great variety o f mechanisms, and that it's important to remember that the development of first generation PRMT5 inhibitors was not highly successful. And therefore, I want to draw your attention to the very specific nature of this oral compound. This is a molecule that will only have activity in the specific setting of MTAP gene deletion.
MTAP gene deletion will lead to an accumulation of MTA, which per se, partially inhibits PRMT5. In the presence of MTA interacting with PRMT5, AMG 193 will be able to bind, and therefore lead to a full inhibition of PRMT5. Next slide. MTAP deletion is a frequent event in the setting of cancer. The prevalence is around 15% of cancer, so that represents over 100,000 annual MTAP new patients in the U.S. and probably an equivalent opportunity in Western Europe.
The top five tumors contribute to overall 70% of overall MTAP new patient incidents. And you see these are different tumor types where the prevalence is above the 20%. MTAP deletion is detected through NGS and is routinely reported in various tests that have been approved, including FoundationOne and Tempus results.
If we move to the next slide, this is a busy slide that represents the dose escalation of an ongoing first-in-human study, where AMG 193 is administered orally once daily, with 28-day cycles of continuous dosing. I would like to draw your attention to the key inclusion criteria, which is to be included on the basis of a locally determined MTAP deletion by NGS or a centrally determined MTAP protein loss by immunohistochemistry.
MTAP deletion and CDKN2A deletion coexist. That's why we also allow CDKN2A deletions. Well, we have enrolled 48 patients in seven escalating quarters of once daily 193, ranging from 40 mg to 1,600 mg. Out of these 48 patients, 18 patients have been treated at active dose levels above 800 mg. Let's move now to the next slide.
The activity of AMG 193 in the active dose levels above 800 mg is summarized in this... Well, it's okay. Let's stay on activity, and I will go to safety later, since we already jumped there. So in terms of activity, and this is, as I was saying, the 18 patients treated about 800 mg. What I'm showing here is a 3-D waterfall plot, where you can see both the best change of lesions in diameters and the duration of the activity of the drug.
Well, it's very interesting to highlight that five out of these 18 patients have partial responses in five different tumor types. I would like here to draw your attention to the three patients who have non-small cell lung cancer and have been treated at active dose levels. We have one patient who progressed, we have another patient who is stable disease. This patient with stable disease has clear tumor shrinking that is amplifying over time. I'm happy to report that the second patient that was a stable disease when we presented this data in Boston has now achieved a PR.
If we move now to the toxicity slide, this is overall a drug that has treatment-related adverse events in around 81% of the patients. They were mostly grade 1 and 2. The most common treatment-related adverse events were nausea, fatigue, vomiting, and decreased appetite. Consistent with the tumor selective mechanism of action, there was no clinically significant myelosuppression, which was the main drawback and problem of first generation PRMT5 inhibitors.
If we move to the next slide, which is the summary slide, AMG 193 is an MTA cooperative PRMT5 inhibitor that targets MTAP null solid tumors. This is a reality that is prevalent in around 15% of solid tumors. We are encouraged because we are seeing now activity across 6 different tumor types, including non-small cell lung cancer.
Dose-limiting adverse events and treatment discontinuations were typically due to clinically manageable GI events, and we see a favorable therapeutic window and a clear opportunity to explore potential combinations. We have an ongoing dose expansion course, which will inform the future development strategy. If you move now to the second precision medicine molecule that we have and for which we have data at ESMO, that's sotorasib. Next slide.
We are encouraged by LUMAKRAS data that is measured in colorectal, and I would very briefly touch on small cell lung cancer. For colorectal cancer, I will share with you some of the key slides of our phase 3 trial, CodeBreaK 300, which combine LUMAKRAS with Tecentriq in the third-line setting.
But I also want to remind you all of the very encouraging phase 1b data of LUMAKRAS to Tecentriq plus FOLFIRI, that we have already shown to all of you. In non-small cell lung cancer, we have promising phase 1b data of LUMAKRAS in combination with chemotherapy in chemo-naive KRAS G12C-mutated non-small cell lung cancer that we have shared at ASCO at the World Lung Cancer.
Next slide. But let me focus now on CodeBreaK 300. This is a trial that featured three arms evaluating sotorasib at two different dose levels plus panitumumab. And it was compared to investigator choice of trifluridine/tipiracil or regorafenib, which are standard of care. If we move to the next slide.
The baseline characteristics between the three arms were generally well-balanced, and I want to highlight that 15% of patients received one prior line of therapy, whereas 85% received two or more lines of therapies. If we move to the next slide. This is the primary endpoint, progression-free survival, in the intent to treat population. And it's very clear that the median PFS was improved from 2.2 months in the investigator choice for the median, to 3.9 months at the 240 mg, and 5.6 months at the 960 mg. Reduction in the risk of progression of death was 51% at a 960 mg.
This is something that was demonstrated by PFS, that was evaluated by blind central review, and it shows something that is clinically meaningful for these patients. Next slide. If we look at the forest plot, the benefit in terms of PFS on the left for the 960 mg and on the right for the 240 mg combination is observed, in fact, in every single one of the subgroups. And it's observed both at the 960 and at the 240 mg, even if its nature and the hazard ratio reduction is more obvious at the 960 mg. Next slide.
In terms of response and disease control, the 960 mg combination had a 27% objective response rate and a disease control rate of 72%, as compared to a disease control rate of 46% in the investigator's choice, and no responses in that arm.
Responses were also seen at 240 mg, but to a lesser extent, with a disease control rate of 68%, that still remains superior to the investigator choice. Next slide. Tolerability was exactly as expected, the most common grade three or higher treatment-related adverse events for sotorasib plus panitumumab were hypomagnesemia, acneiform dermatitis, rash and diarrhea. For the investigator choice arms, they were neutropenia, nausea and anemia. And absolutely nothing new to report in terms of new safety. So we can go to the next slide.
I n conclusion, CodeBreaK 300 is a randomized phase two trial that met its primary endpoint for superior PFS of this combination of LUMAKRAS Tecentriq versus investigator choice therapy in metastatic colorectal cancer. We see a clinically meaningful benefit that is demonstrated by a median PFS that went from 2.2 months in the investigator choice to 5.6 months at 960 mg.
The PFS favored the combination in all subgroups. We have higher response rate, higher disease control rate, and OS, which I have not shown in detail, is immature but trending favorably, notably for the 960 mg. We believe that these results, along with previous data from non-small cell lung cancer, support sotorasib 960 mg as the sotorasib dose for use in colorectal cancer. Sotorasib 960 mg plus panitumumab is a potential new standard of care therapy for patients with chemotherapy refractory KRAS G12C-mutated colorectal cancer. Next slide.
Colorectal cancer discussions with this phase three data are obviously ongoing with the regulators, and we are planning to initiate a phase three study of LUMAKRAS, Tecentriq and FOLFIRI in the frontline setting of colorectal cancer. KRAS G12C mutation, as you know, represents 3% to 5% of colorectal cancer.
Encouraged by the activity of chemotherapy LUMAKRAS combination, we have initiated a phase three study of LUMAKRAS plus chemotherapy in the first-line setting of PD-L1 negative KRAS G12C-mutated non-small cell lung cancer. We believe that that population represents around 13,000 patients in the U.S.
Next slide. I will briefly remind you, next slide, that we also have another precision medicine therapy, which is the monoclonal antibody bemarituzumab, that is targeting FGFR2b receptor, extremely prevalently expressed in gastric cancer, which is the 5th most common cancer worldwide. Next slide.
The phase two dataset has shown a clear superiority of the combination of bema with chemotherapy over standard of care chemotherapy. And if we see next slide, we have two ongoing phase three trials that are currently recruited in the frontline gastric setting. The combination of bema with FOLFOX6 versus placebo FOLFOX6, and that's FORTITUDE-101, and we have bema plus chemo plus nivolumab versus placebo chemo nivolumab in the same setting, FORTITUDE-102. With that, I hand it back to you, Dave. Thank you very much for your attention.
Great. Thanks, Jean-Charles, and thanks everyone for staying with us. As we said, we had a, you know, a lot of material today. You know, a couple key messages I'd like to leave you with. You know, we move forward with BLINCYTO development t hat's the roadmap for other bispecifics, you know, into earlier lines of therapy, and now with development of the subQ formulation.
W ith Tarlatamab and Xaluritamig , we believe we have foundational data to launch, you know, phase three trials, but also to begin to think about development in earlier stages of disease. Again, where we really are going to seek to change the natural history in the precision oncology portfolio. AMG 193 is moving forward very briskly, and as we continue to accumulate data into the first part of next year, we'll really start to refine the development program there a nd then I think you're all familiar with LUMAKRAS in the phase three programs that Jean-Charles just outlined.
W ith that, I think we will open it up for questions and answers. If you didn't catch the Tarlatamab and LUMAKRAS papers in the New England Journal over the last few days that were published concomitantly with the presentations at ESMO, I'd urge you to read those carefully.
The Xaluritamig data were also published in Cancer Discovery, and then a few weeks before that, the AMG 193 data were also published in Cancer Discovery as well. There's also a wealth of rich detail in all of these manuscripts. So with that, we'll go ahead and move to the question and answer session. Sarah, can you remind everyone of our procedure here and then open up the lines?
Yes, thank you. If you would like to ask a question, please press star followed by one on your telephone keypad. If for any reason you would like to remove that question, please press star followed by one. Again, to ask a question, it is star one. Our first question comes from the line of Salveen Richte r of Goldman Sachs. You may proceed.
Good morning. Thanks for taking my question. The Tarlatamab results in small cell lung cancer are remarkable in such late line patients. How do you see the drug fitting in as you move to earlier lines? And then could you comment on potential CNS activity for the drug, given the prevalence of CNS metastasis in this population? Thank you.
Yeah, thanks, Salveen. Those are great questions. Y ou know, I, I'll say a few words and then ask Dr. Owonikoko to also comment on those particular points. You know, we're, we're very eager to move Tarlatamab into earlier lines of therapy, where tumor burden may be much reduced compared to the sorts of patients that you saw treated in this third line and beyond setting.
A s I said, and in fact, we expect to launch phase three trials within the next six to eight months in the sort of first line induction maintenance setting, as well as in limited stage disease. The disease is often treated with you know, induction chemotherapy.
Y ou know, a large percentage of patients respond, but the problem is a relatively rapid relapse and then aggressive disease b ut that moment in time where they've achieved a response and a much-reduced tumor burden, we think is a point where, the addition of the bispecific, may actually be able to really alter the natural history of the disease.
Y ou know, that'll be one of the focuses of the development program. Let me ask Dr. Owonikoko to comment on that, and then also the, issue of potential central nervous system activity, which is, of course, quite important to this patient population. So, Dr. Owonikoko?
Yeah, thank you. Those are two very important questions. I believe that Tarlatamab would eventually have a definite role in the treatment of all phases of our patient, especially in the earlier stages. And the two reasons why I said that, one is the current trial in the DeLLphi-301 study. We enrolled patients who had previously received anti-PD-1, PD-L1 therapy, and that did not compromise their ability to benefit further from Tarlatamab, suggesting that these are two potentially complementary mechanisms of immune activation.
S pecifically in small cell, where majority of the tumors are actually cold tumors, I think the mechanism by which Tarlatamab works, by binding to T cell wherever they are, and then taking them into the tumor immune microenvironment, will be an advantage. And I will make this work even earlier in the, in the treatment algorithm for patients.
With regards to brain mets, patients were allowed on this trial if they'd had brain mets treated and stable. We did not have untreated brain mets, so it's difficult at the current time to say what exactly is the role of, efficacy of Tarlatamab in intracranial disease control. So in terms of observation on the study, we did not see any excessive, evidence that majority of the patients were progressing in the brain, which could indicate that perhaps it's not working in that sanctuary site s o we did not observe that.
The second is borrowing from other studies, especially in the front line, with the combination of IO and chemo, where patients with untreated brain metastases were allowed. We know that immunotherapy or immune-based strategy could also reduce the incidence of brain metastases. I would say the jury is still out, but it looks promising based on the aggregate data that Tarlatamab might be able to help patients in terms of brain metastases.
Great. Thank you, Sarah. We'll move on to the next question. Let me just make one clarification. I got a little bit ahead of myself. My team just reminded me on AMG 193, that manuscript is just about to be submitted, but is not yet published. But the others are of course out and available for you. Sarah, what's our next question?
Thank you. Your next question comes from the line of Jay Olsen of Oppenheimer. You may proceed.
Oh, hey, congrats on the update, and thanks for taking the questions. Can you tell whether or not there's higher response rates in patients with higher DLL3 expression for Tarlatamab? Also, if there's any potential correlation between DLL3 expression levels and CRS or ICANS? Separately, are you planning to develop a subQ form of Tarlatamab or Xaluritamig , similar to what you're doing with BLINCYTO? Finally, can you talk about any CNS activity with AMG 193? Thank you.
Yeah. Let me take the first part. I'll ask Jean-Charles to discuss the AMG 193 portion of your question. You know, and we are looking at expression response data now, i.e., DLL3 expression versus response, and should have those data forthcoming. Our general sense, though, is that we saw responses, including major responses, across all levels of DLL3 expression, including in a patient or two with so-called negative tumors a nd I wanted to address that because this is a question we've got, you know, quite frequently over the last few days.
Recall that immunohistochemistry has a threshold of detection of typically, you know, a couple thousand receptor molecules per cell, or more, in order for a positive result to be returned. Based on a wealth of data that we've accumulated in the laboratory over the last decade, we believe that the BiTEs are active, probably at a threshold of a few hundred target molecules per cell surface, and maybe even fewer than that.
M y strong bias is that the DLL3-negative tumors that were reported as responding are in fact DLL3-positive, but just below the limit of detection a nd everyone really needs to keep in mind the assay limitations here. Likewise, we're looking at CRS versus DLL3 expression levels s o far, I don't think there's a major correlation there. There's probably a slightly better correlation with tumor burden, as opposed to target expression levels, especially when we saw target expression in almost all of the tumors here, 96%.
Finally, in terms of subQ development, we are thinking about that across the BiTE portfolio t hat will, you know, vary molecule by molecule, depending on various characteristics, and I'll provide guidance as that work proceeds. In terms of CNS activity with 193, let me ask Jean-Charles if he wants to comment for a moment.
Yes, thank you. We know preclinically that we have a very good CNS penetrant, agent. Our master protocol for 193 will explore a cohort of lung cancer patients with brain mets. We hope to have that started next year.
Great. Thanks, Jean-Charles. Yeah, and specifically, we have demonstrated CNS penetration in various rodent models, preclinically, and we attempt to do relatively rigorous experiments here. T hat formed the basis for exploring this in patients with brain metastases, as Jean-Charles mentioned, beginning next year. Sarah, why don't we go to the next question?
Thank you. Your next question comes from the line of Gregory Renza of RBC Capital Markets. You may proceed.
Great. Good, good morning, Dave and team. Congrats on a productive conference circuit, and thanks for taking my question. Maybe just keeping with AMG 193, just curious if you and the team, Dave, could comment on the 193 in the context of just the broader PRMT5 landscape a nd as you've described the development program, just interested in your comments on the case for combinations, namely with the MTAP, IDE397 and where you see perhaps the biggest impact from combination therapy and perhaps that which could be most transformative here in these patients. Thanks so much.
Yeah, thanks. Thanks for the comment or question. And you open up, I think, a you know, very important avenue, which is what is the development path for a molecule like AMG 193 that has now demonstrated activity in at least six different tumors.
You know, so one of the things that we will be thinking about as we, you know, generate additional efficacy and safety data and finalize dosing is there a tumor-agnostic pathway potentially supplemented with specific indications? Will we proceed in specific indications? You know, these are all of the things that are top of mind, but I think they are all possibilities based on what we are seeing here.
In terms of the MAT2A combination with IDE397, this, you know, this is, you know, based on the biologic rationale that two basically orthogonal hits on this pathway may be additive or synergistic. We're just beginning to generate those data and obviously looking at that very, you know, we'll be looking at that very keenly.
I think the clinical profile, including tolerability that we have observed so far, does set this molecule up for potential wide range of combinations. A s we get into 2024, we'll start thinking of talking about some of our thoughts there. As you mentioned, in many of the specific solid tumor indications, ultimately, combination therapy may in fact be the best use of a molecule like AMG 193. Thank you. Sarah, why don't we go to the next question?
Thank you. Your next question comes from the line of Umar Raffat with Evercore ISI. You may proceed.
Oh, hi, this is Chen Shan, for Umar. Just want to ask a question on Tarlatamab phase two data. T here's a higher number of patient deaths before post-baseline scan on the 100 mg dose. Can we get more color on this difference between the two, those arms, and why these patients on 100 mg seems to progress faster? And also, just a follow-up on the DLL3-negative patients there. The number of patients in this trial is small, but what is the expectation for this subgroup of patients? Thank you.
Yeah, thanks. So in terms of the, you know, the progression, I, you know, I suspect on a... One of the things we noted on the 10-mg arm versus the 100-mg arm is that patients, because of tolerability, patients were able to get on average, you know, a couple more cycles of therapy at 10 mg. And that may in fact have led to the difference in overall response rate, for example.
And always in these patients, you know, dose selection is trying to optimize the risk-benefit in the clinic. Based on everything that we saw, you know, we really feel that 10 mg at this point is at least for now, the go-forward dose.
The second question about, you know, true DLL3 negative patients. You know, here we saw 96% patients with some level of DLL3 expression. If you look at the literature, in almost all studies, it's above 80%, and in most studies, it's in the 85 or 90% plus range. So I think that's very consistent. You know, DLL3 is a marker that is present on neuroendocrine stem cells, and small cell lung cancer is a neuroendocrine stem cell-derived tumor.
T herefore, it's perhaps biologically not surprising that you have very high levels of DLL3 expression. My guess is that we will continue to see that kind of expression pattern going forward. Thanks, Sarah. Next question.
Your next question comes from the line of David Risinger with Leerink Partners. You may proceed.
Yes, thanks very much. W ith regard to Tarlatamab, and particularly in light of the comment that you just made, could you talk about the market opportunity as you see it? Certainly seems like it may be much larger than many appreciate, but how do you see the market opportunity for Tarlatamab, particularly as you move it into earlier lines of therapy? And then, as Xaluritamig is evaluated in earlier lines of therapy, how do you see it being positioned in an increasingly crowded prostate cancer treatment landscape? Thank you.
Thanks, David. You know, I'll take the Tarlatamab question, and then I'll ask Dr. Kelly to comment on how you think about developing a molecule like Xaluritamig in prostate cancer, given his decades of experience in this field. Again, for Tarlatamab, I would go back and look at the BLINCYTO development program.
You know, as you saw from the epidemiology figures that we shared, you know, it's 2,000 to 4,000 patients with third-line-plus disease, but that's not the end game here. And if we're able to demonstrate good efficacy and almost certainly the safety profile will improve as you move to lower tumor burden settings.
The real goal here is to be incorporated into that first line and, and limited stage, disease setting, where you can then potentially have the drug available to patients across, this spectrum. And, and as I mentioned, there are, you know, on the order of roughly 30,000, maybe a few more patients across that spectrum, in the United States each year, comparable numbers in, in Europe.
The numbers in Asia are actually quite large, where small cell lung cancer is relatively, prevalent. I think the, the market opportunity if we're able, to successfully move into these earlier lines of therapy is, much, much larger than that, few thousands of patients that you see in the true third line and beyond, setting.
Now, Kevin, you know, perhaps we could ask you to comment on how you would think about the development of an agent like Xaluritamig , as you move along the prostate cancer continuum, which is, of course, a complex treatment landscape. G o ahead.
Yeah. Yes, David, it's very complex, and it's getting complex by the day. But, you know, the basic premises of most patients with advanced prostate cancer is, is they do not like hormonal therapy, and they do not like chemotherapy.
Even in the early settings, they try to look for any alternatives to hormonal therapy s o I think there's a really a possibility as you move this up, you could either, you know, I wouldn't say replace it, but actually, maybe modify your different therapies up front, so it's more tolerable for patients. I do think that patients are looking for alternatives, both to chemotherapy and hormonal therapy, all the way through the spectrum and the journey of prostate cancer. I think there's a huge opportunity to move this forward.
You know, radioligands are also gonna play an important role. Again, as the question is, how can we synergize, how this new drug could synergize with radioligands and really accomplish eradicating more of the cancer and have patients free of hormonal therapy and chemotherapy? That's the way I look at it.
Great. Thank you, Dr. Kelly. Sarah, why don't we move to the next question?
Thank you. Your next question comes from the line of Mohit Bansal with Wells Fargo. You may proceed.
Hi, this is Reid Hunt from Mohit. Thank you for taking my question, and congrats on all the data. O n Tarlatamab and FDA discussions and next steps, I mean, what's the likelihood of including DeLLphi-304 Tarlatamab efficacy and safety data in that FDA package, as well as the part three data from DELPHI-301 that we saw over the weekend? Thank you.
Yeah, of course, we don't comment specifically on FDA discussions, but you could certainly anticipate that any package would include, you know, Part three data. We are briskly enrolling the second-line head-to-head study, and I'll provide guidance as that continues to enroll.
The other thing to mention that was also called out during the previous discussion is that we are investigating short monitoring periods based on the safety profile that we've observed a nd when I say, you know, with Tarlatamab, we see much less significant CRS than we've seen with other molecules w hat I mean is that higher grade CRS, like grade three and beyond, really requires intervention.
You know, one of the key facts that I hope you pick up on is that only one patient required in the 10-mg dose tocilizumab, and that's usually, you know, the threshold when a treating physician feels that they need to intervene s o, you know, so we're looking at you know short monitoring periods over the first few cycles that could, we hope, ultimately lead to an outpatient regimen. We have to do that development, but you know, I think there's clear path forward there. Thank you again for the question.
Your next question comes from the line of Geoff Meacham with Bank of America. You may proceed.
Hey, guys. Thanks for the, for doing this call. Just had a couple of quick ones. For, for Tarlatamab, I just maybe wanted to ask you, you know, you, you mentioned the, the, the dose response and kind of your view of that i s it worth it to, you know, to further optimize that, going into, you know, as you start to think about regulatory and, and, and, you know, pivotal strategies?
A re you guys, you know, confirmed to, to do the 10-mg dose, you know, for, for that? And then on the, on the CodeBreaK 300, on the LUMAKRAS study, I know obviously the higher dose plus Vectibix, you know, was the, you know, was the, best, best PFS, best responder, and that's probably the, the what's gonna be filed.
I n this population, are there lessons to be learned from optimizing and looking at these patients that look at, you know, other, other tumor types, with respect to G12C, that you can, you know, again, take this doublet into, assuming obviously you have to confirm, you know, G12, G12C, mutations? Thank you.
... Yeah, thanks, Jeff. Yeah, in terms of Tarlatamab, you know, dose response, you know, as I mentioned, for the, you know, currently enrolling, head-to-head trial in second line, we have taken forward the 10-mg dose. We did extensive modeling, and in fact, we had doses in between 10 and 100 in the first-in-human study. And so, you know, we wanted to look at doses that we thought would be, number one, very effective, but also would have, you know, some degree of pharmacokinetic separation.
You know, if you marched up by, like, 10 mg increments here, you know, the degree of pharmacokinetic difference is not great and, you know, I'm not sure there's a lot of utility in, you know, in doing huge numbers of patients to try to answer that question. Obviously, you know, with drugs like this, you know, dose exploration often goes up, you know, on for some time. But, you know, here, you know, we really tried to follow Project Optimist and, you know, the guidance and explore two meaningful doses in this randomized phase two trial.
In terms of CodeBreaK 300, and the dose question, you know, I think probably the broader context here is that at least now in three settings where, you know, number one, we've got the first-in-human data that everyone forgets about now, where we saw numerically higher response rates with 960 mg when we looked at, you know, comparing against lower doses like 240 mg and 360 mg. Of course, the non-small cell lung cancer data that were included in the FDA briefing document and have been submitted for presentation.
T hen finally, the colorectal data, which I think showed, you know, obviously clear difference in both progression-free survival and overall response rate at the 960 mg dose. So that's certainly, you know, what we're looking at going forward right now. We are looking at this doublet of LUMAKRAS and Vectibix in non-small cell lung cancer and pancreatic cancer in our master protocol. And obviously, what we've learned from CodeBreaK 300 will inform those studies. Thank you. Sarah?
Your next question comes from the line of Evan Segerman with BMO Capital Markets. You may proceed.
Hi, guys. Thank you so much for taking my question. Congrats on all the data, both here at ESMO and at the Triple Meeting. So on 193 or PRMT5, looks really encouraging, but I kind of would love for you to expand a little more as to where you think this ultimately best could be used in terms of tumor type, line of treatment. You know, and while we did see some partial responses at the ENA meeting, do you expect these to deepen over time? Maybe these patients are just too far gone, but maybe some color as to what we could see with further iterations of this data set or a new data set. Thank you.
Yeah, thanks, Evan. I'll comment, and then I'll ask Jean-Charles if he wants to add anything. You know, clearly, non-small cell lung cancer, you know, ultimately, you know, glioblastoma, you know, pancreatic cancer, you know, some of the high-prevalence tumors, in terms of MTAP deletion frequency, will be areas of focus, as we go forward. You do bring up an important point, which is the kinetics of response here.
And, this is something that's now been observed across the field, that, you know, in contrast to some targeted therapies like receptor tyrosine kinase inhibitors, where responses are very rapid. Here we see, in many of these patients, a slow deepening over time, and many of them that had partial responses actually converted to a partial response after 8, 12, 16 weeks on therapy.
You know, we're actually trying to do paired biopsies on as many patients we can, and additional preclinical work to understand why that kinetics is a little different than has been observed with other targeted therapies and, you know, how to potentially exploit anything that we then learn mechanistically. Jean-Charles, anything you want to add to that?
Yes. Thank you, Dave. And, for those who pay attention to the 3D waterfall plot, you will see exactly what Dave just described, which is some patients were stable before becoming PR at the second or third CT scan. And one of the reasons we are combining our molecule with IDE397 is that we recognize the importance of combinations to deepen clinical responses, to accelerate time to respond and extend durability. And this is why this is being explored with this compound as well as other combinations.
As for the expansion course, we will be led by the data we see. Certainly, expansions are planned for non-small cell lung cancer, pancreas, head and neck, and biliary tract cancers, but we will be driven by the data, correct? You need to remember, this is the first in man, drug development is not a sprint, it's a marathon. We will follow the science.
Thank you. Your next question comes from the line of Carla... Sorry, Colin Bristol of UBS. You may proceed.
Thank you. Interesting mistake. But good morning. Congrats on all the data. Maybe first on Tarlatamab, can you talk about the hospitalization requirement that's gonna be present in the phase three studies? T hen second on 193, maybe could just sort of bigger picture, can you talk about the competitive landscape and how you see 193 as being differentiated? Thanks.
... Yeah, sure. And thanks, Colin. In terms of the Tarlatamab, you know, patients have to be hospitalized, you know, for, you know, a day for the first, you know, first few doses, and then things transition to, you know, a less rigorous, first few cycles and then less rigorous monitoring a s I mentioned, we're actually exploring.
You know, more limited observation based on the safety profile that's seen and would hope that as these phase three programs move forward, in time, they will be able to be amended to incorporate these lower degrees of monitoring. And then, for AMG 193, let me ask Jean-Charles to comment. Yeah, I apologize. What exactly was the question on 193? I think the question was around potential differentiation, you know?
Yeah, well, you know, as I say, these are small molecules, t ime will tell us what are the key characteristics. We are very confident in the profile of our molecule, like, activity across six different tumor types, CNS penetration, tolerability profile that clearly suggests combinability.
Y ou know, we are also very confident on the clinical trial execution of our teams. W e are seeing great appetite and active involvement in this trial, to complement what I already said on the expansion cohorts in non-small cell lung cancer, biliary tract carcinoma, pancreatic, and head and neck w e also have a tumor agnostic one that has started enrolling.
Great, thank you. Next question, Sarah.
Thank you. Your next question comes from the line of Tim Anderson with Wolfe Research. You may proceed.
Hi, thanks for taking our questions. This is Alice Nettleton on for Tim Anderson. Just on Tarlatamab and the earlier line phase three studies, will these only enroll patients with DLL3 expression or maybe specific subtypes that have higher DLL3 expression? And then also, are the phase three studies enrolling an older population? Because I think the discussant pointed out the phase two study population was slightly younger than what is seen in the real world. Thank you.
Yeah, thanks for the question. You know, so obviously we're discussing with regulatory authorities, you know, specific inclusion criteria, but our belief, based on the near uniform expression of DLL3 in these patients, is that DLL3 selection should not be required. And certainly, you know, we're not going to require a certain threshold of expression, such as 2+ or beyond, with immunohistochemistry.
This just points to the sort of exquisite potency of these BiTE molecules and their ability to induce an anti-tumor immune response with only, you know, potentially as little as a few hundred target molecules per cell surface. In terms of the patient population, for the earlier lines of therapy, yeah, absolutely, you know, we intend to open this up to the broad representative range of patients with small cell lung cancer. Thank you. Next question, Sarah.
Thank you. Your next question comes from the line of Michael Schmidt with Guggenheim Securities. Please proceed.
Hi, it's Sidi on for Michael. Thanks for taking our questions, and congrats on the updates. On AMG 509, have you looked at the different expression levels of STEAP1 in patients and whether there's any correlation between higher expression level and response or efficacy? And then separately, what's your current thinking on a combo strategy, and will you evaluate any combo regimens in expansion cohort? Thank you.
Yeah, thanks, Michael. I'll take those questions. In terms of, so we are looking at expression response data. It's worth pointing out that like DLL3 in small cell lung cancer, STEAP1 is almost uniformly expressed, in other words, expressed on a very high percentage of advanced prostate cancer patients i n fact, there's some evidence, you know, preclinical evidence that hormonal therapy, androgen deprivation, actually upregulates STEAP1 expression on the surface of these tumor cells. And that may in fact be contributing due to the very high expression rates in advanced disease.
Y ou know, again, this is something that we'll look at as we go forward, but right now, we anticipate a very, you know, broad population. In expansion cohorts, we are looking at different combinations, including with various hormonal agents. T hat is, you know, something that as those data mature will help define the development program, as you heard Dr. Kelly describe earlier, as we move forward. So thank you. Sarah?
Thank you. Your next question comes from the line of Dane Leone with Raymond James. You may proceed.
Hello, thank you for all the questions and taking the time to answer them, and good progress across the entire oncology portfolio. Two questions from me. The first one being on Tarlatamab. What is the size of the cohort that you have at the lower dose? ... I think the step-down was to 3 mg under the 10 mg dose for Tarlatamab, the dose escalation study.
The reason I ask that is: what do you think the potential is for the FDA to come back and ask for further dose escalation work, given there was not a dose response between the 10-100 mg dosage, but there was a grade five seemingly treatment-related adverse event at the 10-mg dosage? Just what's your team's thoughts on maybe having to explore and compare a sub-10-mg dosage for Tarlatamab? Then the second question I'd like to ask is, on Xaluritamig .
Could you just provide some clarity around the commentary of what the required or estimated hospitalization is for each step dose that the patients undertake for what you think the three-step dosage is that seems to be optimal? I think at ESMO, there was some confusion around the length of hospital stay that these patients are required to have. Thank you.
Y eah, two question o ne, dosing on Tarlatamab, and then the hospitalization requirement for Xaluritamig . You know, on Tarlatamab, one of the things that our belief in looking at the totality of the first-in-human data is we sort of saw a threshold effect in terms of a jump in efficacy when we got to the 10 mg and above dose. You know, with as you saw, then not, you know, great increments beyond 10 mg in terms of additional efficacy, but some toxicity.
In terms of the Grade five event, let me comment on that briefly, 'cause I know there's been some discussion. This is a patient that was quite ill, you know, had chronic obstructive pulmonary disease, was on baseline supplemental oxygen, had extensive tumor burden, developed cytokine release syndrome, and actually, you know, elected not to have, you know, additional aggressive therapy, including treatment in the ICU.
Unfortunately, this is a, you know, situation that is encountered with these patients, where they're quite ill with, you know, very aggressive, rapidly progressive disease, and a heavy tumor burden. I wouldn't overread that particular event, especially vis-a-vis dosing. To me, and we've obviously looked at this and discussed with the treating physician extensively t his was, you know, very much, you know, a combination of aggressive disease and a frail patient and, you know, in the setting of concomitant cytokine release syndrome.
In terms of Xaluritamig , yeah, to clarify the hospitalization requirements, it's a day, you know, as patients go through that, you know, each week, I think it was, as they go through that, you know, step up in the first month, you know a t ESMO, I did hear in the hall some people saying, oh, were they admitted to the hospital for the entire first month? The answer is no. It's four short hospitalizations, and then it transitions away from that. Over time, again, as we, you know, refine the dosing and scheduling here, we would really like to point this towards outpatient administration as well. All right, Sarah, why don't we move on?
Thank you. Your next question comes from the line of Carter Gold with Barclays. You may proceed.
Hi, this is Leon Wang, on for Carter. Thanks for a great presentation, and Carter wished he could join, but, he's midair right now. For our question, so at this point, what's your expectation regarding monitoring for Tarlatamab? And, how, you know, if at all, do you expect, data from the reduced inpatient monitoring cohort to be potentially, incorporated into a label? And lastly, how should we think about monitoring in, DELPHI 304? Thank you.
Yeah. I mean, so the monitoring is sort of standard clinical monitoring here, you know, for these patients. Obviously, you're trying to detect cytokine release syndrome. The vital signs are actually, you know, temperature, heart rate, are often the first signs, you know, of cytokine release. So that's the typical monitoring that is done for these patients a s I mentioned, you know, we're looking at reduced length of monitoring that would lend itself to the outpatient setting. Our plan is as we move into phase three.
As we generate additional safety data with the reduced monitoring, you know, we anticipate being able to decrease that monitoring in a stepwise fashion in the clinical trials. It's too early to comment on the outpatient cohort w e're generating that data right now. But you know, that's something obviously we will provide guidance on.
The other thing to remember is that you know, the cytokine release, certainly significant cytokine release, is by and large a first and second cycle, first and second dose phenomenon, and then becomes much, much less frequent. So this is something that treating physicians you know have to be very attentive to as they're initiating therapy. But patients that have been on for weeks and months it is much, much less of an issue.
It's far too early to speculate on what could be included in a label you know should we be able to achieve an approval on the basis of these data at this time. But obviously, we'll provide guidance as we get insights there.
You know, I see we're past 90 minutes now, so I think we'll draw things to a close. If there are additional questions, our investor relations team will be standing by all day, and of course, we'll be happy to address those. I'd like to really thank Doctors Owonikoko and Kelly for their perspectives. It has been quite valuable, and thank all of you for staying with us for a long session. Have a good day, everyone.
This concludes our Amgen conference call following the 2023 European Society for Medical Oncology Congress. You may now disconnect.