BREAKWATER trial: Dr. Kopetz (2023)

Manju George 0:00
Hello everyone. Welcome to DocTalks. I’m Dr Manju George, the Scientific Director at PALTOWN Development Foundation, the nonprofit that supports COLONTOWN. And today we have the pleasure of having Dr. Scott Kopetz with us, who’s going to tell us about the BREAKWATER trial. But before we start, Dr. Kopetz can you tell us how you got interested in doing clinical trials and working in GI oncology?

Dr. Scott Kopetz 0:25
Most certainly. So I think, like many, I had personal reasons to get into oncology. I lost my mother to cancer at a young age, and so I was motivated to tackle this, and ended up in GI oncology, because I just fell in with a wonderful mentor, Paul, who was here at MD Anderson at the time, and was working in colorectal cancer and just kind of fell in love with the clinical problems and the wonderful patients of course, and really have been inspired ever since by all of our patients.

Manju George 1:08
Thank you for sharing. So then, do you want to share your screen?

Dr. Scott Kopetz 1:11
Yep, absolutely. Yeah. So just delighted. This is always so much fun. And I just start by saying, really a delight to be able to discuss and to share some of the updates here, and want to touch on some of the efforts that are ongoing. I know it’s been a little while since we’ve had an update, and so I’ll start with a little bit of background, and then dive into where the field is now and where we’re going. So some conflicts: very involved in a lot of these companies that are involved in developing novel therapies for BRAF. So kind of a key point I always like to start off with, and so apologies for those of you that have seen this slide a dozen times before. But the idea is that this is a cancer that when we have a BRAF mutation, it results in activation of growth factors, or a growth signaling pathway, right? This is a normal, healthy pathway in your body. When you cut your skin, your epithelium- your skin cells, turn it on to grow and repair, and then it gets turned off. The problem when there’s a mutation in the pathway like BRAF is that it’s constantly on and these cells are then growing. And what we found, though, is that these cancer cells like to be in this state, and that when you inhibit BRAF, with a medicine like encorafinib, that you indeed can shut down that pathway. The growth turns off, but the tumor adapts. The cancer likes this state. And then in cancer terms, we talk about this as homeostatic regulation. It’s like the thermostat: If it’s hot or cold, things get turned on or off with your heat or AC to adjust, and it’s the same thing with with cancer cells. And so there’s a transient inhibition, but the tumor adapts, has all these feedback mechanisms. The wiring that turns on other things upstream through the EGFR receptor is one of the prominent ones, and then what happens is that same signaling pathway gets turned back on.

Dr. Scott Kopetz 1:11
So the fundamental concept, and why we are using combination therapy and BRAF is because when you inhibit that second node, the EGFR, then you can shut down that adaptive mechanism, and so the combination provides benefit where either one alone doesn’t. So of course, this is the rationale behind the BEACON study, which looked at the encorafinib, the cetuximab, the BRAF and EGFR, compared it to chemotherapy control, then and looked at both triplet with a MEK, which didn’t provide any benefit, or the doublet with the BRAF and EGFR, which showed very nice results and improved overall survival, increased response rate, was a nice building block then for us to now become a standard of care, but also recognizing ways that we want to improve.

Dr. Scott Kopetz 2:42
So one way to look at this is to say it’s clearly active providing benefit from patients. There’s a subset of patients who can be on this regimen for a really long time. There’s also a number of patients that get some benefit for several months, and then the tumor adapts and progresses. So one of the questions is, well, why is that? And one of the areas that we’ve been able to characterize is really understanding these mechanisms of resistance. This is a complex slide, but what I want to do is just to have you visually look at the control and looking for any red mark, and a red mark means there’s some acquired event in the tumor. You can see very little evidence of red but when you look at the treatments with the BRAF and EGFR, you see all of these red marks. These red marks are predominantly around RAS mutations. There’s some other ones. But really, this idea that KRAS and NRAS can get mutated, the tumor mutates those in order to maintain that addiction to that growth signaling. And so, there’s an example here of a case study. And this is something I reported last year at ESMO. And this is a patient that was on the trial and at the time of progression, after about eight months on treatment that we looked in the tumor by circulating tumor DNA. So all of these KRAS mutations. These are all present in different subclones. And this is a real challenge, right?

Dr. Scott Kopetz 2:42
How do we prevent these subclones from growing out and developing resistance to the therapies? So put a pencil on that -we’ll come back to that, and some interesting hypotheses coming on that, but just acknowledging that, that’s one of the limitations that we’re dealing with. So where’s the field going? This is a good foundation, as I mentioned, and I’ll talk about some of the studies here briefly, and not really focusing a bit on BREAKWATER study, which is our first-line trial, really trying to understand how we best utilize this.

Dr. Scott Kopetz 2:42
So first, let me share some of the preclinical data that’s ongoing, and asking, “Can we do better? Is the idea of targeted therapy and more traditional chemotherapy, can we combine those and get more benefit out of that?”. Well, one of the findings that we had when we looked at this in our mice work is–in the mouse, we can generate the tumors, we can treat them with one therapy, and then move into second-line in the mouse, and then, compare this to when we do it altogether. And what we can see is that this interesting phenomenon. We think about chemotherapy and targeted therapy is two different things, but the reality is that there is some degree of cross-resistance between them, meaning that when a tumor develops resistance to chemotherapy, itcan sometimes develop resistance to the BRAF inhibitor, even though it’s never seen the BRAF inhibitor, and then vice versa. So these are kind of complex figures, but I think the way to look at it is to say, here is the benefit of encoafinib in this model, when you give encorafinib and cetuximab in first-line, the tumor has never seen a chemotherapy. However, if you give chemotherapy first, wait for the tumor to progress, and then give the BRAF and EGFR, you don’t get as much benefit. So these models aren’t under control for as long. And interesting– the same with the chemotherapy, so the prior targeted therapy may impact that. So the question is that sequential may not always be optimal in that situation. And so when we look at this and say, ‘Well, what if we put them together? What if we put the chemotherapy together with this?’.

Dr. Scott Kopetz 2:42
If you’re not used to looking at these mouse model graphs, what you’re looking for are tumors that are shrinking, going below the lines. And here you can see in the blue, these are the lowest, the best, and the combination of the targeted therapy and chemotherapy may actually induce more activity. So some of the conceptual rationale behind the BREAKWATER study: This is a large international phase III study that’s ongoing, and I’ll show you some of the data from the safety lead-in which was just ensuring, as we thought, that this would be safe to combine chemo, either FOLFOX or FOLFIRI, with the encorafinib and cetuximab. The ongoing study from phase III has three arms currently as you can see here. We don’t have any results from that, so nothing I can share yet on the randomized portion. Well, I’ll share some of the really promising data on this safety lead-in. First we should reflect and remember that chemotherapy alone in first-line gives us about a 40% response rate, the targeted therapy about a 20% in the later lines. And so we’re looking at some of these response rates, now the combination and seeing in first-line now 68/75% of the patients are having their tumors shrink down by more than half in volume. And even in second-line, where we expect maybe a 10% activity of the chemotherapy, you can see really promising, 40 or so percent shrinkage. and that duration of response is really fairly long. So remembering that with encorafenib-cetuximab we’re seeing duration of responses in under six months or so, we seem going much higher. The other way we can look at it is these progression-free survival curves where we’re seeing PFS’s that are really promising here, even in second-line, where medium PFS is somewhere in that four to six months with our current standard of care now, these small cohorts see really promising data. So, just acknowledging encouraging numbers, these are small cohorts, but I think giving us in the field a lot of enthusiasm that we’re going to see benefit with these combinations.

Dr. Scott Kopetz 2:42
Alright, so let’s go back to this–what about the mechanisms of resistance? So, a little complex– throwing a lot of scientific terms out here, but you we can actually look and see what’s changing in the tumor. And the bottom line is that when tumors progress on chemotherapy or targeted therapy or the combination, they actually have a very different pattern. And you see a number of different changes that suggest that we’re constraining the potential mechanisms of resistance, and that when you give the cancer fewer opportunities to progress there are fewer solutions to the problem of how to grow it in this regimen, what we see is that means that the tumors have a longer period of disease control. So I think the biology is really suggesting that.

Dr. Scott Kopetz 2:42
Now, interestingly, if we look at not BRAF colorectal cancer tumors, but if we look at patients that don’t have a BRAF mutation or a RAS mutation, these are ones that would benefit from the EGFR inhibition alone. There’s some data that we presented just recently in 2 JCO papers that reflect on the fact that RAS mutations occur in 40 and 20% KRAS and NRAS of patients treated with an EGFR inhibitor alone, but when you combine that in first-line with chemotherapy, it turns out that less than 10% of patients develop one of these secondary alterations. So we’re going for more than 50% like we see in BEACON, acquiring these secondary alterations. Now, when we combine it with chemotherapy earlier on, you don’t see the tumors picking that mechanism of resistance of acquiring RAS mutations. So we don’t know, I think it’s going to be really interesting to find out, but the same could occur, right? Can the combined chemotherapy prevent some of these acquired RAS mutations? Now this kind of makes sense, if we recognize that RAS mutations actually don’t result in resistance to chemotherapy, right? So RAS mutations may be the easy way out for developing resistance to the BRAF, but when you’re giving a combination, the tumor has got to find a way to grow through the BRAF inhibitor and the EGFR inhibitor, and through the chemotherapy. And if the acquired RAS mutations doesn’t result in resistance to the cytotoxic chemotherapy. Well, that’s not a solution to the tumor to grow. It’s got to find a harder way an alternate way. So this conceptually makes sense, that we’re cutting off pathways of resistance that may occur. Now the other question that we’ve asked is, well, this combination chemotherapy, we know that at some point with oxaliplatin, we need to stop the oxaliplatin. We use these maintenance regimens. So how do we do that optimally?

Dr. Scott Kopetz 14:26
And and the mouse modeling at least, suggests, probably what we would think makes sense, which is, you can’t just do maintenance with encorafenib. You need both encorafenib and cetuximab, and then also that you may get some benefit by continuing some of that 5-FU alone with it, as we had been alluding to, resulting in some of the alternate mechanisms. So we really think that the maintenance regimens, and this is how it’s written in the study, should be like a 5FU, encorafinib, and cetuximab, once a patient has received a maximal amount of oxaliplatin.

Dr. Scott Kopetz 10:19
All right, so where else is the field going? I’ll share a little bit about some of the updates in the IO space here. And this is building on some nice data that MAPK pathway inhibition, can enhance some of the immune responses in BRAF patients. And so this is that actually, from Ryan Corcoran’s group, looking at – these are old studies that we have done in years past, looking at, in responding patients, it turns out that you see an evidence of immune infiltration. And when you look at paired biopsies from patients who were gracious enough to consent to those, you see this increase in these these T cells. So we know that even though there’s no immunotherapy given in these figures, that just the targeted therapy alone may drive an immune response. And so there was nice data for those interested, looking at a BRAF, MEK, PD-L1 that is in that prior publication, thinking about how do we build on encorafinib and cetuximab, a nice trial led by Van Morris in our group looking at this, saying, “Can you add a PD-1 on top of this, even in microsatellite stable?”, so a small study but encouraging 50% response rate, which favorably compares the 20% we’d expect with the encorafinib-cetuximab alone. And then increasing the durability of this, and I think really seeing some patients that are having amazing durability to their disease.

Dr. Scott Kopetz 16:43
So that is an ongoing randomized study that’s currently enrolling nationwide for patients in second or third-line to be randomized, encorafinib-cetuximab, with or without nivolumab. So two to one randomization, so every three people enrolled, two get the nivolumab and one with the encorafinib-cetuximab. I will mention as an aside that there’s some data suggest maybe the PD-1 can rescue resistance in some settings. So there is a study, or now a cohort, that’s open– encorafenib-cetuximab-nivolumab at our institution, even if patients that had prior encorafenib and cetuximab, there are openings there. So it’s an option to consider.

Dr. Scott Kopetz 1:11
The final study I’ll mention is the rare subset of patients that have MSI high, which is more immune-sensitive and a BRAF mutation. And this is a trial ongoing that’s randomizing an initial first line setting; Pembro or PD-1 with or without the encorafenib, cetuximab to try to again, show that synergy between immunotherapy and targeted therapy. All right, so with that, just to conclude, I think this group knows: BRAF mutations, poor prognosis. We should be testing for it. We should make sure that this is a known status and that combination strategies are certainly successful, the encorafenib-cetuximab’s, the current standard of care. But hopefully I convince you that there’s some good rationale, pre-clinically and preliminary data from our first 60 patients, of potential benefit when we combine chemotherapy with encorafenib-cetuximab, and that study is ongoing, the BREAKWATER study, but there’s really interesting biology suggesting that you may be influencing and constraining the mechanisms of resistance. So if we can really shut off some of those RAS mutations, for example, that would be a substantial benefit. A lot of other areas, I don’t have time to go through all of them, but just updating where we are with the PD-1 combination: There’s work going on in neoadjuvant in the UK and adjuvant settings here in the US, a number of novel combinations are ongoing, including – I’d highlight this really interesting data that came out of an unbiased screening study with BET inhibition which is a epigenetic modifier in BRAF-mutated colorectal cancer models that was presented at AACR this year, and there’s actually a trial through the NCI network that will be opening up here the next few months to test that in patients who’ve previously been treated with encorafenib and cetuximab. So with that, thanks, as always, for your time and interest.

Manju George 19:37
Thank you very much. So, I think I will ask the first question. For a newly diagnosed patient who is BRAF mutated, with all these trials available, what do you think – if they have access to all the trials, what would be the good sequence for them to enroll?

Dr. Scott Kopetz 20:01
I think if they have MSI-H tumor, about 20% of BRAF patients will, the SEAMARK study, the last one that I showed is a great one, thinking about, how do we combine immunotherapy and targeted therapy. In patients who have microsatellite stable, 80% of BRAF patients, those are ones that we really think the BREAKWATER study is a great one to participate in. I think it is really an exciting study. We really hope it will be beneficial there. After that, if after patients have been exposed to encorafenib and cetuximab in some way, again, thinking about, can immunotherapy rescue that, as Dr. Morris’ study here is exploring, but then thinking also about how these other novel therapies, deeper inhibition of MAP kinase pathway and others may play a role.

Manju George 21:01
So basically, you’re saying that – it’s really nice that, Dr. Morris’ study is now accepting patients with encorafenib and cetuximab, right? Because that was something that people were concerned about. And then the other thing is that, so you really believe that the combination plus chemo is better instead of waiting and then, having that separately and then getting on, say, for example, the Van Morris trial?

Dr. Scott Kopetz 21:27
Yeah, so the SWOG study. Right – and I think, and for patients that are maybe on the control arm, for example, of BREAKWATER, I think the SWOG study is a great one. I think your point’s a good one. Just participating in clinical trials is important, and not all trials will be available to all sites, but we really do think that these are some of the more compelling directions that the field could go.

Manju George 22:00
Annie has a question, “Have you seen responses in BRAF patients with peritoneal mets?”

Dr. Scott Kopetz 22:05
Hi Annie, great, great question, as always. So yes, we have. You know, peritoneal disease is sometimes hard to measure and so response rates kind of get a little murky. Without getting too detailed, peritoneal is a, kind of a strip more, kind of across a surface of a tumor. The way that the guidance is to measure tumors, is that you measure the longest dimension of the tumor. So if you think of a strip of cancer, you’ve got to kind of measure that the long dimension. So even if the tumor kind of shrinks down this way, it doesn’t really get reflected. So you will see lower response rates. But part of that’s a bit of a function, a little artificial, just how we quantify the responses, and so you don’t always appreciate the extent of that, but yes, we can see responses in that setting.

Manju George 23:07
OK. I have a question about the schema of BREAKWATER. It seems that they have many cohorts, some of them, I think the main studies, like FOLFIRI plus encorafenib, plus cetuximab, and then they have an additional cohort, like a side one cohort D or something, where they are combining with FOLFOX. And then I also heard that there is some kind of prioritization that patients would be first enrolled into the encorafenib plus cetuximab arm. So, these are some of the questions that patients have, if I’m a newly diagnosed patient and I’m considering BREAKWATER, what are my chances of getting into each of these arms? Because, for example, if I’m just going to get into encorafenib plus cetuximab and I won’t get into a combination arm, then patients are thinking whether that’s a good strategy for them first, to get exposed to it, because then you can’t get on, it shouldn’t narrow down the options that are available to them later.

Dr. Scott Kopetz 24:01
Yeah, right. Yeah, it is. And I think it is important things to understand; So a little clarification: There are some amendments coming to BREAKWATER, really to focus that down a little bit more. And what we’re seeing is that the FOLFIRI component will be evaluated in a bit of a later point, and won’t be part of the initial randomization. So it’s still going to be a FOLFOX based chemotherapy backbone. Just to say, there are some changes coming that will make it a little more condensed and I think a little more patient friendly. Because I think the arms that we really are interested in is, how much does the combination of chemotherapy and targeted therapy compare to what right now is considered the standard of care, which is the chemotherapy alone. So that’s the main question. And I think the goal of really trying to get to that question as soon as possible.

Manju George 25:08
Okay, okay… okay – we will see if there are other questions. I think Annie had maybe one more.

Dr. Scott Kopetz 25:15
Oh yeah, how full SWOG 2107 is right? So, yeah, it’s enrolling. There’s still openings. And I suspect at least over the next six months or so, we’ll have openings there as well.

Manju George 25:33
Then she’s asking about class two and class three mutations.

Dr. Scott Kopetz 25:37
Yeah, great. Yeah, the class two and class three. So class one, is the BRAF V600E. The other mutations in BRAFget separated out into two different classes of therapies. There were some low levels of activity that were presented with a number of different trials. It was a little heterogeneous across many different kinds of settings. Not a great home run evidence of activity in colorectal cancer there. So I’m not sure we have a great solution to those yet, but the rationale is still there. I think part of the problem is that these are very heterogeneous, like not all class twos behave the same, not all class threes behave the same. So it is a little hard to sort out, and they are a bit rare, but we’re learning. We’re making progress. There’s hints of activity, but not any amazing responses yet.

Manju George 26:45
There’s a question from Katie, are you able to get into the BREAKWATER trial, as a second line of treatment?

Dr. Scott Kopetz 26:52
So not into the BREAKWATER. Even though I showed some data from the safety lead-in that included second-line patients, that was just in the safety lead-in. Right now, in the randomized phase III portion it’s patients that are previously untreated that are entering. So the second-line would be more the SWOG 2107 study, enco-cetux with or without PD-1.

Manju George 27:18
Yeah, I think Annie has a question. We had a few patients on the BREAKWATER trial, what is the best next treatment? I think you had mentioned some in your talk, right?

Dr. Scott Kopetz 27:26
Yeah, good question. If they were on the chemotherapy arm, they could then go over to the SWOG study, for example. If they were on the encorafenib-cetuximab, or the combination arm with chemotherapy and encorafenib-cetuximab, then, at that point, you’re right thinking about, if they were just on encorafenib-cetuximab, you could certainly think about chemotherapy at that point. Or, like mentioned, there are clinical trials ongoing in that setting to try to explore.

Manju George 27:27
With the safety lead-in, there were some differences in results with FOLFOX and FOLFIRI, right? So, I’ve heard some people ask, with FOLFIRI, there were some interactions, and the drug availability was less… or something. And then the main randomized portion of the trial is now with FOLFOX, but then the long term data show that FOLFIRI as acombination has been better, right?

Dr. Scott Kopetz 28:35
Yeah, so, we don’t really know for sure, I think it’s fair to say. I hate to make too much out of these cohorts of 10 or 15 patients and try to combine in one or the other way. So I think I would be a little more cautious there. There’s a little bit of a PK interaction as I was mentioning, so you don’t get the same exposure to the drugs as you would normally. But not sure that’s playing a big deal based on the results that we’re seeing. Like you said, it was certainly encouraging. So I think that the data really suggests that there’s substantial benefit with the FOLFOX out of the safety lead-in so I’ve been very comfortable in recommending that to the patients. I don’t think we’re missing an opportunity necessarily, on the right partner.

Manju George 29:31
Okay, okay. And then once they finish the chemo plus the Encorafenib+Cetuximab potion, then are you thinking that, say for example, if they don’t have access, we have many – because BREAKWATER is open worldwide, we are fortunate to have the SWOG 2107 right? But many other countries, they don’t. The the idea of combining encorafenib plus cetuximab with nivolumab isn’t that common. So do you think that in that case, they can get LONSURF+bev, or once they progress on the trial, what options could they consider?

Dr. Scott Kopetz 30:08
Right, yeah, so, there’s always the alternate side of toxic regimens that may make a difference. LONSURF+bev I think certainly is reasonable as well. So we do, you’re right, just kind of lean back on what kind of works in general, in colorectal cancer.

Manju George 30:23
Okay, and then, when you look at the resistance mutations, there are so many met amplifications and things like that. Do you think STIVARGA (regorafenib) has worked for people? I’ve seen that some people prefer to use STIVARGA when they get progression on encorafenib plus cetuximab. So what is your personal —

Dr. Scott Kopetz 30:44
–Yeah – we don’t – It’s not great data on that, necessarily. I think it’s a reasonable option, but I don’t know that it’s not something we’ve seen pan out in our preclinical studies, that we’re driving towards a more sensitive phenotype to regorafenib, but certainly a reasonable option.

Dr. Scott Kopetz 31:05
Okay. Were there any learnings from ANCHOR CRC trial regarding PFS or OS to those without peritoneal mets?

Dr. Scott Kopetz 31:14
Yeah, so ANCHOR was a study looking at the encorafenib plus cetuximab plus a MEK inhibitor, and that was running in parallel with BEACON, and we learned from BEACON that the MEK was adding more toxicity, not adding as much benefit. So it’s a little harder to extrapolate some of the ANCHOR data otherwise, but I think what we recognized is that the PFS was kind of in the same range as what we’d expect with the chemotherapy alone and the OS, likewise, looked encouraging, but it was non-randomized for the OS, which makes it hard to interpret. So, the breakdown by with/without, peritoneal metastasis is not really well laid out.

Manju George 32:00
Okay. And then could you say something more about that BET inhibitor trial?

Dr. Scott Kopetz 32:11
Sure. So, this is through an unbiased screen where we asked, ‘if you have a patient or a tumor on encorafenib-cetuximanb, and we screen 1000s of different nodes for ways to modify and we find a node that really tends to be a vulnerability of the cancer, and that turns out to be a bromodomain, which is a regulator ofgene expression. And so there is actually an inhibitor of bromodomain, so we were able to then show the benefits there and bring that together into a clinical trial. So there’s a bromodomain inhibitor plus encorafenib and cetuximab. What it’s doing is, really for those aficionados, is deeper inhibition of the MAP kinase, as well as shutting down MYC signaling, which is a key survival mechanism. So it’s a really way to inhibit MYC, which is one of the key oncogenes.

Manju George 33:09
Okay, I think it’s sort of hard to get the word out to BRAF folks about this trial. Has enrollment been fairly brisk at NCI centers and academic centers worldwide?

Dr. Scott Kopetz 33:22
Uh, let’s see. So I’m not sure which trial?

Manju George 33:27
I think BREAKWATER.

Dr. Scott Kopetz 33:28
Oh, BREAKWATER, yes, it is. It’s going, you know, first-line studies are a little harder, because a lot of times we don’t always know the BRAF status by the time that patients start treatment. So it’s not quite as fast as BEACON but it’s going reasonably well. We’ll get it done. Not always as fast as we like, but we’ll get it done. And I think we’re kind of on track on projections at the moment.

Manju George 33:57
Yeah, yeah. I think that we are working with Pfizer to get, in COLONTOWN University, we are going to be having a featured trial, we’re doing that for BREAKWATER. So my other question would be, since you have those mouse lines that seemed very interesting, where you’re doing sequential treatment and testing, what kind of resistance develops. Are you also doing experiments where you’re doing the encorafenib plus cetuximab plus FOLFOX and seeing what else you can give those mice?

Dr. Scott Kopetz 34:25
Right, so, we haven’t pursued that. I think it’s an interesting area to say, ‘how do you even improve upon where the BREAKWATER is going to be’, right? But no, we haven’t started that type of work yet. But I like the way you’re thinking, let’s take a step ahead.

Manju George 34:44
Yeah, because I’m sure that in a year or two, then you’ll have lots of enrollment, and then people are going to be asking, ‘what next?’.

Dr. Scott Kopetz 34:53
So that’s right, – have something ready – because that’s right… we’re looking for good post docs to do that. If anyone knows of some good post docs out there, let us know.

Manju George 35:02
Okay, okay, yeah. So Annie says it was great to see that there was an epithelial to mesenchymal transition in preclinical research. Is that showing up in BREAKWATER patients too?

Dr. Scott Kopetz 35:15
Good question. We don’t know. You know, we don’t have progression biopsies on patients on BREAKWATER, orany biopsies, for that matter. So as phase III, they tend to not have that same degree of translational research. So we’ll have blood, but we can’t always assess some of these transition states, like you mentioned Annie, in some of the samples that we’re collecting. So we’re going to rely on other ancillary, smaller phase II studies or preclinical models.

Manju George 35:48
Okay, I think we have gone through this really fast.

Dr. Scott Kopetz 35:53
Wonderful. Yeah, no, that’s great. Well, thanks so much to everyone for the time and interest and happy to answer any other questions that come up offline.

Manju George 36:03
Thank you so much.

Dr. Scott Kopetz 36:06
Thanks.

Manju George 36:07
Bye

Dr. Scott Kopetz 36:08
Bye bye.