Manju George  0:00 
Hi, everyone. I’m Dr. Manju George, the Scientific Director of Paltown. Today we have with us Dr. Michael Lee. He’s an assistant professor at MD Anderson. And he finished his MD from Duke University. And he’s board certified in internal medicine, hematology and oncology. Dr. Lee, I’m really excited and happy to have you here with us. Please take it away.

Dr. Michael Lee  0:24 
Thank you very much. Can I just confirm you’re seeing my slides and slide screen view?

Manju George  0:30 
Yes, I think yeah, yes.

Dr. Michael Lee  0:32 
There we go. All right. So I’m very pleased to be here. Thank you so much for inviting me to talk about this exciting new study, that we and many other centers are getting underway, looking at novel targeted therapy combinations, particularly focused on this new class of drugs called ERK inhibitors, in certain molecularly defined subclasses of colorectal cancer. This is the HERKULES 3 study. So just as a way of background, cancer cells in general, or cells in general, are very finely tuned regarding when they proliferate and multiply. Typically, when a cell multiplies, it only does so in response to when the environment is right. And usually in that situation, there will be molecules called growth factors released around the cells and these bind to receptors on the surface of the cell. In particular, in colorectal cancer, something called the epidermal growth factor receptor, or EGFR is a very important growth factor. Now typically, when this binding occurs, this triggers kind of the cascade of proteins being activated into an active state, and kind of propagating the signal through one protein through another through another, until it eventually leads to a number of cellular changes that actually cause the cell to multiply, you can think of these intermediate steps as a series of molecular switches. In particular, this MAP kinase pathway, so to speak, which is downstream of this EGFR receptor is a very important kind of modulator of cell multiplication. Normally, this process is very tightly regulated, as I said, in a normal cell. However, in the process of colorectal cancers going from a normal colon cell to a cancer cell, typically, these cells acquire abnormal activating mutations in one of these molecular switches. And we know that a significant proportions of patients with colorectal cancer actually have activating mutations, in one of these key genes, that eventually leads to this kind of pro growth switch being turned on all the time, inappropriately.

Dr. Michael Lee  2:41 
So we know about 45 to 50% of patients have a mutation in a gene called KRAS or NRAS, which causes constant activation of these growth pathways. Another 5 to 10% of patients have activating mutation in a gene called BRAF, with the particular mutation in BRAF called the V600E mutation most common among the BRAF mutations. These are very clearly driver mutations driving the biology of these cancers. And while we’re starting to develop new therapies, kind of targeting these very clear potential vulnerabilities of these cells, we need more novel, more effective therapies for these ranges of mutations.Clearly, the cells are being driven by abnormal signaling through these kinds of constantly turned on genes. And if we can find more effective ways to switch off these genes, or kind of block the downstream signaling that is a consequence.and this is a potentially very powerful strategy. ERK is one of the key downstream kind of effectors –downstream of activated RAS or BRAF. ERK is one of the last kind of switches that then goes on to directly activate a number of these kind of transcription factors that cause the cell to go on to multiply, and so on and so forth. So it’s one of the last common nodes in this pathway that we could target. And kind of because it’s further downstream, there’s a lot of preclinical and laboratory data showing that targeting ERK maybe a particularly potent strategy, even more so than targeting some of these upstream components. And in fact while they’re not currently ERK inhibitors that are FDA approved, there are several novel ERK inhibitors that are being developed, and one that’s particularly exciting is being studied in the HERKULES 3 study. This is the ERAS-007 compound. This is an oral pill based treatment, that’s a selective inhibiting ERK and it’s been active in the laboratory. So without going into too many nitty gritties actually, shown here are on the left hand panel are a number of mouse models of KRAS or BRAF, mutated colorectal, or pancreatic, or other cancers. And you can see here the red line on the bottom actually shows the activity of the ERK inhibitor, which was previously called a different name. And you can see that kind of when you looked at it compared to other kinds of earlier ERK inhibitors, or other classes of drugs targeting upstream like at MEK or BRAF, that the ERK inhibitor, at least as a single agent for a limited period of time in these mouse models seem to have the most promising level of activity. On the right here, you can see specifically in a range of colorectal cancers, that the ERK inhibitor was active in the majority of the mouse models that were studied. And in particular, here, the shaded kind of  maroon or blue bar show KRAS or BRAF mutated mouse models where you can particularly see benefit.

Dr. Michael Lee  6:00 
Now, with all that being said as much as  we’ve studied single agent or inhibitors and the early phase studies looking at single agent drugs, we know that from long experience with kind of inhibitors of this pathway, that you have better activity for a longer duration of time, if you target in combinations of therapies. Without going into too much detail, generally in the past when we tried targeting this path of the single agent, for example, MEK inhibitors or BRAF inhibitors, there’s been a lot of kind of adaptation within the cancer cell, that kind of reactivates upstream signaling, and it can kind of bypass the level of drug inhibition. As a consequence, we’ve learned that we -and studies in the lab have also shown- that we have better outcomes, if you treat with combinations of therapies, we really think the best chance of having more activity that’s clinically significant for our patients, is using combinations of ERK inhibitors with other rationally targeted drugs. So one combination that’s being studied in the HERKULES-3  study in KRAS and NRAS mutated patients, which again, about 45 to 50%, of colorectal cancers, is combining this ERK inhibitor with a compound of drugs called the cyclin dependent kinase 4/6 inhibitor CDK4/6 . The reason this is rational is that one of the other key pathways that is activated when you have activation of the signaling pathway, it leads to activation of CDK 4/6 –which is very important for helping the cell multiply its DNA and ultimately divide. The cell cannot multiply and divide without actually going through the cell cycle process to replicate its DNA. So if you can block that process, the thought is that if you’re blocking it at 2 different levels, both kind of at the ERK inhibitor level plus at the cell cycle pathway level, that this would be more effective. Andactually, our laboratory has shown that impairing that kinase pathway in combination CDK 4/6 inhibitors was synergistic -was particularly effective- in a range of KRAS mutated models, both in cells in the laboratory and also in mouse models. And consequently that’s combining ERK inhibitors -which again, as we think would be a more potent strategy with the CDK 4/6 inhibitors- we’re hopeful will be even more likely to be effective. Palbociclib  is the drug that’s being studied in combination with the ERAS-007 compound. And this is a CDK 4/6 inhibitor that is actually currently standardly used in some other cancer types, like breast cancer,  is being studied in clinical trials in a number of other cancer types as well, typically in combination with other kind of targeted drugs. And so that’s one rational combination that we’re looking to study. In the BRAF mutated patients, this study will be looking to combine ERK inhibitors with other targeted therapies, targeting BRAF. In particular, as we’ve kind of learned in the last couple of years, the current standard of care for patients with BRAF mutated Colorectal cancer is to treat with a combination of drugs called encorafenib and it is a BRAF inhibitor directly impairing BRAF. And again, kind of talking about this multi level inhibition strategy, combining it with a drug targeting upstream at the EGFR level, called cetuximab. So the combination of encorafenib and cetuximab is currently FDA approved for BRAFV600E mutated colorectal cancer.

Dr. Michael Lee  9:40 
And this is based on the positive results of a large phase III study the Beacon CRC study, which did kind of represent an important advance in our management of these patients with BRAF mutated cancer. While this was absolutely an important step, we also know that there’s more improvement to go. We know from the Beacon CRC study that the response rate among patients was about 20%, which means only about one in five patients were having a significant shrinkage of their tumors, the remainder of the patients are having stable disease or even growth, despite this being our kind of active, a combination, targeted therapy approach. We know that the median duration of time that patients did not progress through the study was about 4 months, 4.3 months, and the median survival for the patients receiving this combination was 9.3 months. Now, this was actually a significant improvement compared to the prior standard treatment. But I think we all acknowledge that we want to improve on these numbers, there’s more we need to do for these patients. And that’s motivated kind of new strategies to look at how can we build on this ground to further improve outcomes here. There has been a range of laboratory studies that actually shows that another level of inhibition, hopefully more potent inhibition, would better allay the resistance that can develop when you’re treating with just the BRAF inhibitor plus the EGFR antibody. For example, we’ve seen that you can see emergence of small sub clones of mutated cells with other kinds of resistance mutations elsewhere in this pathway, which renders resistance to just the encorafenib and cetuximab . And as a consequence, there’s additional preclinical data showing that adding an ERK inhibitor, like ERAS-007, to the BRAF inhibitor and the EGFR antibody, may well be more effective in treating or preventing the onset of resistance. And that has motivated another arm of the study looking at encorafenib and cetuximab plus ERAS-007.

Dr. Michael Lee  11:44 
Now you may be asking, what do we know about the tolerability and side effects ERAS-007. So this is a drug that was previously studied in a single agent, prior clinical trial. So they looked at just the tolerability of ERAS-007 alone. I will note that in that single arm study, while this was a single drug given –not even a combination, there were some patients with a range of BRAF or other RAS mutated cancers that actually did have significant shrinkage of their tumors. Now granted, none of the tumors that shrink was meant to be colorectal cancer. But I think this does provide an important proof of concept that this ERK inhibitor approach can be quite potent in the right patient with the right kind of mutational profile, further motivating this, the HERKULES 3 study. The side effects from this study were as expected, and generally included side effects we would have expected with this class of drugs we have learned to manage pretty well. And they include things like nausea, diarrhea, rash, and eye side effects, which do require kind of being vigilant for any new changes in vision or other concerning eye side effects. And the study does require ongoing eye exams just for safety through the course of the study. With that being said, these are side effects that are pretty common to this class of MAP kinase inhibitors. And so these are not unexpected per se, and certainly things that we would aim to be able to manage with supportive care.

Dr. Michael Lee  13:18 
So that’s motivated the HERKULES 3 study. So this is a study that has two different arms based on the mutational profile of the patients. This study at present is currently up, enrolling patients only who have either a KRAS or NRAS activating mutation –again, about 45 to 50% of patients, or patients who have a BRAF V600E mutation, about 5 to 10% of patients. Unfortunately, if your cancer does not harbor one of those mutations at this point, you would not be a candidate for this study, just based on the principle that we’re trying to kind of find the best personalized approaches based on the underlying mutational profile. There are other trial options. Aside from HERKULES 3 for patients who don’t have a mutation in any of these genes. Patients who have a mutation in KRAS or NRAS as I mentioned, they will be studying the combination of the ERK inhibitor ERAS-007 with the CDK4/6 inhibitor, palbociclib. For patients who have a BRAF V600E mutation study will look at the combination of the ERK inhibitor ERAS-007 with an otherwise standard approach of encorafenib and cetuximab.

Dr. Michael Lee  14:36 
It is important to make sure that patients who are interested in this study know what the key eligibility criteria are when at the point in their disease, it is really important for you to be evaluated for this study. All clinical trials have particular time points –or are kind of they’re designed around particular points in a patient’s journey with typically stage four colorectal cancer, at which they should be considered for the study. And if you’re not quite at the right point in your journey, the trial would not be the right fit for you. So in particular, the HERKULES 3 study is looking at patients who have had some prior standard chemotherapy regimen. So for the most part, this specific study is not for patients who have had no prior therapy. But usually they will have gotten a standard prior chemotherapy based regimen. It also requires that they haven’t been given drugs that are usually given in patients who are more refractory to standard chemo therapies, drugs like regorafenib or tipiracil/trifluridine — these are oral drugs that are FDA approved, are usually given after kind of prior lines of IV based chemotherapeutic regimens. And so, if you’ve gotten one of those treatments before, this wouldn’t be a good fit. So you really should come evaluated for this study, before your oncologist is talking about putting you on regorafenib or tipiracil/trifluridine, because if we start that you won’t be eligible for this study anymore. It also requires the patients who have not had prior RAS, MEK, ERK inhibitors, these are not currently standardfor patients. So I wouldn’t expect you to have gotten this unless you were on a prior clinical trial. And while the criteria are evolving, it’s preferred that patients with the BRAF V600E mutation have not previously received encorafenib and cetuximab. So ideally, if your oncologist is talking about putting you on that combination, you would kind of quickly get into a center which has the study open to try to get onto this study, if you’re interested.

Dr. Michael Lee  16:45 
I think a lot of the patients are probably familiar with clinical trials.gov. But you can get more information for this study, look up the sites that are currently enrolling on the study, because it’s several sites, not just MD Anderson. So you can go to clinical trials.gov and type in a keyword like HERKULES 3 or this specific identifier number. This was just kind of the header. But if you scroll down, you’ll see more extensive inclusion and exclusion criteria, the sites that are currently enrolling, contact information for the study. So I would encourage anyone who’s interested to go to this site for more information. Again, this is a very exciting study, it only recently got underway. So we do think that there will be a lot of slots in the upcoming months for patients to go on the study. There are a number of sites that are active and continuing to be activated across the country. So looking to kind of where your closest site is, we’re always happy to see folks here at MD Anderson. But I’m very excited about the study. I think it’s very promising and I  I’m happy to answer any questions from anyone.

Manju George  17:57 
Yeah Dr. Lee, thank you very much. This was very informative. There are a couple of questions in the chat. So maybe we can go through that first. So this question is about prior BRAF and MAPK pathway treatments, are you okay, if people wait for a little bit? Or you said ideally, you don’t want any prior BRAF or —

Dr. Michael Lee  18:19 
Yeah, so it’s a great question. I think in general, patients try to determine what’s the best timing for coming into being evaluated for a clinical trial. It can be hard, because the reality is that logistically, there’s always a little bit of lead time that’s required to get in a new study, especially if you have to travel and figure out kind of life issues with that. And the reality is, if you’re kind of actively progressing, sometimes patients may have more significant symptoms that are building. What we don’t want is for a patient to wait, not get any active therapy before they know that they’ve been off of therapy for a couple of months and then start having worsening symptoms or other issues. I’d encourage patients in general, if you’re interested in the study, you know that you have a potential activating mutation in one of these key genes, to get an opinion at one of the sites that has the study. While you’re in the middle of your first line therapy, you may be able to get a kind of with a planned restaging scan. That way you can get plugged in well in advance, you talked about the study, you have an updated sense of the actual slot availability. Particularly in earlier phase, the earliest portion of the study, I will tell you we do have to be a little bit slow and methodical in how we enroll patients, just because we were looking very cautiously for safety of these new combinations. And so we don’t want to enroll a ton of patients all at once and find out there was a significant toxicity and we have to adjust the dose. So there are kind of slots that come and go particularly in the early phase of the study. So it is helpful to get plugged in and really get an updated sense of what are the study options — really other study options other than HERKULES 3. While this is a very promising study, there may be other study options that may be right for you. So rather than waiting until you’re progressing, and then risking a long wait time to try to get into the center, I think it’s good to try to get in kind of earlier, when you have a little bit more breathing room to figure out what the options are, so that when the time comes, you can get in quickly.

Manju George  20:21 
Yeah. Okay. So what you’re saying is that, so is it true that when a person starts, say, for example, FOLFOXIRI, and do they have to wait through like eight cycles or till progression to start thinking about this trial? Or should they initially  start thinking about it and get talking about it?

Dr. Michael Lee  20:42 
Well, I encourage patients in general to think about trial options, even from the beginning. So if  know you’re very motivated to go for trials, you understand. I mean, I always advise all my patients, there’s always kinds of downsides, particularly having to travel  farther than normal to get on a study –it is important to be aware of logistically what’s involved. With all that being said, if you know you’re interested in a trial, I think it always behooves you to get plugged in to a center with a large number of trials earlier in your course. When you’re getting standard FOLFOXIRI based therapy,  or even a chemotherapy doublet, if that’s whatever standard therapy you’re getting. If you’re having a really amazing response to therapy, I don’t think anyone would tell you to stop what’s working. And we would hope that that response would last for a long time. But of course, we also understand that at some point, that response may run its course, and we want to be prepared and have this plan ready to go at that time. Usually, that requires restaging every two to three months, we typically will do it every two months at our center to keep an eye on things. And so if you already know you’re interested in the study, many patients will actually get their restaging scans done with us, for example, so that we are immediately aware of when we need to switch gears.

Manju George  22:02 
Yeah. I had a question about the side effects of ERAS-007. You talked about the ocular side effects, what particularly are you seeing or what is known?

Speaker 1  22:13 
Well, these classes of side effects in general can be associated with a retinopathy, which is a retinal inflammation, or, specifically, if you recognize it, and you hold the drug, it does get better. And it may manifests in things like blurred vision or flashers or floaters. The study is building in regular eye exams, but you should also be aware, and kind of letting us know if you’re having any of those side effects. This is a class of side effects that generally we’ve seen with other kinds of MAP kinase inhibitors, even other nodes of that pathway. So for example, this is a common side effect we see with MEK inhibitors as well. So it’s not unexpected, but it is something we need to be aware of. And of course, when you’re giving drugs in new combinations, we have to be aware of that maybe a different side effect profile, again, kind of part of the reason in the early phases study, we proceed with due diligence and caution to make sure we’re maximizing patient safety.

Manju George  23:13 
Okay. So the other question was you mentioned a couple of doses, right for thyroid cancer and for the other cancers, 180 milligrams and 250. So what is the dosing? Are you also dose escalating during this initial part of the study?

Speaker 1  23:27 
The initial part of the study does have a dose escalation. Now the initial that’s kind of part of the slot, the slow and steady kind of slot determination, there is an ultimate dose expansion that’s planned. But we are planning a priori for the potential for needing to modulate the doses based on the toxicities we’re seeing –the unique novel combinations. So there will be ongoing tweaking of those doses.

Manju George  23:49 
Okay. And then about this ERK inhibitor, this is ERK1 and 2 inhibitor combined, right, blocking both? –And how does it compare to say the other ones available? Like ulixertinib or the BVD drug? –What is the difference?

Dr. Michael Lee  24:06 
So, I mean, every drug pharmacologically has different kinds of affinity for binding for the receptor and different kind of selectivity. Generally, the more selective the drug is for its intended target, and the less it hits off target, we would hope for better toxicity profiles, we do also see differences in the pharmacokinetics, which is kind of how long the drug persists. And that not only affects dosing, but the idea is that it can affect the optimal effectiveness level of the drug. This is a little bit subjective. But there are folks who will even say that this is more promising, I think you had seen in those preclinical studies that responses did tend to look better than then some of the predecessor ERK inhibitor –the prior ERK inhibitors. So we’re very hopeful that this will be even more effective than kind of prior drugs in the class.

Manju George  25:07 
Okay, I think there’s a question about what information do you have on palbociclib? In other cancers, what is the toxicity or efficacy, what have you seen?

Speaker 1  25:16 
Sure. So we have a pretty good handle on the expected side effects of palbociclib — at least kind of as a single drug. As I mentioned, it is approved with kind of estrogen directed hormonal therapies in combination in a range of estrogen receptor positive breast cancers. In that context we typically will see the biggest potential side effects with palbociclib typically is your blood counts. So it can cause low red blood cells or white blood cells or platelets. So that’s a known side effect we would have to follow, it actually doesn’t usually cause too bad of like febrile neutropenia, which is what we usually worry about with, say, chemotherapy and low blood counts. But that being said, we obviously do have to monitor and be very wary of potential infection and keep an eye on your counts. It can be other side effects like fatigue, like, rarely lung toxicity, or pneumonitis. Rarely, things like mouth sores. These are things we would obviously pay attention to. And obviously, their risk in combination will be more potentially there. Palbociclibn isn’t really given as a single agent, really, in any disease type, it hasn’t shown much activity, it tends to probably work best in combination, when there’s another targeted drug that’s already partially impairing cell cycle pathways, and then you further hit the cell cycle pathway. So tends to synergize better with other targeted drugs.

Manju George  26:37 
Yeah, I think there’s another question about the combination of the ERK inhibitor with KRAS-G12C inhibitors, do you know anything about it?

Speaker 1  26:49 
That would obviously be very exciting. There are a range of trials that are ongoing, obviously, specifically for the G12C patients. If you hypothetically had a KRAS-G12C  inhibitor, you could go on this study in the KRAS arm. With that being said, there are a wealth of studies that are specifically looking at direct KRAS-G12C inhibitors, as we’re all aware of. And it’s actually there’s an increasing number of compounds and an increasing number of combination approaches. And frankly, that would be a really good option. And something that’d be more unique to you if you had a KRAS-G12C mutation. So while you certainly could consider the study, and I would consider it, I would also look very hard into KRAS-G12C  inhibitor based combinations, because, there is a rationale to look at G12C plus other inhibitors of the EGFR MAP kinase pathway that is being studied in colorectal cancer. The exact best strategy remains to be seen, but most of the studies we have we’ve enrolled a number of patients on on other G12C  inhibitor trials, and they’re looking at an ever increasing number of potential new combinations to look to see, is there a signal of being more active while remaining tolerable compared to just single agent? So there’s a lot more options if you do have a G12C  mutation.

Manju George  28:13 
Yeah, and the other one question here is about EGFR inhibitors. So prior EGFR inhibitors don’t affect being on the trial at all right?

Speaker 1  28:24 
Well, if you have a KRAS, or NRAS mutation, you should not have gotten a prior EGFR antibody. So it would be a moot point. For the BRAF arm, it’s more relevant about if you’ve had prior BRAF in general, I wouldn’t expect you to be getting an EGFR antibody alone. But even if you hypothetically did, it will really depend on whether the trials at that phase of whether it’s enrolling patients with prior BRAF and or EGFR antibody therapy or not. But I would say if you have a BRAF mutation, even if you’re getting standard of care, it really should be in combination with another targeted agent, like the BRAF.

Manju George  29:07 
Okay. Okay. And then so the exclusion or  you prefer to have people who don’t have prior BRAF inhibitor exposure, right?

Speaker 1  29:20 
The study actually, the reason I phrase it that way is actually different phases of the study, it may allow or may specifically prohibit prior therapy. So generally, it will be safer if you haven’t had prior therapy, because at some point, the study will reach a phase where if you’ve had prior therapy it will actually probably be an exclusion criterion for this study.

Manju George  29:42 
Okay, so that means that for right now, prior BRAF inhibition is not an exclusion but it could be later. Yes, okay. Okay. And then we have one question from a patient she’s currently on FOLFOXIRI plus Avastin. And then she’s asked she’s got an HAI pump and to get to the liver resection and she’s asking, this would be the best time to think about this trial, right? For her?

Speaker 1  30:07 
I would think about it for sure, I think the biggest question for you specifically is going to be do you in fact, get to the point of a liver resection happening. Because if you have, what it would mean is that your liver metastases have responded very well, and that you’re actually having your shot at surgery. So, if you actually do have surgery and have all visible, known tumors removed with no evidence of radiographic disease remaining, then frankly, wouldn’t really be a candidate for this study. But that’d be great. So I would think about it just in case it doesn’t happen. But obviously, the hope would be that you would get to resection.

Manju George  30:46 
Okay. How can a BRAF V600 patient decide between Beacon doublet and this trial and which is more likely to help?

Dr. Michael Lee  30:57 
Well, Beacon is your standard of care doublet, right? That’s always available to you, as a standard of care with your local oncologist. I think but knowing what we know, about expected response rate, progression free survival and wanting to continue to push things forward, improve outcomes, I do think there’s an important role for novel therapies, looking at trying to see if the addition of the ERK inhibitor will build on the Beacon kind of backbone. So, ultimately, I think, if you’re willing to go on a trial and kind of have the logistical bandwidth to go on a study, I would highly encourage you to at least look into it. I think if for other reasons lifestyle, quality of life, it just doesn’t make sense, that’s totally understandable. And the Beacon regimen is going to be totally reasonable to get as your standard of care and is obviously the best standard care approach you could take.

Manju George  32:05 
The next question is about washouts. So if somebody is on chemo, how long do they have to wait till they get on the trial?

Speaker 1  32:13 
I believe it’s three weeks,  let me confirm it. It would. It would be in the clinical trials. I believe it’s three weeks though.

Manju George  32:24 
Okay. So not too much of a wait time. Yes. Yeah. Okay. Any other questions? When you showed the figure with the mouse models, you had some wild type animals in there, too. Right?

Dr. Michael Lee  32:43 
In the mouse models, there were wild type as well. Yes.

Manju George  32:47 
So it’s responding to people who don’t have the cancers which don’t have mutations in the BRAF and KRAF too?

Speaker 1  32:58 
So at least from the mouse data, it did look like that was the case now. Certainly, that the potential future area of investigation, because we obviously know that all patients with a range of kind of mutation profiles, we want to push things forward and have new trial options. So, but I think the study was designed with this priority for now, because we know there’s a particular need for patients with these mutations. I think I saw a question about what is the known toxicity profile. The study has started enrolling, but it’s actually quite early in its course, there haven’t been any major unexpected toxicity so far. But this is with a very small handful of patients. And certainly hasn’t been, like, reported at a meeting or anything, just because it’s still so small. I can assure you there are very regular safety calls ongoing to make sure all investigators in the study are staying abreast of any updated safety kind of in real time, which we do standardly for any new combination of drugs, and that’s certainly happening with this as well.

Steve Schwarze  34:01 
Manju, can I jump in? Sorry. Yeah, just I mean, obviously, we know something or like we have some data about CDK 4/6 for KRAS patients. Do we have any sort of evidence about what that would do for BRAF patients?

Speaker 1  34:25 
The CDK 4/6? Yeah. It’s a great question. We are increasingly looking, we’ve been looking at CDK 4/6 in a range of mouse models, actually. And while there certainly is kind of some promising preclinical data, I think. It certainly would be another realm of investigation for us to want to look into. There are a lot of really promising BRAF trials right now actually, that are trying to build on Beacon so really the question has been a matter of what is the most promising way to go? So CDK 4/6, certainly there’s a lot of interest in it. I will tell you at our center, my colleague, Van Morris, who I’m sure you all are very familiar with, has probably talked to you about some other emerging data about kind of the Beacon regimen plus immune checkpoint inhibitor therapy, and that he’ll actually be discussing those outcomes at the upcoming GI ASCO meeting. With the early data, and, there’s ongoing discussions about that becoming a larger, kind of much larger study. So I think we’re very excited about that data, in particular for BRAF patients.

Manju George  35:44 
Okay. Again, going back to the mouse data, so you had the HCT 119 cell lines right? In that figure, so is that like a subcutaneous model? Or do you have you checked in like a PDX model or something?

Speaker 1  35:59 
So it’s looked both kind of traditional cell line models, right. But on the right side of that figure was actually a range of colorectal PDX , is specifically patient derived xenografts. So it was looking both at kind of traditional cell line models plus PDXs.

Manju George  36:18 
What else? This is very useful. Thank you so much for your time. And we’ll probably give like one or two minutes, if anybody has any other questions.

Speaker 1  36:29 
I think someone had asked about efficacy even in the last few months. I wish I could tell you something more concrete. But right now, it’s still extremely early in the course of the study. We’re still even kind of at a point of getting dosing or firming up the dosing and the tolerability. So it’s very hard to say right now anything broadly with just a handful of patients.

Steve Schwarze  36:58 
Can I ask one, Manju? That dosing question is really important. I mean, so I was on a Beacon doublet, on the trial arm,  like four years ago, and then over the past year, I did it again with ulixertinib, through their expanded access program, and like I ended up getting eight months, I got twice as long on this combo with ERK inhibitor –I got four months on the trial, even though I’m much farther out. But it was a real challenge to try to juggle those doses, because we really didn’t know how much and I had a lot of toxicities related to it. So, yeah, I don’t really have a question. It’s just more of an n of 1 example, that it was figuring out what those right dosage was gonna be.

Speaker 1  37:52 
And I think that’s really important, because it’s exactly what we’re getting at. And I will say that targeted therapies, some patients think, oh, targeted therapies are not going to have any side effects like cytotoxic chemotherapy. And that’s, of course, not the case. It’s a different side effect profile, right? It’s more not like the really bad toxicity that gets better. It’s more like we have to learn how to live with these toxicities over a long time. So like a moderate toxicity that just never goes away, is quite bothersome as well, and perhaps arguably more so than a more significant toxicity that goes away in a couple of days. Right? And so part of the study is looking very carefully at what is the best dosing schedule along with dosing there are. That’s all kind of being pre specified, and still active discussion, and that’s kind of a key point of the early phase of the study. So we know what is the best strategy to go to before we kind of go into a larger expansion phase where the slots aren’t going to be so limited, we will have a better handle so that other clinicians, the investigators on the study, have a better sense instead of feeling like they’re having to go it alone to figure out the dosing, right?  which may have been your n of 1 experience.

Manju George  39:05 
Yeah, I think there’s a question. He’s asking, do you have a sense of how quickly you expect to see results or not? So are you going to have like interim results when you have the safety part done before you go into a dose expansion?

Speaker 1  39:21 
Yes, and no, I mean, so, of course there will be ongoing evaluation of the results, but it’s always very tricky when you have only like a handful of patients to make a firm conclusion about the efficacy of the study. Even the Beacon regimen, which as we all recognize was a major advance, had a response rate of about 20%. So hypothetically, I mean, I know actually, the earlier patients actually had a really high response rate, but hypothetically, if you’d had a treatment that had a one in five response rate and your first five patients you didn’t happen to see anyone have a response, you might prematurely say, “Oh, that’s not active” — and that wouldn’t really be accurate. So you do have to be really careful about that. We obviously do want to get the results as quickly as you can, but we also need to recognize that we need to get a large enough sample to know really what the true efficacy is.

Manju George  40:20 
Yeah. Okay. I have a question. So, in Dr. Corcoran’s trial, where he had the Spartalizumab with the MEK inhibitor and the BRAF inhibitor, he was using CtDNA to see whether the BRAF levels go down, and that would be an early indicator of effficacy, right? Are you planning to do something like that? What exploratory endpoints are you looking at?

Speaker 1  40:42 
Sure I mean, there are a range of –any early phase study has a lot of endpoints like, additional correlative studies, a lot of them are pharmacokinetic studies where they’re really looking to see what is the dosing level obtained by the drug and like, what is the level of the drug in your body at that time point that standard. It’s pretty cumbersome, honestly, for the patient to have, but that standard. CtDNA is built into practically every study at this point, I will tell you, it’s probably not like an immediate readout or necessarily going to be used to determine if it’s working or not–continue or stop. From that perspective, we’ll still be using the tried and true kind of radiographic imaging based endpoints. But, pharmacodynamics, and pharmacokinetics are a key point of what happens in these early studies. We’re very grateful that patients are so willing to take those steps, we can truly know was the drug working, was it doing what we intended it to do, because we really need patients to be willing to get extra blood draws or even biopsies and things as needed. So we’re very thankful for patients to be willing to do that.

Manju George  42:03 
Okay, thank you for that. Yeah, I think we covered all the questions. And this has been very useful. So what I’ll do is that I’ll have the video available in Colontown University as well as Colontown. And if you want, if you’re interested in having your patients watch it, or somebody who’s interested in the trial watching it, I’ll be happy to share a link so that you can have them watch it.

Dr. Michael Lee  42:31 
Yeah, that would be great. Thank you so much.

Manju George  42:34 
Yeah. Okay. Thank you very much for your time.

Dr. Michael Lee  42:37 
Thank you, everyone.

Steve Schwarze  42:38 
Thank you. Bye bye.