Tackling targeted therapy refractory BRAF V600E mCRC: Dr. Kopetz (2021)

This is an automatically generated transcript.

Dr. Scott Kopetz 0:00
So thank you all for coming together and spending a little bit of time to talk about how we’re tackling targeted therapy refractory to BRAF, decent center D, metastatic colorectal cancer. I am Scott Kopetz faculty at MD Anderson. I had a few slides just to kind of set the stage and where we are. And then we’ll dive into some discussion on, on, some of the efforts ongoing, just to set the stage a bit, I think this group knows well that BRAF has been a bit of an enigma for colorectal cancer, in the sense that that treatments that have worked well in melanoma did not work well in in colorectal cancer, even though the same drug, same mutation, and so this really kind of sets the stage for a lot of how we are thinking about a kind of a treatment refractory colorectal cancer. What are the key findings? And I have just a few science slides here to show but some of the key findings is that really we have in colorectal cancer, we had a hard time really fully inhibiting that pathway. So when we give a drug, what we can see is that in melanoma, you get really nice inhibition of the pathway. And so what we can see in western blots is where there’s a dark, dark line that’s an expression of a protein. And so this is signaling through this key pathway that we’ll come back to in melanoma, really single dose of the drug, and you get this complete inhibition, you know, whiteness here on this area, but in colorectal cancer, on the top, what’s seen is that you get very transient inhibition, and then the signaling starts to restore. And so this is kind of the science that’s the fundamental behind the issue in colorectal cancer, which is one of kind of adaptive resistance. And so adaptive resistance is, I describe this as really kind of the homeostatic regulation. So networks have a way of wanting to go back to where they were. And so, you know, when you have a really complex system, think about, you know, a the power grid, right? Someone can, can drive into a power pole, knock it down, the lights blink, and the power is back. You know, before you’ve had, you know, a chance to even acknowledge that the lights were temporarily out because the network has a lot of redundancies and other pathways, and is the networks restored. And so the same thing happens in biologic systems. And so cancer has a set point, like a thermostat of where it wants these, these pathways to be, and when you try to perturb it, what the system does is it is it adapts and rewires to try to restore that signal. And so what we’ll be talking about is really this concept of adaptive resistance, homeostatic regulation. So what does that look like? Well, it means that this is our signaling cascade, where we have growth factors that come in, and these are a series of cascading proteins that signal one into the other. And they do these in a way to try to coalesce a number of different signals. So we have this as a very linear process here, but there are multiple growth factor receptors. We’ll come back to that, that all kind of feed down into this growth signaling pathway here. And there’s also amplification steps that occur. So each step down, the signal gets amplified, other inputs get interrogated. So the end results is, you have ERK, which is the factor that really goes in the nucleus and that starts to change the program of the cell. So what happens is, when you give up the BRAF, the here, green is activation, blue is is, is quiet or inactivation. We give a BRAF inhibitor. You get a transient inhibition downstream signaling. What happens is you see all these arrows going up. These are some of the adaptive feedback mechanisms. And what happens is this, these negative regulators then get inhibited as well. So you’re inhibiting a negative regulator. What happens now is then you get upstream activation. And so this is where we see EGFR now, all of a sudden become important. Signaling drives this, and it drives through KRAS and then BRAF is a family of RAF. There’s ARAF BRAF CRAF, right. And within our cell, we’ve got one mutated copy of BRAF and a colorectal tumor. But then there’s a wild type BRAF that’s there as well, right? So they have two copies of everything that get passed along in most cancers. And so what happens is that it can use the existing normal signal signaling, kind of signal around the BRAF, and then restore the pathway homeostatic response. And this is how the tumor so the key finding was that when you inhibit EGFR as one of the kind of key feedback mechanisms, now you block BRAF, you block what pops up, and then your signaling can be inhibited. And so that’s the was the rationale between a lot of studies and just highlighting the one that led to FDA approval, the BEACON study, of course, where we’re looking at the doublet of a BRAF and an EGFR inhibitor versus control. And that was what ultimately the FDA approved as a current standard of care. Now there was another arm, bimimetinib, and that was the MEK inhibitor. And so the idea here was, well, maybe we just need to hit a little bit further downstream with the MEK inhibitor, and that’s going to even any leakage that we had, maybe that’s going to blunt it even further, right? And so that was the hope. Now we know, unfortunately, that this hypothesis didn’t pan out, and that when we looked at the overall survival, we saw clear improvements with the BRAF and EGFR, but the MEK turned out didn’t do anything, right and and you know, part of that is, you know, the balance of toxicities and efficacy, and that’s despite the fact that what we see is, we saw higher response rate, and I won’t show you the data, but you know, we saw that the tumor shrink down more. They just didn’t stay down quite as long, or they stayed down just as long, I should say, is the BRAF and EGFR alone, so that added toxicity didn’t really provide any benefit for patients long term. So, you know, this is where the field has been. And really kind of thinking about, how do we inhibit this, and how do we improve upon it? And what I want to highlight, because this is certainly an area of interest to this group, is how do we really understand signaling at progression and clinical approaches to modulate resistance, and so that really kind of sets the stage. Now we’ve known for many years, and this is now almost worked far as maybe 10 years ago, that at the time of resistance to some of these inhibitors, you get number of different things that can occur, EGFR amplification, KRAS amplification here, and there’s a number of these different things that have been seen circulating tumor DNA has provided a lot of insights into terms of KRAS and NRAS mutations that also appear. One of the key features that we see is that all of these are converging onto what we call a MAP kinase pathway reactivation. So this is intriguing, because in other settings and other tumor types, you may have resistance that develops to a treatment, but it may be four or five very different pathways that may get turned back on right. maybe this pathway over here got turned on in one patient, a different pathway in another patient. But what we can tell, and I think we’ve now seen enough to say that this is probably the vast majority of patients. Then the tumor starts to progress on treatment. It’s still very dependent on this exact same pathway, the matpatus pathway. So even though there is a whole smattering of different mechanisms, they all appear to be going down to the exact same pathway. So it is useful sometimes to understand why patients are progressing on a given therapy. But that doesn’t preclude the fact, even if we don’t know that, we just know by all the studies that we’ve done what the tumor is still dependent on. So in we borrow a lot of evolutionary terms in cancer biology, so we call this convergent evolution, right? And so this is the classic like we learn in biology, that the sharks and the dinosaurs, the reptiles, penguins,dolphins, mammals, looked very different a long time ago, but they all evolved to have a very similar shape, because that was the most efficient when you’re swimming through the water, right? So this idea of kind of multiple different mechanisms to get to the same, the same behavior pattern. So that sets the stage for a number of different strategies. And there are studies looking at Other MAP kinase pathways. There’s a few different ERK studies, so Lilly studies, Asana ERK inhibitors, for example. And then kind of a big study that Novartis is doing, looking at a number of different combinations here. This is a word salad here. I’ll put the PD-1 kind of at the end, and we’ll kind of come back to that one in a minute, because that’s a bit of an outlier in the concepts that we’re discussing in these other items. But the idea here is, how do we learn from these and how do we try to explore what’s going to be best tolerated and give us that best therapeutic window? So we go back to our now slightly tweaked pattern here. This study is actually looking at BRAF, the bratinib, and an erk inhibitor. And so you can see that it’s under my yellow X here. But this is the ltt 462, inhibitor, erk inhibitor, that’s being utilized. And the idea is that we really want to try to block these downstream signaling, but erk inhibitor alone can’t fully shut off signaling, and that that there’s if there’s a lot of signaling from above, there’s still going to be leakage through. So it’s really about, how do you try to tamp down that upstream signaling? And so the three areas that are being looked at are, well, mek, so let’s just BRAF, mek, try to really go downstream. Find best doses for those instead of MEK, there’s others looking at pan RAF. So that’s the LX 254, Pan RAF inhibitor. Remember I said RAF is a family, so it’s kind of ARAF BRAF CRAF so you’re trying to kind of block that bypass where everything upstream is sneaking around, BRAF to get through. So that’s shutting off another leak in the dike, as it were, and then the other is looking at shp2. Now, shp2 is a is kind of an adapter. You also may hear a sauce inhibitors and their sauce MEK combinations being explored, but, but recognizing that there are a number of different rtks, fgfr, EGFR, pdgfr, all these have been implicated at various times or others. And while we think EGFR is a dominant one, certainly we see other ones appearing there for family members as well, and they all feed through shp2 to then activate KRAS. So this is kind of the funnel, you know, it’s a area, and the funnel that, if we hit inhibit shp2 , in essence, where it’s like inhibiting a lot of the receptor tyrosine kinases and so, which is good, but it also can come up with some toxicities, because you’re inhibiting, you know, EGFR and lots of other, you know, her family members and so. So trying to, you know, find these right combinations, our goal then as well. So these are kind of some of the combinations that are being explored in these studies. And this is just showing, you know, the study and how that’s being explored within the water study in particular. But let’s go back to erk inhibitor for just a minute. And again, we’re inhibiting this downstream. And there was some early work, maybe five years ago now, kind of showing in a number in this red box, yellow means more inhibition. That when you give a HERK inhibitor, especially in combination with some of these, that you can improve activity, and that this is another preclinical work now showing that a lot of the doublets here, even the triplets, BRAF mek, EGFR, don’t see a lot of regression in some of these models, but it’s only with the addition of erk top of some of these BRAF targeted strategies that make sense. So you know, there are studies launching looking at BRAF, EGFR, erk, for example, to explore that. And one of the things is that, and this was some really nice work where they looked at Mark good, and this is out of Ryan Corcoran’s Group. So this is a slide from him, where they actually looked at a number of different combinations. And then when they did the combination with the ERK inhibitor, what they could do is prevent outgrowth of some of these clones, right? So the kind of KRAS clones that were present that could prevent those from growing out. So that was, you know, some of the rationale for exploring that. And so I think, you know, just acknowledging, of course, what we know that we need novel therapies. Here we have encorafenib cetuximab. And there’s a lot of work going on about, how do you move into first line or into adjuvant setting? And then some of these, you know, combinations there as well. One final comment about PD-1. So there’s a about 20% of patients with a BRAF metastatic BRAF tumor will also have an MSI high, and that responds well to immunotherapy, but there’s a proportion of patients that progress immediately in immunotherapy and don’t respond. And so there’s a question about, well, what if you target the BRAF, EGFR, and the PD-1, for example, is that something that could be beneficial. And this parallels a whole other area of work that we and others are working on, thinking about PD-1 in a microsatellite stable population. And so there’s NCTN, a large US cooperative group study that’s launching looking at a BEACON regimen and corrective Cetuximab with or without a PD -1 inhibitor for MSS patients. But the Novartis study, for example, is really looking at, can you improve upon outcomes in the MSI high population as well. So there’s a lot of kind of really interesting biology there. So with that, I’ll, I’ll stop and and, you know, take any questions and really make sure I have some time for some discussion around this really interesting area.

Manju George 16:37
Thank you so much for that introduction. So we have got nine questions, and I’ll go through them quickly. The first one was about about the trial design itself. The question was, can the same patient be on two different arms of the trial at two different times, since this is a safety trial,

Dr. Scott Kopetz 16:55
Yep, yeah, there is a safety and then an expansion cohorts in there as well. There’s nothing in the in the trial that prohibits that there are two different cohorts for groups of patients that have not had encorafinib cetuximab before or not any MAP kinase targeted therapies before, and those that have. And so there’s a possibility to go on those that have not had it get treated with it and then potentially re-enroll in the converse. There’s not anything that is in the current version of the protocol that is precluding that, so we’ll certainly be exploring it. The only thing is that if, if a patient has to stop therapy because of toxicities. For example, the you know, ERK caused some toxicities for which one had to stop, then you wouldn’t be able, or wouldn’t, probably want to either kind of go back out of the same regimen. So there is a caveat here.

Manju George 17:55
If a patient has been on the on dabrafinib previously, could they get that on this trial immediately, or is prior dabrafinib an exclusion? If not, do you need to have, okay, okay, so do you need to have an intervening chemo period? Or can they come back?

Dr. Scott Kopetz 18:12
Nope, they can come right in. You know, there’s a requirement that patients have had at least one prior line of chemo therapy. So, yeah, it shouldn’t, shouldn’t be a problem.

Manju George 18:24
Okay, so if they’re on the other like, for example, the -?–emab you know, Dr Corcoran’s trial with the dabrofinib, and they could still come back on the Novartis without any any problems. Okay, okay, good to know. Thank you.

Manju George 18:41
yeah, in between the different trial arms, could you tell us, like, if a patient had to choose, are there particular arms that would be better, and why would you think so?

Dr. Scott Kopetz 18:51
Yeah, that’s a good question. And so, you know, part of it is that with these studies, the way that they tend to work, even a trial that has lots of arms like this, you know, right now, like, if I, you know, somebody that I wanted to put on study this week, there really wouldn’t be any arms available, right? So there’s, you know, the the I think the further we get into the study, the more opportunities and slots, you know, may be available. So it may get to a point where there is a bit of, you know, opportunity to kind of pick and choose, you know, efficacy we just don’t know. And I think the question for all of these is really one of a therapeutic window, meaning how much to inhibit the pathway and really maintain kind of safety. So a lot of work trying to get those doses just right, figure out kind of where things are going to settle down with those treatments. So I think all of them are, you know, based on really good science and good rationale. And I think it’s really going to be a factor of, you know, what doses are achievable and and how effective are we at inhibiting the pathway, and that, unfortunately, just going to come with. Time. So the short answer is, the best arm is the one that you can kind of get on when you need it, you know, I think they’re all very, very reasonable.

Manju George 20:12
Okay, okay, so I’ll just ask one question. So in your talk, you thought that, like with the data, that you showed the BRAF inhibition, the MEK inhibition, and the ERK inhibition, or, you know, this, like that, seems to be having the most, you know, the bars are going down, right? There are some of the arms they’re just taking SHP2. They’re not blocking all the three nodes in a sequence, right?

Dr. Scott Kopetz 20:37
And so acknowledging, of course, that they, you know that one study didn’t, didn’t run, that was in cell culture, right? So there’s some caveats there. And we didn’t really explore all of those different, you know, all of those different combinations, or actually, they didn’t explore all those different combinations. So I, you know, I would be a little hesitant to say that’s absolutely the winner? I think there’s, you know, there’s a lot of thoughts about, well, how do you bring this forward, like, what does the next study look like based on these results? So I’m hopeful that that combination, you know, may be explored, and that’s being explored in other studies, but, but I think trying to think about where one can go with, you know, with a signal like, what is it? What do we need to see in order to move this forward for patients?

Manju George 21:31
Okay, so the next question is, like, we have a patient who has a co occurring, Akt1 e17k mutation. So do you think that particular arm would be better, like with that particular mutation?

Dr. Scott Kopetz 21:43
Yeah, it’s a good question. We don’t have a – it’s a rare mutation, but certainly is activating of that pathway. We can learn from the PIK3CA mutations that have been seen, which is which is slightly upstream of the Akt signal. So the Akt, when it’s activated, PIK3CA, will activate AKT. And when the PIK3CA, when we looked at it, we went into this several years ago, thinking, well, if you had that mutation, conceptually, it seems like maybe the treatments wouldn’t be beneficial. When we looked at some of the earlier data, it actually looked like that for reasons we didn’t understand. The outcomes were even slightly better with the patients who had a PIK3CA, even though you were targeting the MAP kinase pathway and some of the randomized studies that didn’t pan out. So we look at, so I don’t know about the Akt inhibitor alone, but the PIK3CA activating mutations did not appear to be a major, major driver. So, you know, we think about that maybe that mutation was critical early in the development of the cancer, and that as the cancer evolved, it became less of a dominant driver. And it really all became about map kinase pathway,

Manju George 23:07
The next one like I think we have to go quickly so monomer versus dimer, ras inhibitors, and what you know, there is an arm combining both of them along with their inhibitor. If you want to say something about that?

Dr. Scott Kopetz 23:24
So, you know, the idea, obviously, BRAF, we know it targets the oncogene and the wild type BRAF, but you know, the hope for the pan RAFs is that it can help modulate, you know, the other signaling around, kind of the leakage, as we talked about, around that. So, so, you know, that’s, I think, you know, hopeful that some of these pan RAF inhibitors will be more, you know, more effective in this thing. But it still remains to be seen. Again, it comes back to tolerability, right? You know, BRAF’s great because you hit BRAF. And you know your normal skin is okay, you knock out BRAF, but your normal skin has CRAF right? So it can still do what it needs to do with CRAF. So the problem, of course, is if you’re blocking all of RAF, you’re blocking all the raf in the tumor, but you’re blocking all RAF in your skin as well, right? And so or your GI tract, or other areas. So that’s where really trying to make sure that there’s a therapeutic window. So it’s not always what looks great on this simplified signaling diagram, but what is happening in the normal tissues as well.

Manju George 24:29
And safety and toxicity of SHP2 inhibitors. So there’s some data with the KRAS mutant study. So I mean, do you have any advice on what are you seeing?

Dr. Scott Kopetz 24:38
Yeah. I mean, I think shift two is an incredibly interesting class, and I think we’re really kind of excited about the potential there. You know, receptor tyrosine kinases are very ubiquitous throughout the skin, the GI tract as well, and so we need some signaling in our healthy tissue to kind of. Through that. And so again, comes back to the same thing that, you know, it looks great targeting the cancer cells, but it’s, you know, how tolerable is that going to be? And how do we adjust things to look at that we know, for example, EGFR and MEK inhibitors, and we put those together, they’re really difficult to tolerate those two together. Now, turns out, when you look at other different combinations, then it may be a little better, you know, ERK and EGFR may be better. You know, BRAF, MEK, EGFR is much improved because of some of the feedback mechanisms in the skin, for example, so that we know that some of the SHP2 combinations, we may run into some of those same limiting toxicity. So still a little early, but I think very promising.

Manju George 25:53
This was about TKI inhibitors combining with like the BEACON doublet.

Dr. Scott Kopetz 26:00
Yeah. So, yeah. So good question there is, you know, one of the things that Stivarga does is it does have, it’s a multi kinase inhibitor, meaning that predominantly hits a VEGF, so it’s mostly an angiogenic effect. But they also do hit some other pathways, PDGFR right, which is one of those other receptor tyrosine kinases that, in rare cases, can be kind of a dominant feedback. So the concept is certainly, you know, intriguing to think about, you know, regoragenib combined with it. I think that may work in the kind of unique case that PDGFR is the dominant one in a given tumor or patient. But I think the concern is that we see so many other different ways that the tumor evolves and adapts. That concern that it may not be quite as ubiquitous of a solution, although I certainly can acknowledge in a few select patients, it may be.

Manju George 27:04
Letinatinib (?) is also kind of similar in range of targeting multiple…

Dr. Scott Kopetz 27:10
It has maybe a little bit more selectivity than regorafenib, but still very much hits a lot of other things that may actually be driving whatever efficacy we’re seeing outside of that job.

Manju George 27:22
Question about drug availability and addition of slots, for example, in Europe, or –

Dr. Scott Kopetz 27:26
Yeah, so certainly, the largest studies enrolling in Europe, the slot availability is managed worldwide. For this study, like most studies, meaning if there’s no slot in the US, there’s no slot in Europe, there’s not separate slots for for separate separate sites.

Manju George 27:48
We’ve had some off label experiments going on where people have tried, like the BEACON plus ERK inhibitor.

Dr. Scott Kopetz 27:55
Great to hear. And I think, you know, trying that’s the direction I think we need to go as a field to really better understand it.

Manju George 28:04
So when do you expect to report out some of the findings?

Dr. Scott Kopetz 28:07
You know, a lot of these studies are early on, including, you know, Novartis study, a lot of times they’ll want to have the expansion cohorts enrolled before to really understand a little bit better about the safety. So, so it won’t be ASCO gi I think the question will be ASCO, or would it slip into the Fall even?

Manju George 28:33
What about Dr van Morris’s study like the BEACON plus nivolumab? When can we expect some results?

Dr. Scott Kopetz 28:40
Yeah, going very well there. We’ll have some coming out at GI ASCO. I anticipate, again, the results are sufficiently promising that, you know, the follow on randomized study is, is launching, yeah, so the nivolumab for MSS patients, in addition to the Enocrafenib.

Manju George 29:07
So I think the other question is, are you going to add more arms to the Novartis man? Are you expecting more to be added?

Dr. Scott Kopetz 29:12
Yeah, it’s designed for that. So we very well may see some additional arms come in. There’s a lot of arms already, but there’s, it’s designed that new things can come in there, and then the arms will pause at various times when there are efficacy barriers. So, you know, we don’t see a certain amount of activity. An arm may pause enrollment and prioritize other arms as well.