BRAF V600E research update: Dr. Corcoran (2020)

This is an automatically generated transcript.

Manju George 0:00
I have today, Dr Ryan Corcoran with us. He’s the director of the gastrointestinal cancer program at Mass General Hospital, and I don’t think he needs much introduction in our group, because we are all familiar with the work he’s doing. And with that, let’s start since we don’t have too much time, welcome, Dr Corcoran

Dr. Ryan Corcoran 0:22
Thank you, Manju and thank you to Manju and Steve for the invitation to talk to the foreign town community. I was able to actually do an in person event like this. I want to imagine it was about two years ago, yeah, a year and a half ago. But the in person events are hard to do these days, so we’ll settle for zoom. But anyway, I’m thrilled to be here as always. These are always great discussions. And what I thought we’d do today is I just have just a very brief set of slides. I don’t want to intend for it to take any more than 20 or 30 minutes of the time just to kind of go over some of the recent progress in the state of the field for B rapid, 600 colorectal cancer, in particular. And then, you know, feel, please, feel free to interrupt with questions and any any discussion topics. And then, of course, that should hopefully leave us with some time after, after to talk about anything that’s of interest. So with that, I wanted to entitle the talk today improving clinical outcomes for bref e6 100 colorectal cancer. And this really represents, I think, a summation of a lot of work by many people over the last 10 years or more. And I’ll go ahead and begin. So these are my financial disclosures. And so, you know, this is this, this is the, the, you know, the issue we’re dealing with, right? Is that about, you know, almost 10 years or more ago now, we we had the entry into the clinic of specific BRAF and MEK inhibitors. And, you know, initially, BRAF inhibitors, particularly in the roughly half of melanoma patients that Harvard BRAF v600 mutations, began producing phenomenal response rates of 50% or more. And this really led to a lot of excitement and a hope that, you know, we could perhaps start treating people, not so much by their specific tumor type, but actually by the act the driving mutation present in each tumor. And because the next most common group of patients at Harvard BRAF V600 mutations, were colorectal cancer patients, we were very hopeful that this benefit would translate over. But as we all know, that was not the case. And interestingly, even though same e mutation, exact same braf inhibitor, we barely observed a 5% response rate in colorectal cancer patients, despite this incredible activity in melanoma, and this has really, I think, been the key issue that we’ve really struggled with now for over a decade. And while there’s definitely been some progress, as we talk to you today, this is, this is constantly, it’s these same key issues that we are continuing to strive to surmount. So what’s going on here? Well, you know, early on, after these data came out, actually, a long time ago, actually, when I was still in Jeff engelman’s lab as a trainee, as a postdoc, I actually got very interested in this difference, and started to compare BRAF mutant melanoma models to BRAF mutant colorectal cancer. And early on, after this, I think at the time, what most people expected was maybe colorectal cancers just didn’t, didn’t rely as much on BRAF, or didn’t, weren’t dependent on the Braf or MAP kinase pathway to the same degree that melanoma was or other cancers were. And what we found, though, is that that that perhaps, didn’t seem to be the case. And the big difference we noted is that in a melanoma model, you could give a BRAF inhibitor, you could turn off the Braf MAP kinase pathway, and you could keep it off for an extended period of time. But if you did that same thing in colorectal cancer models, you could turn the pathway off transiently for a few hours, but then very quickly, the pathway would just turn itself back on, even if you kept refreshing the amount of BRAF inhibitor that you added to these cells, and this suggested the possibility that maybe BRAF mutant colorectal cancers are just as sensitive or just as dependent, let me put it that way, on the Braf MAP kinase pathway as melanomas. It’s just that we’re not actually shutting the pathway down in these cancer cells. So why would that be? So this is a little bit this is a very simple depiction of the Braf pathway. And what this is part of one of the most commonly mutated pathways in all of cancer, where rtks, or receptor tyrosine kinases, as they’re called, are cell surface receptors such as EGFR HER2 met things that we hear about and are known targets of various cancer drugs. And these receptor tyrosine kinases typically receive a signal from the from the exterior of the cell, and then they transmit that to a number of key downstream pathways, one of the most important being the RAS MAP kinase pathway. So by activating RAS which has three family members, KRas, NRas, or HRAs, which we all have heard mentioned many times, then RAS proteins will then activate the RAF family of kinases, which include ARaf, BRAF and CRaf, which then activate MEK kinases, which activate erk kinases. And once erk is activated, erk has hundreds of substrates within the cell that regulate important processes, gene expression, cell division, survival signals, and this is really what promotes survival here. So one of the other things that’s downstream of erk is actually some very robust negative feedback signals, which actually prevent receptor tyrosine kinases from activating the RAS MAP kinase pathway through the normal route that is present in normal cells. And so as long as erk is highly active, these signals kind of put almost like an automatic break on this normal entry into the signaling pathway. And therefore, in a tumor, essentially all of the pathway activity really is coming from mutated BRAF and nothing is coming from a normal upstream source. However, in colorectal cancers, when you give a BRAF inhibitor, you transiently shut the pathway down, and you lose these negative feedback signals and that now receptor tyrosine kinases, in particular, EGFR, which seems to be one of the more dominant receptor tyrosine kinases in colorectal cancer can then engage and activate RAs, which can then bypass B RAF inhibitors through some of the other RAF family members, and turn the pathway right back on. So why does this happen in colorectal cancer and not other other tumors? Well, it turns out it actually does. It’s just that the pathway is far more robust and colorectal cancer, and that’s because there’s very high level expression of many rtks, including EGFR, and very high level of baseline activation. And so something like melanoma has almost none of this. And something like lung cancer, which kind of falls in between, as far as the responsiveness we get, response rate to maybe 30% with the BRAF inhibitor alone in lung cancer have very modest kind of feedback reactivation. So this is really kind of the critical issue that we believe is constraining, and to this day, constraining the efficacy in BRAF color cancer. So what this also suggests to us is there is a potential opportunity that maybe these cells, if they work so hard to turn the pathway back on, are just as dependent on this pathway as melanomas, but we just need a different strategy to ensure that we keep the pathway off. So this led to a series of clinical trials where we looked at combinations of BRAF inhibitors with downstream inhibitors like MEK or upstream inhibitors like EGFR antibodies, or actually inhibitors of all three. And what we asked is, by combined, by blocking this, what we call adaptive feedback reactivation of the Braf pathway, could we enhance efficacy? And what I’m showing here is actually some data from biopsies, tumor biopsies that were taken before starting treatment, and again at day 15, while patients were on treatment across a range of clinical trials shown here of BRAF even colorectal cancer patients treated with various combinations, which I’ll go through in just a second, but what I’m comparing them to is the same thing done in melanoma patients treated just with a BRAF inhibitor. And what you see here is by day 15, the Braf MAP kinase pathway is very highly suppressed to about 80 to 90% of baseline levels with just a single BRAF inhibitor in a melanoma patients, but in colorectal cancer patients, we don’t get this optimal suppression. And this is actually why we have incorporated and continue to incorporate these biopsies into our our subsequent trials, because they really tell us what’s happening in the patient’s tumor and let us know if we’re we’re achieving what we think we are, or if we still have work to do. So first, the first trial we ran was a BRAF and MEK inhibitor combination, and what we found here is that, okay, we’re now inhibiting the pathway in everybody to some degree, but on average, to a much lesser extent than we’re getting in melanoma, maybe to only 30 to 40% then we led a trial combining BRAF and EGFR inhibition, and as many of you know, there’s now an FDA approved option of a BRAF and an EGFR inhibitor combination. But we found here is something actually quite interesting, that even though we saw a better activity compared to BRAF inhibition alone. We found that we really only inhibited the pathway in a handful of patients, and then in many patients, we had no inhibition, or maybe even some activation of the pathway. And then when we added all three drugs together, a BRAF a mek and an EGFR we actually started to get much better suppression of the pathway much closer to what we’re getting in melanoma, but still falling short, even though we’re using three drugs here and only one drug here. So this suggested that we still have, you know, have yet to run a clinical trial where with the combination of inhibitors that we’re giving, we’re actually achieving the same degree of pathway suppression than we get with just a BRAF inhibitor in melanoma. And that’s perhaps why we’ve never seen our response rates reach that, that kind of 50% threshold that we saw initially in melanoma. And this is, this is a key issue that we need to continue to work on. As you know, though, you know, just in the last few months, there was finally the first FDA approval for specifically for colorectal cancer patients. This was almost a decade in the making, just a testament to how hard this tumor has been to treat. And what the beacon study did was it looked at the combination of BRAF and EGFR antibody as well as the combination of a BRAF EGFR antibody and MEK inhibitor, similar to the version of the trial that we ran and I showed on the prior slide. And what this showed is that both the triple and the double combination improved response rate relative to standard chemotherapy, which had about a 2% response rate, the doublet had about a 20% response rate, and the triplet ultimately showed a 27% response rate. So definitely better. But interestingly, the triplet failed to really create a convincing improvement in survival relative to the doublet, even though both doublet and triplet were substantially better than the control. And for that reason, only the doublet was considered for FDA approval. So this is where the fields stand. And while this is a very important moment for patients that we finally have a treatment option here that is reimbursed and FDA approved, we still have some significant issues that we need to face. And one is that the response rate remains low. Only 20% of patients respond. One out of every five patients has a true tumor response. We have to do way better than that, and additional issue that we’re facing is that the durability of benefit that we see here is very, very, is very short. And, you know, on average, patients are on this therapy for only about four to four and a half months. And we really need to do better than this. This is, this is actually perhaps even one of the biggest hurdles that we face, is that even patients who benefit only stay on for a very brief period of time. So why is this? Well, this is a process that we call secondary or acquired resistance. So this is, this is a scenario where patients may actually sometimes have a phenomenal initial response, but may very rapidly progress. And this is a situation with a BRAF mutant melanoma patient who had a dramatic response, but then just eight weeks after that response had had widespread progression again. And we can study this process by actually looking at tumors at the start of treatment and then again at the time of progression. And we can actually biopsy these these tumors and figure out what the resistance mechanism here, shown in red, that has emerged during treatment. And this can tell us what the tumor is doing to get around these therapies. And this is something that we began to do almost 10 years ago. Now, what we’ve learned from this is that almost every patient seems to come up with their own way, or every patient’s cancer seems to come up with its own way of getting around the various BRAF inhibitor combinations that we give. And initially, this painted a very daunting picture of complexity, and led us to scratch our heads and said, How are we ever going to get around this if we’re finding 678, different mechanisms of resistance, this is going to make it so complicated to propose kind of generalizable strategies to restore response or to prevent resistance in patients. But what we started to know as we began to accumulate these cases, is that all the resistance mechanisms that we found seem to all occur within the very pathway that we’re inhibiting. And what they all have in common is that they all lead to reactivation of this pathway despite the presence of drugs. So we can see alterations upstream and in EGFR are met, we can see amplification or mutation of RAS, which is the most common thing we see. We see RAS mutations in probably about half to two thirds of patients, we can see alterations of BRAF itself, either amplification or or actually some deletions or splice variants, where parts of BRAF are spliced away and then also finally mutations downstream in MEK. But one thing that we noticed in the lab when we first published these about five years ago is that it appeared that all of these resistance mutations all converged on the final point of the pathway. They all led to reactivation of ERK. And what we found is that by incorporating a new class of inhibitors called erk inhibitors, we could potentially overcome the resistance mediated by the majority of these resistance mechanisms to make things more complicated, what we started to realize is that patient, while each patient’s often often developed a different resistance mechanism from another patient. We found that actually patients could develop distinct resistance mechanisms in different lesions within their own tumor. And this is what we call tumor heterogeneity. So this can arise as intralesional heterogeneity, where different metastatic lesions independently involve their own resistance mechanism. And it can get even more complex, where within a single lesion, we can have multiple different sub clones of a tumor that have independently revolved sometimes a totally distinct resistance mechanism. And we’ve used and for this reason, we realized that by biopsying patients after progression to try and figure out why they’re resistant, we may be we may be missing a great deal of what we call this molecular heterogeneity that may be driving resistance in many patients. And we’ve turned more recently to in parallel, assessing another modality called circulating tumor DNA. And this can be done from a simple blood draw before and after treatment. We can also track, as I’ll show you in a few slides from now, we can track the efficacy of a given therapy by looking at the levels of BRAF mutation in circulating tumor DNA. And this has been a very valuable tool. One thing that this has shown us, though, is that if we look in cell-free DNA, because circulating tumor dating is shed by tumor cells throughout the body, we can get a much more complete picture of all of the resistance mechanisms that are there. And so, for example, when we when we follow patients at the beginning of treatment, at the time of response, where we see a very dramatic drop in BRAF levels. We almost always, we basically always see a rebound in levels at the time of progression. And what we see is the emergence of, in this case, k RAS or n RAS mutations, sometimes one, sometimes many. And in one clinical trial we did of EGFR, BRAF and MEK inhibition, we found that about half of patients developed at least one RAS mutation, and many of those patients developed multiple it can get even more complicated than that. Here is a patient who had a very nice initial response, but then progressed, and we found at the time of progression, this patient had developed eight independent resistance mechanisms, all within this this RAS BRAF MAP kinase pathway leading to progression. So, so how are we going to overcome this complexity of very rapid resistance that emerges? Well, one thought is, if we can target a convergent signaling node through which all of these resistance mechanisms depend, and that really represents the potential of erk inhibition, which is, as I showed you on the previous slide. And what we think is that actually, rather than waiting for a patient to become resistant to a therapy, this might actually be even more effective if we give, if we give this combination to a therapy upfront, before these rare, resistant sub clones have a time to grow out. And we modeled this briefly, and I’ll explain this is a little bit of a complicated slide, but I’ll explain what this means. We basically, we basically took a laboratory model of colorectal cancer that is fairly sensitive to most BRAF inhibitor combinations, and then we made a version of that model, multiple versions of that model that harbored individually, each of the of the resistance mechanisms that we’ve ever observed clinically in treating patients at the time of this work. Then we took all of those resistant clones and pooled them together at about 1% frequency each into a background of sensitive of the original sensitive model. And this really simulates how most patients tumors start where they have rare tumor populations that have these pre existing resistance mechanisms that get selected out during therapy. And that what we did was we treated patients with BRAF and EGFR combinations, BRAF and MEK the triple combination, or we saw what happened if we could substitute in erk inhibitors instead of a MEK inhibitor. And what we found is that by trading out a MEK inhibitor for an erk inhibitor and the triple combination, we can now shrink these tumors in mice. If we, if we injected this population of cells harboring every known resistance mechanism into mice, just by using a new class of inhibitors called erk inhibitors, we could actually cause these tumors to shrink. And importantly, when we exposed these populations to some of the earlier therapies, we could actually track how much each individual resistant clone expanded, and we found that that under a lot of these initial these kind of first generation therapies, we saw rapid expansion of these resistant clones that essentially took over the majority of the tumor. But when we looked at the triple combination with (_?_), we completely took away any advantage that these resistant clonesones had. So there’s actually now several clinical trials, one that’s currently open from Eli Lilly, one that’s opening in a few months, hopefully from Novartis, that’s actually looking at incorporating erk inhibitors, instead of MEK inhibitors, into BRAF inhibitor combinations with various combination partners. The Lilly trial is essentially adding their erk inhibitor to the currently approved beacon regimen. And the Novartis trial will be, will be using a BRAF and erk inhibitor core in combination with about five other other drugs. And so these are are good considerations for patients, particularly people who have, who have kind of been treated with a standard beacon regimen, either during the trial or since the FDA approval, or who’ve had any prior BRAF therapy, as these trials allow prior BRAF inhibitor. But what else can we do? Well, one of the things that we really hope here, and this will be the topic that I’ll end on, is we really want to see better durability of responses here amongst our patients. And one thing that we noticed, if we look back through all of our prior trials, is that we noticed that there were always a handful of patients who went on to have one or two year responses, and sometimes more. And it turned out, when we looked at the molecular features of those tumors, we couldn’t really find a common thread, except for one thing that they all had in common, and that it was all of those cancers that went on to have responses of a year or more, co harbor microsatellite instability. And as many of you may know, microsatellite instability is something that we see concurrent with about 10 to 15% of metastatic BRAF mutant colorectal cancer. And as we as we’ve learned since, because microsatellite and stable tumors are are much more immunogenic. They respond to immunotherapy, and they have more mutations that the immune system can recognize. It’s possible that when we gave those patients BRAF inhibitor combinations prior to the advent of immunotherapy, what we were doing was actually augmenting an existing immune response that led those patients to go on and have long term disease control, including one patient who on our very first trial of BRAF macqua, I believe is out over seven years now, I believe no longer receiving therapy, potentially cured. So we tried to figure out, by targeting the Braf pathway, are we potentially enhancing the immune response. But when we looked again at these really valuable paired biopsies that we take, and I know that from a patient’s perspective, having an additional biopsy before starting an already nervewracking clinical trial and then having another one a few weeks in the trial is is not everyone’s first choice, but this is truly a testament to patients and their willingness to be, be, really, be part of the team that you know that is doing this research, because what we’ve learned from these biopsies over the years, identifying failure to inhibit the pathway as the big problem now, kind of looking at what I’m about to show you here, this would not be possible if patients didn’t weren’t really, I think, willing to put themselves, not just through inconvenience, but under a potential risk to really kind of contribute to our ability to advance this field. What we did notice in these paired biopsies is that after two weeks of treatment, we noticed a marked increase in the amount of immune cells, including T cells, as well as cytotoxic or killer T cells, as they’re called, that made their way into the tumor, suggesting that we may be augmenting a tumor response. Again, just by using BRAF directed targeted therapy, we also were able to model this in a mouse model that has a competent immune system, and in this model of colorectal cancer, we found that targeting the MAP kinase pathway, in this case, with the Braf and mek inhibitor combination alone, or with an anti PD one immunotherapy alone, had very modest effects. But when these were combined, shown in blue, we now saw actually regressions in most cancers, and even in one case, were able to cure a particular mouse of their cancer. And this again suggested us that targeting the Braf pathway may lead to these to the down regulation of some key immunosuppressive signals that we believe BRAF turns on in colorectal cancers, as well as in other cancers like melanoma. And this led to the development of this trial, which we just presented the initial data for about a month, about a month ago at ESMO Gi. This study was originally designed to evaluate the combination of a PD one antibody, a BRAF inhibitor and a MEK inhibitor using a safe dose established in melanoma patients, in 25 patients with colorectal cancer. We reserved eight slots for patients who had microsatellite instability. These are patients who are already expected to respond better to immunotherapy. So we wanted to see if the potential addition of BRAF targeting and combination might further enhance this. And then the most important critical group, I would say, just. Because we really don’t have good treatment options for this subgroup are these are the microsatellite stable patients who, in general, have a more poor prognosis and don’t have an immunotherapy option. We initially started the trial allowing patients who could who have had prior BRAF MEK inhibitor therapy or immunotherapy. But after the first few patients, we began to notice that these patients, perhaps did not do as well. And for the time being amended the trial to no longer allow prior therapy. And as of the time that that we presented this, this trial started in October, so about a little over a year and a half ago, almost two years ago now, we had enrolled 21 patients. We’ve currently enrolled 25 patients. But as I’ll show you in a moment, the trial has now been expanded to a total of 40 based on encouraging initial signal. I’ll go through this slide very quickly. There’s nothing very typical, very typical profile of a population of patients, and really no surprises on tolerability, what we saw most often was fever, some fatigue, and then very much a lot of other side effects that are typical of BRAF and MEK inhibition, such as rash, some nausea or diarrhea and some decreased blood counts. What we found in the first 21 patients actually was some very encouraging initial signs of efficacy. So if we looked at all patients, which includes the microsatellites unstable as well as the previously treated patients, we had a 33% response rate and a 76% disease control rate. And for comparison, we we have a historical control from a trial of about 43 patients that we treated just with BRAF and MEK alone with the same inhibitors dubratanib and trametinib, where a 12% response rate was observed. Really interestingly, when we when we look just at what we think is our primarily, primary population of interest, these are micro satellite, stable patients who had no prior treatment with BRAF or Mac inhibitors or immunotherapy. We actually found that the response rate was was near, near 40% and that what was very exciting is these responses appeared to be durable. For example, we have one patient who had 100% tumor response who’s now approaching the two year mark. And as you can see, while this is a little out of date, we’re about three or four months down the road. Now we have many patients who are out close, close to a year or passing a year, and this is something that we really have not seen before in microsatellite stable colorectal cancer, and something that I think is very exciting and has us very interested in this trial, a couple of things that we’re doing to learn more about about what’s happening here, and also what we can do To further enhance our tools for patients is we’ve actually been monitoring levels and circulating tumor DNA in real time during therapy, and what we can see is that after just two to four weeks of therapy, patients who go on to respond typically have very dramatic drops down to almost undetectable levels, or often undetectable levels after just the first month or so of therapy. Unfortunately, in patients where we don’t see this, these patients, unfortunately are ones who end up not responding to therapy. And so this is really something that we’re working to get into our clinical lab now so that we can actually offer this test in real time to patients actually across all cancer types as a kind of a more effective CEA or a more effective ca 19-9 that’s much more rapid and much more accurate. The other thing that we’re doing is taking advantage of a really new technology that we’ve implemented at Mass General, that we’ve to actually really understand what’s happening within the tumor biopsies as we take them, and what one thing that we are doing on this trial, probably one of the first trials where this has been incorporated regularly, is to do single cell sequencing. And what we what single cell sequencing allows us to do is within every biopsy we can sequence about 10,000 individual cells, figure out what type of cell they are. Are they a tumor cell in blue? Are they a T cell in purple, or another type of cell? And then we can look at how those cells change in number during treatment. So here in this patient who’s gone on to have an almost two year response, we see a reduction in tumor cells and a dramatic expansion in T cells, consistent with kind of an augmented immune response. But we can also look at the gene expression changes seen in these in these cells, so we actually know what our therapy is doing. And so here we can see that in the tumor cells, we’re effectively inhibiting a target of the Braf pathway. So we know we’re inhibiting the pathway in these tumor cells, but in the T cells, we’re also seeing that we’re inducing these Mark. Of active immune response, in this case, what we call a cytotoxic T cell marker. And we also can compare what’s happening in the patients who are doing well and what’s happening in the patients who aren’t doing this well, the responders and the non responders. And what we’re finding is that if we look just in the tumor cells, we’re turning on just by inhibiting the Braf pathway, some very key immune response programs within the tumor cells that are that are happening in the patients who are responding, but not the ones who aren’t responding. And we can actually tell that this is just from from targeting the BRAF pathway, because we’re also developing what we call organoid models, which are kind of like three to three dimensional living models of each patient’s tumor that we can culture and grow and test in the lab. We find that if we take these isolated in a dish and treat them with BRAF and MEK inhibitors, we can get these we can see these same modulation of immune pathways within this isolated tumor cell population, suggesting that, again, it’s an effect of BRAF inhibition on the tumor cells themselves, which seems to be critical for this response. So just to conclude, this will be my last slide – so far, our trial of combined immunotherapy, BRAF and MEK inhibitor is been very well tolerated. We have a favorable response rate, 33% overall and about 40% overall in the key previously untreated microsatellite stable group. This compares very favorably to the 12% response rate we saw with just the Braf and MEK inhibitor alone. So it suggests to us that there’s there’s definitely a clear cooperativity of these two agents, particularly because the MSS population is one which we’d expect to have no response to immunotherapy, and a lot of our correlative trials are studies, including single cell sequencer, are really helping us focus in on the key mechanism that’s underlying this potential cooperativity between immunotherapy and BRAF targeted therapy, and this can help us hone future versions of this to really maximize the potential benefit here and based on this favorable activity, Novartis has agreed to fund an expansion of an additional 15 patients, all microsatellite stable with no prior B RAF or immunotherapy, so that we can really get a get a much better view of this group. We have about, probably about 12, 12-11, or 12 slots left in this 15 cohort expansion, as well as we still have about four slots available for patients who have microcidal instability on this trial, but are hoping that we’ll complete enrollment of this trial toward the end of the year and be able to supply some final results that will help guide where we go next. And so, of course, it’s important to think that patients, first and foremost, and their families for participating in this study and and many of the past studies, I think, without their cooperation, we really would not have learned half of what we’ve learned, and been able to advance the field as quickly as as I think it has. This particular trial that I showed you, the drug supply and trial funding is provided by Novartis, and then our Stand Up to cancer colorectal Dream Team, of which several COLONTOWN members, including Manju and Steve, are and Eric are our members of funding from from this grant has supplied some of these key correlative studies that I showed you. So again, Thanks all for your attention. Maybe a few minutes longer than I meant to go, but I wanted to stop there and see if there were any questions, and leave the rest of time for discussion.

Participant Question 33:32
Hi, Dr Corcoran, thank you for that. The trial for ERK inhibition, that will accept patients with prior BRAF treatment?

Dr. Ryan Corcoran 33:44
yes. What was the question

Participant Question 33:47
Whether that trial will accept patients who had prior beacon treatment?

Dr. Ryan Corcoran 33:53
Yes, absolutely. So, so that’s because that’s a key issue now, is that a lot of patients are, are coming to, you know, are saying, Listen, I’ve had now the beacon regimen, or I was part of the beacon the beacon trial. What do I do next? And you know, there are a couple other similar trials of immunotherapy and BRAF targeted agents that are being run similar to the one I just showed you, and none of those trials allow prior Brad patients. The question is, what do you do as a BRAF Music Center colorectal cancer patient if you if you’ve had one of these agents already, and that’s where these are inhibitor trials, I think will be very valuable. So as I mentioned, the Eli Lilly trial is currently open and enrolling, and that that’s an option presently for patients who’ve had prior BRAF inhibitors. And then the new Novartis study, which will look at their BRAF and erk inhibitor actually with the same immunotherapy agent that I was that we were using in our trial, as well as with some other inhibitors, like a shp2 inhibitor and a few others, that will be a very interesting option as well for patients who’ve seen prior therapy, or patients who perhaps were on the trial that I just showed you. So we’ve actually been taking any patients who come off of our of our of the trial I showed you and and looking at some of the ERK inhibitor-based options as a next step.

Manju George 35:27
I have a question those people that have you know, progressed on Beacon or ANCHOR. Do you prefer for them to have, like, a break with chemo before they go on – adding erk inhibitor or what do you think?

Dr. Ryan Corcoran 35:43
I don’t know that we know the answer to that yet. We’re very, very early in the assessment of the erk inhibitor. In fact, I think that, you know, we’re still in the dose escalation portion of the ELI Lilly trial. So we really don’t have any data that suggests whether you’re more or less likely to respond. I think that the issue is that for people who’ve had beacon, it means they’ve typically had, you know, first and or second line chemotherapy, or they’ve had, you know, FOLFOX series. So they’ve had all of the kind of available chemotherapy options this first line, and that really doesn’t leave any good, good therapy options, you know, to go to. So in that situation, I do think it makes sense to try to go on to one of those trials. If, for example, you came off the anchor study and you’ve never had FOLFOX, surgery, or never had FOLFOX never had FOLFIRI it might be reasonable to do that instead. And then you know what? You know, what a potential advantage of that is that you know, if that therapy has some, you know, some period of disease control the field is moving very rapidly right now, and there potentially may be more options, you know, available to go on to after that. So I don’t know that. I would say hard and fast, one way or another. We certainly have been putting patients straight on to these trials. It’s, it kind of depends on what, what, what patients interests are as well.

Manju George 36:59
So my other question would be, if somebody’s just finishing up first line chemo and they have metastatic disease, you know, in your mind, what would be if you have to line up all the options available to them? What? How would you rate them?

Dr. Ryan Corcoran 37:16
Yeah, so like I said, I think the beacon doublet is a great option. It’s, it’s, it’s, it’s wonderful that we finally, it’s been very frustrating to me how long it’s taken to get an FDA approved therapy. Even though we’ve, we’ve had combinations that have developed, that have demonstrated some degree of efficacy for maybe four or five years now, but due to some, you know, weird eccentricities of how the trial was run, or who, what company supported it and what their priorities, you know, we, we really, you know, weren’t able to so we had a number of things that made it onto the NCCN guidelines, as many of you aware, and we could often, you know, work with insurance companies to cover those. But it’s really, I think, very important that we have enough to hit adoption now. We know we have very good data for what that, that that beacon regimen does. It’s a 20% response rate and a four, 4.3 month progression free survival. You know, I think that that, that you know what you’re getting with that, and I think that it’s definitely valuable to have, but it’s also something that I’m convinced we can do better. And so when we have clinical trial options either that are that involve the beacon regimen plus something else. So for example, the lily trial is the beacon doublet plus an ERK inhibitor. And you actually could go straight on to that trial without having the beacon regimen first, as long as there’s not a huge safety risk with the addition of that agent, there’s some safety data that, to me, at least seems okay. Well, I’m getting at least the beacon regimen plus something else. You know that, you know, I think that also for any other clinical trial, even if it’s not exactly the beacon regimen for So, for example, you know, the trial I just presented has different agents, right? But, but at least now we haven’t. We have enough data that I think suggests that you’re seeing activity that’s at least comparable, and you know, while it’s smaller numbers, still maybe even a little better than the beacon regimen, although you can’t say that at this stage of development, but one that we’re actually seeing, what what none of the other targeted only trials have shown us, which is the chance for durability. And that’s why I’ve been advising more patients, not just because it’s my trial, but I’ve advised more patients to look at these trials. There’s no we have one open there’s one at MD Anderson, and there’s one at UCSF, that are all all similar, just different agents and different components. These to me, even though we don’t have any data, any data yet, from the that we’ve seen from the M Anders and UCSF trials, I think that that many of those seem like, I mean, the prediction would be that they’ll all will look very similar. And so I do, I would encourage patients to see what options like that are available. Or, you know, for example, this new Novartis trial that will be, will be taking patients without prior B RAF inhibitor therapy. You know, if. If there’s something that we think really offers a different, you know, an additional transit benefit that That, to me, is a hard thing to turn down.

Speaker 1 40:14
Do you know, do these trials exclude patients with autoimmune disease like Ms?

Dr. Ryan Corcoran 40:19
That’s a great question. So, so some of the immunotherapy trials do. And I think, without I, you know, I think that what I would say would be that it’s worth looking very carefully at the inclusion exclusion criteria, and, you know, to discuss with the potential treating physician or the investigator about whether that would formally exclude, I think, you know, obviously the concern, just to kind of clarify for everyone, is that one of the big risks, you know, immunotherapies, particularly anti PD, one agents are fairly well tolerated overall. The one issue that we do have is that in addition to kind of revving the immune system up against your tumor cell that in, you know, a small percentage of patients, it can kind of rev the immune system up against your normal tissues. And so if you already and this can cause a number, a whole wide range of autoimmune side effects. So these are very rare in most people, but if you already have an autoimmune disease, it’s possible that that these therapy could worsen that, and that’s why that is often an exclusion. I don’t know if Ms formally would be excluded from these trials, but it would be something that would need to be discussed and thought about very carefully before doing this. So I think if in a situation like that, you know, for a patient who has that issue, I would, I would, I would recommend, kind of having a careful conversation with the investigator and really thinking about that, and perhaps even having consultations with that patient’s rheumatologist or or or neurologist, if it were, MS, about the risks and benefits.

Manju George 41:54
Okay, I have one more question nobody else is asking. So you from the figure that you showed where you’re comparing the melanoma with the different combinations of drugs against the CRC, so now the beacon is like two drugs, right, EGFR inhibitor and the B RAF inhibitor, right? Do you think that in those patients who are not responding as well, adding the MEK inhibitor would be beneficial? Or do you think that, you know, if they’re not responding, they should better get off and try to say FOLFIRI plus bev or something?

Dr. Ryan Corcoran 42:27
It’s a really interesting question. I think that, you know, clearly, when we start people with BRAF, EGFR and MEK, we get better pathway inhibition. And bottom line is, we get a better response rate. So, you know, even in the beacon study, there was a 27% response rate versus a 20% response rate. And while 7% difference may not sound like much, if you think about it, going from 20 to 27% that’s an increase in almost, you know, 30% you know, about a third of patients additionally, are responding, you know, relative to who responds to the sort of the relative increase that’s pretty substantial. And on our trial, you know, it was interesting that we saw a much bigger impact, or at least we thought of adding the MEK inhibitor. So we really thought that that substantially improved the response rate. But again, we didn’t see a huge difference in progression free survival just because the cancer can, can kind of get through it so quickly. So what we also found is that we, in that trial, we would take people who started with BRAF EGFR, and put put them on to BRAF MEK, EGFR when they progressed. And in general, we found that didn’t help very much. And so my sense is, once you kind of start to push the cancer toward this adaptive pathway of reactivating the pathway, we are this Adaptive Path toward reactive turning the pathway back on the MEK inhibitor, kind of doesn’t it’s kind of lost its window to benefit. What we hope, though, is that by actually replacing MEK inhibitor with an erk inhibitor, is that actually that initial pathway suppression will be better, and that we might start to see those, all those dots on the biopsy plots, kind of being down at the same level we saw with melanoma that we and that that might provide us the opportunity to, number one, get a response in more patients, so to increase the response rate, but also can prevent, as we showed in the mouse model, the outgrowth of these resistant clones. You know, we have to see how that goes, but that’s certainly the hope that we still have. I mean, it’s amazing that after 10 years, we still and after trying as many as three drugs at a time, we still are not turning off that pathway as well as one drug is a melanoma, and that, that, to me, is we can’t start looking at past that until we accomplish that first. That’s our that’s job number one right now. And while I think we can look at things in parallel, like adding immunotherapy, but ultimately, that’s almost assuredly going to work better when we combine it with a core that really turns that the Braf pathway off. Now maybe that core will be BRAF erk, which is kind of what the Novartis follow up study will look at. Maybe it’ll be maybe it’ll be a four drug combination. Maybe we’ll be adding a. The BRAF MEK and EGFR. We we have to figure that out, but I think that we’re probably not going to get to really the next level with BRAF until we find a combination of drugs that can just shut the Braf pathway off and keep it off. And that’s, I think, something that I hope we’ll see with with ERK inhibitors in the near future.

Participant Question 45:21
Hi, Dr Corcoran. A couple of quick questions. How did you choose your three drugs in this trial versus some of the other ones that are out there? There’s, you know, the MEK and the BRAF inhibitors from beacon. You’re not using those. You’re using different one. You’re not using nivolumab. You’re using cebartolizomab (_?_), very similar. PD, one inhibitor, how did you choose these? And then, what are your thoughts on starting with, I guess, Stivarga or regorafanib with one of the PD ones versus starting with braf and MEK inhibitors?

Dr. Ryan Corcoran 45:50
So, both really good questions. So, you know, part of the reason we chose this was, you know, these specific agents was, I think it was due to a number of different region reasons. One is that we had a long standing, you know, really kind of working relationship with, with, with, initially, it was GSK that developed Rac intermetenib (_?_). And then those assets were, were, were essentially treated to Novartis for about five or six years ago. So, you know, we had run a lot of our initial trials with those agents. And so, you know, in kind of bringing these pretty clinical data to a company and trying to convince them to do a trial, sometimes it’s easier to convince people who know you and have worked with you before. And so we were able to, you know, for better, for worse, Novartis, and I appreciate that they did, were able to agree to support the study. And part of that, I think, was just, was just kind of having worked with them before. The other reason is that we it was, in our mind, an advantage to use therapies that already had an established safety track record, so that we didn’t have to worry about dose escalation, and then we can kind of just start and and, you know, and basically, you know, take an effect, an ideally effective dose, into patients. And so because dubrafanib intrametinib With PDR 1, which is actually Novartis’s PD, one inhibitor had already been evaluated in melanoma patients, that allowed us to do that. So encorafinib and binimetinib, for example, had not been evaluated in that scenario yet, so that would have required us to do a dose escalation and a safety leading. So that was another reason. But, you know, and but that’s really it? I don’t think there’s any. There’s no magical reason why we chose one or the other. I think it was about trying to get anytime you kind of get the very first version of a trial always takes a lot longer than you thought. It took about two years to get the trial open, you know, and then so sometimes you have to, you have to, you know, take just figure out how to, how to, how to get this to patients, you know, sooner rather than later. And in this case, this, this is what made sense. And you know, so far, you know, I think the activity is very encouraging. The next question you asked was about looking at PD one combinations with regorafinib or stivarga, which is, as people may know, a multi kinase VEGF inhibitor. So you know, regorafinib alone is approved for late line colorectal cancer. It has about a 2% response rate on its own, overall, about a two month progression free survival really not a very effective therapy on its own. I often don’t use it, to be honest. I’m much more interested in finding a clinical trial, but there were some very intriguing data that came out of Japan about a year or so ago showing about a 33% response rate in colorectal cancer patients when nivolumab and regarofinib combined. So nivolumab, again, a PD one inhibitor, this generated a lot of interest, although there were some questions about, okay, it’s a small study. It’s also an entirely Asian population. Will that translate over to a western population? And you know, we’ve seen a lot of trials of immunotherapy combinations that have, you know, had a few for, you know, a handful of early responses that then just haven’t held up when we’ve added more patients. So nevertheless, there was a lot of interest in that. But you know, just in the last few months, both between ASCO and esmo gi, we’ve seen a number of presentations of follow up studies, two of them involving actual, actually nivolumab and regorafenib, one of them involving avelumab, which is Pfizer’s Pdl one inhibitor and regorafinib. And all three of those studies have shown zero responses across about somewhere around 50 patients together. Now those studies were all conducted in the US. It’s still possible that the nevorego, which is what they call the nivolumab regular combination, might might have some characteristic that makes it more effective in Asian colorectal cancer patients, but, but it’s. Also possible that that that seems that that efficacy signal may not be upheld. And so So right now, it unfortunately looks like that does not appear to be a great option for kind of your average patient in the US or Europe. And so right now, I would not recommend that people do that before something like the trial I showed or one of the resistance therapies, I think, certainly fine to try if there’s no other other intriguing clinical trial options. But you know, the follow up data to that initial report has been disappointing.

Participant Question 45:51
One follow up question, and what about adding a PD one to Beacon drugs triplet, if those seem to stop working, can you add a new one to the midstream?

Dr. Ryan Corcoran 50:21
I mean, not, not. I mean, the you could do that off label, right, right? Because they’re all approved drugs. It’s just that that it’s not clear. If, I think getting an insurance company to pay for that will be very challenging. It’s not impossible, but it would take a lot of work to do that. You can sometimes – we’ve had success kind of figuring out these single agent, single patient, indies or compassionate use arrangements. But it’s, it’s those are often very difficult for the average patient to get so, you know, I think that that that most likely, you know, while certainly if that’s something that that a specific patient is able to kind of arrange for themselves. It’s fine to try, but this will hopefully be something we’ll get to with kind of subsequent clinical trials. You know, I do think, though, that that the data suggests that kind of this sequential or adding on when something’s not working may not be as effective as starting everything at once from the very beginning. And so, you know, I think kind of starting with one thing and then modifying it part way through has, in general, been disappointing across a lot of oncology. And what we find is that, you know, it’s kind of like if you’re trying to shut down traffic through a busy city, if you block, you know, you know, a major a major road, and then, you know, two days later, you pick that block up and move it to a different road, you’re not going to really slow down traffic. But if you block all three major roads at once, you know you’re going to have some pretty major disruption. I really look at it that same way, that that you want to kind of put as much you want to cut up as many escape routes for the tumor as you can, realizing that that, you know, the more things we throw at patients, the more chance there is for kind of cumulative toxicity. So we have to balance that, that, that that very carefully.

Participant Question 52:31
thank you very much.

Manju George 52:40
So I think this may be the last question. In our group, we find that when people are on the beacon drugs, initially they have the CEA and CA, 19-9 go down quite a bit, and then they slowly start seeing it rise up again. But then, you know, everyone is scared because the scans don’t catch up with it like until it’s like too much. So they’re always confused to wait for to see something on the scan, because from our experience, we find that it’s all always too late, and then if you know to act on the rising CEA CA 19-9 the doctors are very hesitant. So what advice do you have?

Dr. Ryan Corcoran 53:17
And that’s a very challenging situation. It’s why we’re very excited about the circulating tumor DNA data that I showed that actually, if we had an assay that could monitor B RAF physics center in real time, which we do, we just need to move it into a clinical setting. That that’s been, I think, one of the best predictors of whether and sometimes we’ve had scans where we look and we’re okay, is that actually progression, or is that non specific inflammation. We’ve had a patient who’s had, you know, had kind of a, you know, a subclinical pneumonia. Essentially, they didn’t even notice anything. And there was something in the lung that the radiologist was concerned about progression. But, you know, the Braf levels remained undetectable. And it turned out, you know, a month or two later, that spot was gone and it was just inflammatory. So having a, having something we can really rely upon would be really useful. You know, CA and 19-9 while, while they’re better than nothing, are not the best markers. They’re slow. They have long half life, so they don’t they don’t move quickly. And they’re also a bit non specific. And we kind of did a large scale comparison of citing tumor DNA and CEA CA 19-9 we published a few months ago that really showed that that ctdna markedly outperforms that. It’s a hard thing for me to say that, because, again, like I said, we’re hoping to make that available to patients, perhaps by the end of the year, but it’s not going to be something that’s widely available to patients, and so that, I don’t think that helps you very much for me to say that right now, to answer the actual question you asked, you know, I think you have to factor in everything from the situation. I think that you need to pay attention to a rising cea and CA 19-9, and at the very least, start getting prepared for what the next steps are. I think if there’s a great next step, like if there’s a spot, like a slot open in a really interesting clinical trial, like one of these or inhibitor trials that. Maybe is only going to be open for a period of time, you know, then maybe you want to make the decision to to kind of, you know, cup eight early and just switch over. But if there’s not a good option, you know, I think what a lot of doctors say is, Listen, you know, even if your tumor starting to grow, maybe, maybe we’re slowing the growth of the tumor, and that we may want to get as much mileage as we can out of this, because we don’t necessarily have another hormone therapy to put you on next. And so I do think you got to look at this in a case by case fashion, but always kind of being very proactive about kind of mapping out the kind of the next set of clinical trials or opportunities that you’ll go on to, you know, and realizing what, what factors might make those possible or not possible? You know, as far as you know, slot closures and how long it’s gonna take for a trial to open, etc, etc, if you have that plan, I think, I think factoring that into the decision is important, but I don’t think you can. I think what you say is a big problem, that when BRAF colorectal cancer starts to move, it moves very quickly, often, so I typically do, if there’s a good treatment option out there, I typically encourage people to kind of move on fairly quickly to that.

Manju George 56:06
Okay, so this is the last one. It’s like a more personal question. We know how the BRAF mutant CRC is. I mean, what inspires you to continue doing the stuff that you’re doing, and how do you deal with all the losses?

Dr. Ryan Corcoran 56:21
Yeah, I mean, it’s an interesting question, because the answer the questions is actually in the question. It’s actually part of the question, in that, you know, it’s an incredibly challenging tumor, incredibly aggressive tumor, one of the more frustrating to treat. And I think seeing that, you know, I’m wondering, maybe you could look at that and say, why would you want to keep doing that? If it’s so frustrating and hard, why wouldn’t you go do something else, but, but that’s that’s just not, that’s not how most of us are built. And you kind of, you can’t watch this and not feel like something has to be done. And that’s why there’s just such a need for better therapies here. And even though we’ve made progress, like I said, you know, I feel like the impact of that progress after 10 years should have been much, much more. And I do think we, you know, in many ways, we’ve it’s taken us a while to figure out, you know, these are a lot of these are a lot of new concepts that came out and now that are helping us figure out what to do with K RAS inhibitors that would have taken us eight years otherwise to figure out. Now we know how to do it in just a few months, so we’re on the verge, I think, of really seeing a lot of work over the last 10 years pay off. And I think that you can’t look at what a terrible diseases is and not be motivated to do something about it. So that’s my reason, at least.

Manju George 57:37
Thank you very much for your time, and I think that maybe I’ll collect other questions. People are going to be watching this from all over the world. And thank you again. Thank you very much and for everything that you do.

Dr. Ryan Corcoran 57:50
No thank you all so much for everything. And I think this is a wonderful organization. I think there’s really been done an amazing job at spreading information and making opportunities available to to patients who this is incredibly daunting to be, to be to confront and just, kind of just everything. And it’s, I think it’s really important that communities like this exist and help help patient navigate it, and, you know, connect people with physicians when needed. And I, you know, always happy to do whatever I can to support that.

Participant Question 58:20
I’m not sure how you get on the question list, but I had a question. If it’s not too late

Speaker 2 58:22
That okay, it’s okay.

Dr. Ryan Corcoran 58:31
Yeah. So this probably needs, this probably will need to be the last one, but yes, one more question is okay.

Participant Question 58:35
Okay, my apologies. Question for people that are have been through several treatments, have already done FOLFOX Have done inhibitors. Have done FOLFIRI all with Avastin. What would be the next step for someone in treatment? I’m getting ready to finish FOLFIRI and if, if the disease is inactive, my oncologist is saying, oh, we’ll put you on Avastin every three weeks for maintenance. So it’s kind of a two part question, if my scans are good and I were to maintenance, what would be a recommendation, and if there’s still visible activity in there, would you jump right into it another treatment? What? What steps would you take to get there?

Dr. Ryan Corcoran 59:20
I mean, my I don’t, I don’t. I don’t typically like to micromanage, you know, the decisions from people’s individual oncologists, because there’s lots of variables and details that it’s hard for me to understand, you know, in the context of a quick question. But you know, my general bias for maintenance is that that it’s if you’re tolerating the therapy fairly well otherwise, either continuing the therapy in its entirety, or at least maybe keeping the the 5FU might, might give you a better option. It’s a more durable control if you’re having a lot of toxicity that changes everything. And sometimes, you know, it’s best to give people a chance to kind of recover and to preserve quality life as well. So that’s, that’s kind of how I would come down on that question. And I wouldn’t say there is always a right answer there. And then as far as what to do next, I think this is where some of the trials that I talked about that allow prior BRAF, some like the BRAF, EGFR, erk or VARs trial, that that would be something that I would consider in this situation. But is MSI and MSS relevant to those they allow, they typically allow both. Obviously, if you’re MSI, there are a number of trials that are immunotherapy focused that might start to become or if a patient is MSI, their immunotherapy trials that might start to look like potentially more interesting options, because we know that MSI tumors, at least have this basal propensity to respond so, so maybe kind of doubling down on the immunotherapy side might be a better but, you know, for MSS, I think that, you know, certainly looking at additional BRAF options is good. But there’s also other interesting trials with newer potentially, you know, whether they’re immunotherapy based, or whether they go after other targets that are present in the tumor. I think these are all considerations, but I do think that kind of a good next step would be, for the situation you described, would be a very careful assessment of kind of all the clinical trial options that would be out there, and what would make the most sense.

Participant Question 1:01:21
Okay, so basically, once you’ve been through those steps, you’re our only options at this point are to find trials that would accept us

Dr. Ryan Corcoran 1:01:30
I think if you’ve been through most of the available therapies, then, then potentially Yes, by definition, that finding clinical trials or coming up with a very unique off label scenario would be, would be the potential option I don’t want, I don’t mean that to imply there’s no options. There might be great options. But this is also something that, going back to my point earlier, of mapping out your steps in advance, you know, kind of as you’re thinking about starting maintenance therapy, this would be a good time to, especially these days now, where virtual consultations are so much easier to do. We actually weren’t able allowed to do these prior to COVID due to state regulations. But now you know, you know, you can see people all over the country in an afternoon, you know, from your laptop. So you know, kind of lining up some consultations and really pushing to understand what the clinical trial options would be. And having, having people take a different look, a deeper look at the tumor, and seeing, is there anything else there besides just the Braf that that could be relevant, that’s kind of what I would do now and in advance of, I wouldn’t wait for the tumor to show that scan to show progression. I would plan that out, you know, hopefully, you know, a couple months or many months in advance of when you might need to actually make that decision.

Manju George 1:02:45
Thank you so much. I don’t want to take any much of your time, any more of your time, and you know, if anyone has questions, we can email Dr Corcoran. So thank you very much.

Speaker 3 1:02:55
Okay, thank you everyone. It was, it was wonderful talking around these are great questions, and I enjoyed, enjoyed the discussion.

Manju George 1:03:02
Thank you. Thank you. Dr Corcoran.