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Targeted therapies and immunotherapy: Dr. Morris (2020)

Doc Talks

Dr. Van Morris from MD Anderson discussed combining targeted therapies and immunotherapy for BRAF patients in this COLONTOWN Doc Talk, recorded in August 2020. 

 

Dr. Morris 00:00
Yeah, thank you guys for inviting me in, as you refer to, we really appreciate just the support of COLONTOWN in general. This goes beyond just kind of, as you mentioned, your support for the COBRA trial, and in the BRAF trials as well, which you guys are obviously incredible in mobilizing patients, through social media, but I will say more experientially as well, you know, this group means a lot to my patients. And it’s common for me to have that patient come to MD Anderson, who’s newly diagnosed with colon cancer and is very understandably afraid and, to hear kind of their testimonies with how helpful COLONTOWN has been, and helping them and other patient advocacy groups who have been in helping them to understand kind of what’s going on with the shock of this news in their lives. So we just want to say we as oncologists appreciate your commitment to helping patients in this effort we’re all fighting against. I will say, you know, I realized that Dr. Corcoran had presented I think, a week or so ago. So some of this may overlap, I’ll try to kind of interject my own opinions about this, but there will be some overlap. There may be some slides that we haven’t published yet. But I did want to share these just share our data. So when I hit the slides, I want to share that kind of why we think what we think, but also just maybe ask for those particular slides, just kind of keeping those confidential, because we haven’t really published this data yet. I’m gonna be talking about kind of combining targeted therapies with immunotherapy. And maybe not using a one-size-fits-all approach for the management of BRAF-mutated metastatic colorectal cancer.

So I always just feel that it’s important to start out with, a patient presentation just to kind of put into context what we’re up against here, and this was a patient that I met during my first year on faculty at MD Anderson. She was a 35-year-old lady from the valley in southern Texas who presented to the ER, with abdominal pain, no past medical history at all. She had a 13-year-old son, a single mother. When she presented with abdominal pain her surgeons locally felt that she had issues with their gallbladder and took her to surgery to remove the gallbladder and were surprised, instead, to find a large transverse colon mass with diffuse metastatic disease in the peritoneum that was responsible for the abdominal pain. The pathology ultimately showed a microsatellite-stable BRAF-mutated CRC tumor. She then came to MD Anderson, where, by the time she arrived at MD Anderson, she already had evolved a large bowel obstruction from her tumor. So this was in 2016, we started her on treatment with FOLFOXFIRI. And she had some initial clinical improvement, but unfortunately, within three months of what is really throwing the kitchen sink at this tumor, in terms of cytotoxic chemotherapy, she was already developing signs of clinical and radiographic progression. Within four months of her initial presentation, the single mother was transferred to hospice and it was horrific to watch this unfold as a new oncologist at that point in time, and I think it just really speaks to the challenge we face with BRAF-mutated colorectal cancer, we recognize that this is a unique population with regards to clinical outcomes. As I’ve alluded to, the responses to chemotherapy aren’t great as we’re used to seeing our BRAF wild-type patients, we recognize the unique pathology here just in terms of where these tumors commonly arise from and how they look under the microscope. And with the genome as well we’ll talk about later the high tumor burden may extend beyond the association with MSI high into the MSS setting as well. But also it’s unique with regard to the epigenome and we recognize these to be hypermethylated tumors. I think that this still represents an untapped biology, that is potentially targetable with regards to this particular subpopulation of colorectal cancer, and possibly, with respect to the transcriptome as well, and we’ll talk kind of about CMS correlations a little bit later, too. So we’re seeing a unique but challenging, but potentially intervenable, clinical presentation. And I’ll kind of go through these slides quickly, because we all recognize that the BRAF mutations, even though it’s typically called an uncommon subpopulation of CRC, when you still consider it’s 5 to 10% of all the patients who have CRC and colorectal cancer represents one of the top causes for cancer mortality in the United States. By absolute numbers, it’s still a large fraction of patients who are faced with the challenge of BRAF-mutated, metastatic CRC. And unfortunately, as we all know here the successes of targeted therapies in terms of response rates that other cancer types see with the same exact BRAF mutation, we just don’t see those in data that Dr. Kopetz and then Dr. Corcoran had shown with BRAF monotherapy and BRAF MEK combination therapy, it just we don’t see either the response rates or the survival outcomes, that we’re accustomed to seeing in the context of other solid tumors as well. So this, oftentimes, when I hear people say that we should be treating tumors agnostically to the primary and according to the molecular subtype, I always just cringe when I hear that, because I think that again, that’s a one-size-fits-all approach. And I think that the BRAF V600E story for colorectal cancer is a very good example of why we can’t practice under such an umbrella. This is just kind of data that, again, we’re all familiar with, from eight years ago now, just kind of showing why in the context of CRC, blocking the BRAF V600E oncoprotein with agents that work in other contexts doesn’t work as well, to kind of have this upregulation of MAP kinase signaling, you get kind of this constitutive activation of… I think I say this to say it again, I don’t… correct me if I’m wrong here, but I think I can probably go pretty quickly through the next couple of slides. I think this group fully understands the recent clinical trials, which have led to clinical outcomes, or new clinical options for these patients; but it was really exciting, I think, to be involved early on with Dr. Kopetz as a fellow even, and working on the SWOG protocol, and seeing this translate from an idea in the data that was coming out of the lab, to showing some benefit in patients.

We looked at a model too that is a different model that was initially had disease control with Vemurafenib and Cetuximab. And we saw similar results in PDX, as we were seeing acquisition of acquired KRAS mutations. This is something that in the Vemurafenib study, when they went to the baseline samples of these patients and looked in their plasma, droplet digital PCR sequencing showed the presence of very, very low allelic frequency of KRAS mutants, you can see 0.21%, 0.31% that were present at baseline that are oftentimes below the limit of detection of assays that were available at that time. When we looked at patients who were treated on a phase one trial at MD Anderson with Vemurafenib, Cetuximab and Irinotecan, we saw that in the black here, you see the relative allelic frequency of the BRAF V600e gene in ctDNA. But again, we were finding in patients the same thing that we had seen in the PDX models, that there were these acquired oncogenes showing up in the resistant setting that had not been present in the pretreatment specimens. So our question then, at that time, and this is the data that we took to Array when Kopetz was pitching the BEACON approach, was: can the addition of the MEK inhibitor overcome the resistance to BRAF, EGFR targeted therapies. I also think with the SHP and SOS inhibitors, which are coming out as well, this also kind of represents something we’re thinking about moving forward as well. And again, what we saw on our PDX was, again, when these tumors grew resistant to the Vemurafenib and Cetuximab, if we added a MEK inhibitor, we could see sensitivity; and I think that Corcoran and his group beat us to the punch in publishing this data, but we certainly felt that what we’re seeing in the lab were being validated by his group as well. And so again, it made a lot of sense to us. So, as we all know, these thoughts led to the creation of the BEACON study. This is kind of flipped here, but the overall response rate of 26% with the triplet, and the 20%, with the doublet, beat that of Irinotecan and Cetuximab. And as you guys are all aware, the addition of the MEK inhibitor didn’t add any overall survival difference between BRAF EGFR and, very excitingly, (oh, this should actually be changed)… Encorafenib, Cetuximab, in February or April 2020, became FDA approved. So this was obviously super exciting for us, and for our patients as well. So one of the questions that comes up with our patients when we talk about this in the clinic is binimetinib, is it a non-viable option for the management of patients with BRAF mutated colorectal cancer? And I honestly don’t fully know how to answer this question because I struggle with the idea that there’s a one-size-fits-all approach for patients with BRAF-mutated metastatic colorectal cancer. You know, I think that we realize, clinically, these are heterogeneous patients, and they’re probably biologically these are heterogeneous patients as well, and just kind of talking out loud, it just seems like when we manage these patients, we oftentimes get a lot of more mixed responses and the BRAF mutated context than we do in maybe the BRAF wild-type, I don’t know, if that’s a thing, I’m actually just kind of talking out loud right now, saying that I haven’t really looked into it, but it’s, you just see this more, I think, than kind of in the BRAF wild type where if patients are going to progress, all of their spots are going to be kind of progressing together. Whereas, oftentimes you’ll have responses in two-thirds of the lesions and then massive changes in the opposite direction in the other third. So, again, I think the underlying biologic heterogeneity, as well, is very interesting, and it points to the challenge of treating this disease. We presented this data at ASCO last year. It’s under review right now for a manuscript.

We looked at our cohort of patients at MD Anderson, if you had been evaluated since 2005. And we found 187 patients with BRAF-mutated metastatic CRC. If you were evaluated at our institution, and we just asked a simple question: if we take both ends of the spectrum and compare the differences what do we see? It wasn’t surprising that in the better survival group there were more MSI-high patients; almost 50% of the patients in whom we had data on had MSI-high tumors. But I think that one of the really interesting things as well, is that the median survival from the time of metastatic disease, and this longest survival, was eighty-four months, and in the lowest survival, it was 8.6. And I think that when we, as oncologists see the BRAF mutation, our minds automatically go to this lower end of the spectrum. But I think that we have to kind of keep open minds that there are patients who do have good survival outcomes. When we looked at what is driving out survival in this longest survival group, – what’s driving the long survival outcome? And we saw that was also heterogeneous as well. Some of these patients were able to go to surgery. And as you can see, in the black line here, many of these patients remained disease-free despite having an initial diagnosis of BRAF mutated, metastatic CRC, you know, 5, 6, 7 years out. But interestingly, and as we would expect, as immunotherapy has unfolded, patients who are MSI-high, were also seeing good long-term outcomes. Interestingly, one of these patients had an MSS tumor. But again, there were seven patients that we found who were doing fairly well for long periods of time on MAP-kinase targeted therapies, this included BRAF EGFR options, BRAF MEK options and BRAF inhibitors alone. So, there is some suggestion here to us that there may be a subpopulation of the BRAF mutated who just need targeting in their MAP-kinase, in their particular tumor is addicted to MAP-kinase signaling in the same way that perhaps an EGFR-mutated lung cancer may be addicted to that EGFR mutation, and being equally sensitive to tyrosine kinase inhibition in that context as well. So, I say that to say that even the drivers for favorable outcomes in the study are heterogeneous and do not always conform to what providers can assume. So, I talked about how this is still ongoing, I think, bench to bedside to bench and back to bedside success story, but how can we lift that tale further.

Obviously, in the MSI setting, response rates, even with a concomitant BRAF V600E mutation, is very good for anti-PD1 with or without anti-CTLA4 therapy. But unfortunately, still within the BRAF V600E context, we feel that the MSI-highs, that concomitant microsatellite instability is still a minority of the patients with BRAF V600E tumors. So, this is where we start getting a little bit more in-depth to our data, which we haven’t published yet, but I did want to share with you. It’s a majority of… we think of BRAF V600E tumors as being kind of high tumor mutation burden. And oftentimes I think the assumption is that, well, there’s this association between microsatellite instability, we all know that MSI tumors have higher mutation burdens and so that’s the reason that BRAF V600E tumors carry this association with having high tumor mutational burdens. We actually looked at four datasets that were available to us: the nursing health data from Memorial Sloan Kettering, data from the TCGA, and then from internal data, we had it at MD Anderson, and we said, let’s pull out the MSI high tumors. And let’s look at just the MSS tumors. And look at the patients and compare BRAF-mutated tumors with the BRAF wild types. We saw the same trends across all four datasets that in general MSS, BRAFV600E mutated tumors harbor higher tumor mutation burdens relative to their MSS, BRAF wild-type counterparts. So this may not be something that’s just MSI-high-driven. And if that’s the case, this may argue for some role of immunotherapy as a component for the MSS BRAF V600E story. We’re also excited to see data that was published in Science last year from Dr. Bardelli’s group in Milan, where they looked at BRAFV600E CRC cell lines and showed that when you treat these with dual BRAF EGFR targeting, you induce, in terms of expression, a loss of expression of the mismatch repair of proteins and can kind of create this transient and MSI-high like state. So, if that’s the case, you know, does that make sense that dual, or I guess, triplet, BRAF EGFR plus PD-1 therapy would make sense in this context. And this is something that we’ve seen as well. This is data we haven’t published yet, but this is from an expansion cohort of patients who were treated with vemurafenib, Irinotecan and cetuximab, – patients with BRAFV600E metastatic CRC. This is an example of a patient with a microsatellite stable tumor, but you can see prior to treatment, you don’t see a lot of immune reactive T cells within the tumor microenvironment, but that upon treatment with a BRAF EGFR inhibitor, you do see recruitment of activated CD8 positive cytotoxic T cells within the microenvironment. So that suggested to us that there may be a role for BRAF EGFR plus immune checkpoint therapy when we were pitching these concepts years ago in our initial letters of intent.

Let’s talk about CMS, you know, we all I think all recognize the role of CMS biology and that again, CMS1 is kind of the immune active group of a subset of CRC tumors, again, often associated with microsatellite instability. We also recognize that BRAFV600E tumors kind of aggregate to CMS1 oftentimes as well. And so our question again was is this association uniquely inherent to this association between MSI high CRC with BRAF V 600E mutations or can you see this in the MSS setting as well. So, we looked at data from the SWOG 1406. And again, it hasn’t been published yet either, but will be kind of forthcoming. And we looked specifically at in the red here from the from the SWOG study. And within the MSS context, the relative distribution of BRAFV600E tumors and as again, as you can see almost half of the MSS BRAF tumors were CMS1, the other kind of large proportion was CMS4. And this is different than what we had seen with an internal cohort of patients at MD Anderson who had MSS BRAF wild types, where you see a very low fraction of CMS1 within the BRAF of wild-type MSS contexts. So again what we’re seeing here is that within this MSS CRC population of patients, there may be some enrichment for a group, at least of BRAFV600E MSS tumors, for this more kind of immunologically hot CMS1 phenotype. We recognize from data that was published by several groups several years ago that already signatures can indeed for their subcategorized, BRAFV600E tumors, BM1, the B RAF mutation, one subgroup, it tends to be more of a kind of KRAS MAP kinase. Whereas the BM2 is more consistent with cell cycle gene regulation. And again, you can see here kind of when they look by CMS subtypes as well you see kind of what we had seen in the in the prior slide in the group where you have more MSS, BRAF mutated tumors, you start seeing more CM4 as well. And I think that it’s a little bit early to know how this will kind of play out but again, kind of argues for the heterogeneous subpopulations within the BRAF V600E contexts.

So I think that, this was the reason that we were thinking, about the BRAF, EGFR PD1 combination, and we’re very excited to kind of see Dr. Corcoran’s data that he presented earlier this summer in virtual Barcelona and then I think to you guys, it sounds like in the recent past here, looking at the Dabrafenib Trametinib Spartalizumab combination. So not exactly the same ideas or it’s just kind of given the mechanism of the BRAF but, I think that one of the things that really stuck out to us was the fact that you don’t see a whole lot of kind of toxicity with this combination. When we approached Array and BMS with this idea several years ago, I think that they internally were worried a lot about the skin toxicity that you were going to see with these combinations. And I think that his early data suggests that, this is a fairly well-tolerated regimen. But very interestingly even though the data are still very early and immature, the gross numbers, just comparing the same BRAF MEK combination with or without a PD1 I mean, it’s really encouraging, like, and it’s very encouraging. And similarly, I think that he saw, kind of with this slide, similar to what I had shown you guys with our multiplex immunofluorescence slide, or data several slides back, but again, that BRAF MEK PD1 does seem to recruit active T cells to the tumor microenvironment for hopeful cytotoxicity. So, this kind of led us to our concept at MD Anderson, which is now enrolling, you know, it’s a trial looking specifically at MSS BRAFV600E mutated CRC for patients who have not had prior BRAF, EGFR, MEK therapies or immunotherapy, I think his trial may have been a little more broader, and its eligibility criteria. But, this was the population we wanted to look at first, to kind of see signal and we put 11 patients on kind of amidst the COVID pandemic and having to stop it for 2 30-day windows to evaluate toxicity. And given the fact that this combination hadn’t been looked at before. And so we’ve enrolled, you know, fairly quickly under this trial, and what we’re seeing is that just kind of as Dr. Corcoran has shown, the safety data is very promising for this combination as well. This is the kind of the selected eligibility criteria for study again, MSS BRAF V600E adenocarcinoma of the colon or rectum, at least one but no more than two prior lines of systemic therapy, and then excluding prior BRAF, MEK or other anti EGFR therapies or immunotherapy. So that trial, like I said, is enrolling kind of at the same time, as we were about to launch, Dr. Atreya at UCSF was interested in looking at a BRAF MEK PD1 combination in the same setting. So we’ve worked with her to kind of get these trials going up in parallel, I believe her trial is open now. And I think that they’re kind of talking to her they’ve been enrolling too. Sorry, I actually don’t know what the safety data is of this combination yet. I haven’t heard that from her. But we presume that it’s going to be well tolerated.

So I want to circle back just to how we can learn from what we’re doing in the lab, and move that forward in this context, as well. We love using PDX models at MD Anderson kind of as I’ve talked about earlier, we feel that these kind of help us to pitch concepts for clinical trials to the NCI and pharmaceutical companies. And we’ve shown again, in data that hasn’t been published yet that what happens clinically, the patients on BRAF, EGFR therapies match what happens in their matched mouse avatar. So we looked at five patients who were treated on the SWOG 1406 study and characterized them by their clinical responses either having stable disease or partial response. And what you can see is that the overall trends for the stable disease patients in the blue mirror that for what was happening in the matched mouse whereas what was happening in the patients who responded clinically to the combination, you see have greater reductions, kind of in the tumor size in their mouse avatars as well. One of the interesting things just kind of anecdotally, just to kind of point out here as well, is that, in some of these mouse models, this was just looking at this one, the patient had a response to vemurafenib, irinotecan and cetuximab. You can see that in this mouse model for this patient, the BRAF EGFR, you know, it developed resistance but then when we added the irinotecan you see a drastic reduction in tumor size, there’s also a trend towards the irinotecan being different than that of the BRAF EGFR. Similarly, here, this mouse model, this patient responded to the combination, the mouse didn’t really benefit from irinotecan alone. But when we added all three, we saw that there was improvement. So, again, it may point, that just the one size doesn’t fit all. And also kind of points to the fact that this heterogeneity that I’m talking about. There is a trial, you know, that’s being developed in moving forward looking at chemo with or without encorafenib cetuximab in the frontline setting. And I think that data like this kind of points, the idea that, hey, maybe there’s some meaningful interaction with chemotherapy and targeted therapies in this context that that we will see. The problem is when it comes to mouse models, these are immunocompromised. So the the ability to study, the encorafenib nivolumab cetuximab combination would be limited in traditional PDX models. So, Dr. Karla in our group at MD Anderson’s, all star, his work to develop these humanized PDX models where tumor tissue from a patient and matched blood is used to create these mouse avatars. And we have funding that’s through an early career SPORE award at MD Anderson to do a clinical trial for our study, to look to see if what happens again in the patient mirrors what happens in with the same treatment combination in a developed humanized PDX model. And likewise, if what you see happening immunologically, in terms of changes, matches what happens in the matched humanized PDX model as well. This was funny, I got through the SPORE award the mentor here is John Allison, who won the Nobel Prize for his work in developing immunotherapy for patients with cancer. And it’s been really exciting to have the chance to work with Dr. Allison on and get his input on the design and science of what’s going on here. This was just kind of work showing some stuff we’re doing with Dr. Tusayan in collaboration with her on this trial, I would also ask this to be confidential and not shared as well, out of respect to her developing technology, but what we’re doing is we’re getting her slices of tumor, from pretreatment biopsies taken from patients on this study. And then she’s slicing these tumors and putting them into individual plates. And we’re testing what’s happening, with various combinations. And this is a patient who responded on our study to the triple combination. And what we saw was that when she treated the small slices of the tumor with encorafenib, and cetuximab by day 18, there was some reduction of tumor cell viability with the BRAF EGFR combination. When we added nivolumab, to that combination, we saw a much deeper reduction in cell viability, I didn’t put the nivolumab here as well, but it was that bar was here. So you didn’t see it wasn’t single-agent nivolumab down here either. So it was interesting to us because we felt that her model could likewise when you have the patient’s own immune cells present within the microenvironment may reflect what’s happening in the matched patient, but also that there may be in some patients some meaningful benefits to the addition of nivolumab. So, I hope that I provided here some rationale for why adding immunotherapy to BRAF, EGFR targeted therapies in MSS BRAF mutated setting makes sense, when these patients historically have been unresponsive to immunotherapy alone. I think we’re all encouraged by Dr. Corcoran’s work. And our hope would be that given the recent FDA indication of encorafenib and cetuximab we can build upon that success with a similar approach, and are certainly working to that and then I think that this will be informed further by preclinical and translational work that remains ongoing.

I was asked just to talk a little bit about atypical BRAF mutations in CRC. These are slides that I borrowed, full disclosure from Dr. Benny Johnson in our group at MD Anderson who really has led our group’s efforts, very valiantly to kind of work. This is a slide I think, had come from maybe Dr. Yeager at Memorial, I’m just kind of showing how the different mechanisms have the traditional RAS independence, BRAF V600E monomer, we associate with a class I, the dimerized. BRAF mutants, we see kind of with class II, and then kind of the, the BRAF inert, class IIIs that kind of has been characterized is these more atypical BRAF mutations. Again, we recognize that, as you can see, in all three of these, the atypical BRAFs tend to fare better than the BRAF V600Es and I would say I don’t think that this is something that all oncologists realize it’s not uncommon, so you get a referral or a call from outside doctors saying, hey, I have a patient with the BRAF mutation can I send them for your trial, and then we find out that it’s like a D594G mutation, kind of one of these more atypicals. So I think this is something we’re really trying to get the word out with oncologists as well, kind of as we learn more. And this is kind of, again, Dr. Johnson here, who I really just want to plug I think, has really had a passion for leading this effort in our group at MD Anderson, but just kind of some of the novel approaches that we’re trying to take at MD Anderson for kind of how we triage patients to various trials, according to their specific BRAF mutation, whether it’s a V600E, or a non V600E. So that kind of sums up what I had to say. I try to be active on Twitter, if you have any questions, please just let me know.

Manju George 37:06
So if I can, I’m going to start the questions, you can hear me, right?

Dr. Morris 37:12
Yes, I can. Yeah.

Manju George 37:13
So you were talking about the heterogeneity, so I was kind of wondering, in the unpublished data that you have, can you said that one part was the MAP kinase signaling pathway, and the other one was a different, you know, cell cycle and all of those pathways? So are you in your different trials are you attempting to find out what those different groups are? And in the reason I asked is, just like you said, we in our group, we find a lot of heterogeneity in how people respond to the different treatments for the BRAF V600E mutation. So it will make sense to us to if we could know what they were, because most of the patients, they already have their genomic testing done. And then if there’s some way to know upfront that you are in the 8.4 months category, not in the 84-month category, then you can plan accordingly how you have to prioritize treatment, right?

Dr. Morris 38:14
Yeah. So I think we’re looking at that we’re certainly collecting biopsies, to look at the transcriptome in RNA sequencing of these patients, and that may kind of inform on what their CMS classifications or BM1 BM2 classifications. I believe that Pfizer is looking at that on the patients who were on the Beacon study as well. So I think it’ll be very interesting if you see here that the BM1 patients are the ones who maybe had more benefit with the triplet, if there was a preferential added benefit with the addition of the MEK inhibitors that the BM1s than the BM twos. So, I’m very interested in this question as well and I hope that we’ll get some information from Pfizer about that. I think that Corcoran had published from his triplet, the dabrafenib, tremetinib, panitumumab work earlier this summer in clinical cancer research some signal kind of saying that, but I think it’ll be very interesting, in a larger cohort in a randomized trial to look at that in a kind of post hoc analysis.

Manju George 39:33
And then my other question would be like, there is this test called immuno score, right? Do you think those kinds of tests can tell you more, I was kind of wondering that if there was any efforts to develop some kind of assays so that you can look at a BRAF patient and say that this would be more BM1 or BM2, even the consensus molecular subtypes if there is, do you know if there is something like that being developed or going on?

Dr. Morris 40:02
I mean, not that I’m aware of I’m sure that it probably is being worked on. And it’s a really good point. But it’s not something that we’re actively working on now.

Manju George 40:13
Okay. And then the other person that you’re collaborating with Houston Yun, like the tissue culture thing. So it’s like an entire section of the biopsies is grown in the wells and you’re seeing that, when you try the combination treatment with the immunotherapy, just with that not inside an animal, you’re still seeing a response. Right? That’s what you said?

Dr. Morris 40:40
Yeah, that’s right. So, I mean, again, like, we’ve put only 11 patients on our trial thus far. And I mean, in full disclosure, with the pandemic, we had to shut down understandably, all optional biopsies for several months. So this limited our ability, thus far to look at this in high numbers, but it is something that we’re opening back up now. And we’ll be looking more stringently to see is there a signal? You always see kind of in the presentations, the N of one? So it’s hard to know for sure iff that’s truly representative, or if people cherry-pick the best for you to show? I don’t know,

Manju George 41:26
Okay. And then you have some results by GI-ASCO. Is that right?

Dr. Morris 41:36
Yeah, I mean, if so, it’d be a late-breaking abstract. I think we have 26 patients that we would plan on putting on study, so we’re just about halfway there. So it would either be a late-breaking, or probably the ASCO next year, we’ll see. We’re moving forward. And we talked to the NCI about what the next step would look like in a more definitive fashion.

Manju George 42:03
So, thank you, let’s see if others have questions. Questions, anyone?

COLONTOWN Member 42:29
Know, I feel like I need to, like, listen to this all again and consume so much information here, it’s been very helpful. But I was really interested to hear about some of the other mutations, you know, that we’re seeing, that are driving when BRAF you know, kind of becomes, you know, less important. So, while you know, I’m, again, I kind of feel like I need to, like review all of that, again, because I don’t think I caught it all. But you know, any other thoughts you have around that? And how we should think about how does treatment progress, as you know, maybe get to the end of what targeted BRAF therapy can do how do you make the decision to move forward from there?

Dr. Morris 43:10
Yeah, I mean, I think it’s a really good question. I think one of the things that hasn’t been fully looked at yet is with what you see in a RAS wild-type setting where there’s this idea of, these patients developing these acquired RAS, KRAS NRAS mutations. And then when you pull away the anti-EGFR therapy, that selective pressure is lost, and that acquired mechanism of resistance decays back down. Dr. Christine, Parsighian in our group had a really nice paper just kind of showing the kinetics of in the acquire resistance study to anti-EGFR therapy, the median half-life is about four to five months. So, before by the time you see 50% of that acquired resistance mechanism go away and then you can re-challenge these patients and see some benefit, and that’s being looked at in multiple clinical trials right now. And then the question is when a patient progresses on BRAF EGFR therapy, is that the end ever in their story and journey for EGFR therapy, or is there a role for rechallenge? None of us knows that. And I think it would be really, really interesting to look at. So I mean, yeah, like I think that’s something we’ve thought about, and I’m not aware of any data out there that’s shown that that’s successful or not successful.

COLONTOWN Member 44:53
Thank you, Manju. Dr. Morris, My name is Rashmi and I’m a caregiver to my husband with BRAF. My question to you is we know the pathway of the BRAF and the EGFR and the MEK and Erk. Looking at the three trials between Dr. Corcoran’s Dr. Kopetz and Dr. Atreya’s it seems that the BRAF and immunotherapy are similar. What’s different is the EGFR versus the MEK. Would you speak something to that? Is there I mean, your study is leaning towards the EGFR versus Dr. Corcoran’s is looking more at the MEK inhibitor?

Dr. Morris 45:39
Yeah, I mean, I think that’s what he’s seeing and the rationale for what we did what we did was similar, I don’t think that we know that BRAF, EGFR PD1 is any better or worse than BRAF MEK PD1, I think for us we realized several years ago that with the SWOG data that probably BRAF EGFR was going to get approved. And how we were going to be able to develop a strategy to, if successful to roll this out to our patients. It made sense in the context of a BRAF EGFR setting. So that’s why we we kind of went with that for approach years ago. He ‘s done a lot of work in the BRAF, MEK. I mean, I can’t speak to why they chose that, but I don’t think that we know that there’s a difference or why or if there’s a difference. Thank you.

Manju George 46:54
Okay, again, I’m going back to the CMS1 and CMS4 subtypes. So in our group, we have patients, we have one patient who has been almost NED, she’s been on the Beacon triplet, and she’s that one patient,who has gotten a phenomenal response. For most of the patients, we see that they’re on the triplet for a certain time, and then you know, things start growing, and then they get back on FOLFIRI + bev and that seems to work really well. So we have a group of patients for whom the FOLFIRI plus bev or FOLFOXIRI plus bev seems to give the best response. So again, I was kind of wondering whether, you know, that goes back to what you said about the BRAF, MEK, ERK pathway being important versus the cell cycle one, because then in that case, the cell cycle one would be more susceptible to chemo, right.?

Dr. Morris 48:01
Yeah, I mean, in theory, yes, but kind of given the fact that, these patients don’t respond in a treatment-refractory setting very well to chemotherapy, whether that translates into, clinical reality, I don’t think we know yet.

Manju George 48:22
Again, like, my push will be to if there could be an assay to tell you what kind of BRAF you are, from a patient perspective, that could make a big difference to patients as to how they approach the different treatments.

Dr. Morris 48:33
It would help us to Yeah, I mean, I think we’re very interested in understanding the different biologies, because again, we recognize it’s not a one-size-fits-all approach here.

Manju George 48:53
I think if there are no more questions, thank you very much for your time, and I guess that people, there are about 250 members many of them will watch the video because we’re going to post this in our group. And then there may be more questions, so then I’ll probably get them to you either by email or on Twitter. And thank you so much for your time.

Dr. Morris 49:20
Thank you, I appreciate it so much.

Manju George 49:23
Bye. Bye. Thanks, everyone.