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Targeting KRAS for patients with CRC

Targeting KRAS for Patients with CRC

DocTalk

2025

Dr. Sahin

KRAS

In this DocTalk, Dr. Ibrahim Sahin discusses targeting KRAS mutations. Recorded in May, 2025.

Transcript

Betsy Post 0:00
Okay, so without further ado, that’s how it’s going to work. And I would like to welcome Dr Ibrahim Sahin. He is a medical oncologist at the University of Pittsburgh, and he is an expert in colorectal cancer, but especially the KRAS mutation. So as we all know, the KRAS mutation makes treating colorectal cancer a little more difficult, and so he is going to talk to us tonight about ways to target this mutation. Also, he is making sure that he does talk tonight about some new studies and some things that are on the horizon to treat KRAS. So we are so excited to have you here. I know it’s seven o’clock in the evening your time, and we can’t be more thankful and grateful, so I’m going to turn it over to you, and I can’t wait to hear everything that you have to present.

Dr. Ibrahim Sahin 0:51
Thank you, yes, thank you for the kind introduction. It’s honor to be here with you guys, and if this can be, anyhow, productive for any of you, it’ll be honor for me, and thanks again for the opportunity. So yeah, I’m a medical oncologist and my primary research is colorectal cancer and and hopefully today, I will try to really summarize some knowledge about the colorectal cancer with KRAS mutation and its clinical relevance, and hopefully, again, as Betsy mentioned, that we will talk about the therapeutic opportunities that is our rapidly evolving right now. So with that, I’ll go ahead and get started with the slides. As an official thing, I have to acknowledge my disclosures. So this is my disclosure here.

Dr. Ibrahim Sahin 1:41
So KRAS mutations are really a common variety of alteration that we see in GI cancers in general, which is why I think GI cancers are biologically highly different than other diseases, including lung cancer. And also they are very heterogeneous. Although we call them KRAS mutations, they don’t mean they are actually behaving the same. Biological they are different. Their locations can be different, as seen here. Exon 2 refers to a specific location, and within that exon in the DNA, there are codons called 12 and 13, and alteration or changes in this specific location in DNA where the KRAS gene is located can create these different different different mutations. And in the past, we really had not that much knowledge about their diversity and biological relevance. But as the science evolved, we learned about more and more how they are different in terms of frequencies, but also biologically So, as we see in colorectal cancer, unlike lung cancer, where we see KRAS G 12 C is the leading type of mutation, in colorectal cancer it is actually KRAS G12V mutation. Overall codon 12 mutations are the most common one as well, and exon 2 mutation, which refers again, codon 12 and 13 represent big majority of the mutations that we see in colorectal cancer. And non- exon 2 mutations are relatively less common in colon. And again, G12C, and this Cs these are all referring to the specific amino acid change. And C here for cysteine, which is a specific amino acid that happens to create a different molecular structure in this mutation. But again, this is unfortunately 3% and reason I’m saying unfortunately 3% because we have already FDA labeled drugs for that. But that doesn’t mean that we are not working on other drug developments, and there are more to come, in addition to G12C inhibitors.

Dr. Ibrahim Sahin 4:03
And again, these mutations in specific exons, specific codons can impact how they are responsive to activatingand inactivating proteins, because there’s always proteins that really interact with each other in cellular metabolism, where things are trying to be regulated, and this mutation can alter them. And specific mutation can have different different impact on how they respond to regulatory proteins and during interaction with also small molecule inhibitors. The interesting hydrolysis activity, which means how they are turned off automatically that normally they should, because there is no really continuous activity of this KRAS, normal gene can be impacted by this mutation and G12C is one of the mutation where the inactivity, autonomous inactivity, is still somewhat preserved, which is why we had chance to develop drugs a lot faster for this mutation compared to other mutations. So although we call all of them KRAS mutation, they are highly different. Their names are different, their biology is different, and that it has significant impact how drug development evolves so far.

Dr. Ibrahim Sahin 5:27
In general KRAS mutations, unfortunately also are related to worse prognosis, and is demonstrated in this study that published years ago by Dr Cremolini and colleagues, showing KRAS mutated colorectal cancer biologically behaves different, and patients with this mutation tend to live, unfortunately, lower expected life than those who doesn’t have this KRAS mutation. So therefore we feel as clinical investigators, physician scientists, there’s a huge unmet need for drug development in that space. And I’m very happy to say there is th just some some optimization needed for faster drug development, particularly for colorectal cancers, which I will touch base later on. So frontline therapy, again, just in general, for everyone to have an idea, chemotherapy is not really affected– choice of chemotherapy, per se, but it is. It does impact the one therapeutic agent that we use in daily practice– anti EGFR treatments, or EGFR blockade, which are panitumumab and cetuximab, and this KRAS mutation unfortunately render resistance. So when the tumor has this mutation in it, then we know the anti EGFR, which is the panitumumab and cetuximab doesn’t work very well. And I think certainly depending on patient preference, considering triplet regimen, or doublet regimen, this is more a discussion, rather than true– one better than the other in terms of efficacy. I would say there is slight improvement overall survival with triplet regimen, which is FOLFOXIRI, but really there’s also toxicity thatcomes with three drug regimen. Therefore, I feel it is often time an informed decision around risk and benefits and it should be individualized, rather than should be one fit for everyone.

Dr. Ibrahim Sahin 7:40
Again, for patient with G12C mutation, now we have approved drugs, so that’s very exciting. Not for all KRAS mutations, but for G12C. And they are already, one of them given accelerated approval, which is adagrasib+ cetuximab, based on single arm study, where response rate was highly promising. And other was randomized trial, which sotorasib and panitumumab. And these were all colorectal cancer patient studies, unlike other studies I’ll be chatting on later on, where early phase drug development is happening. These were all colorectalcancer patients. Benefit was solid enough for FDA to give drug approval, and these were chemotherapy refractory settings. And here’s some of the results, which there are some key information here, I think may be somehow relevant for our industry industry colleagues to learn from studies.

Dr. Ibrahim Sahin 8:39
So in this trial where adagrasib and cetuximab has been investigated, the objective response rate was 46% which is a further partial response, and it was only 19% when it was given as a monotherapy. So it is more than twice the response rate when we combine with anti EGFR, with KRAS G12C inhibitors. This is very important, because I think this is seen sometime in real practice. I’ve seen in real practice, but also in drug development. The randomized trial of sotorasib panitumumab and when sotorasib was being developed, this went through also again. So with sotorasib mono therapy, the efficacy was very minimal when it’s used alone, without panitumumab, but with the combination panitumumab, it resulted in a lot more significant response. And which result which led this randomized trial. And in this randomized trial, the response rate was 24% much better than monotherapy that we’ve seen, which was around 9% 10% and the duration of response, median PFS, was a lot better than what we have in our third line regimens. So that resulted in approval of this regimen in chemo refractory setting, and both of these agents are currently being investigated in combination with chemotherapy in front line. Some of them are looking for early safety data. And there’s another molecule, which is called divarasib. I think I included that as well, which I will talk and they are also looking for safetywhen they are combined, how safe they are in terms of tolerability.

Dr. Ibrahim Sahin 10:37
So a few interesting things that I thought it’s important, and I presented this actually in another talk. I’m hoping this will turn out to be proven in other studies as well, because liver metastasis of colon cancer is biologically more challenging than the lung metastases and I’m sure there were talks in the past how immunotherapy has some effect in those with lung metastases without the liver, and liver metastasis where the challenges are. And this study, the combination of sotorasib and panitumumab had more favorable outcomes in those patients with liver metastasis. So hopefully, maybe the precision medicine therapeutics will help us with more effective treatments for those patients with active liver metastasis. So this was a post-hoc analysis, and I’m really looking forward to see how this is being played out in other studies in the future, when we have those randomized trials in other molecules as well.

Dr. Ibrahim Sahin 11:45
So what other options aside the G12C inhibitors, which we’ll be talking a little later on, there are trials. We classify them in general as concept in 2 groups. One is allele specific inhibitors. Allele means, and when you guys hear, if someone comments we have allele specific RAS inhibitor, that means there is a molecule, an agent that specifically inhibits a specific KRAS mutation, which can be referred as G12D, G13D. Or there’s areNRAS mutation we see in colon cancer as well, and codon 61 mutations are the most common one. So all these specific mutations are referred as alleles and then molecules that specifically inhibits those specific mutations are called allele specific inhibitors. Pan-KRAS inhibitors by definition, inhibits everything in KRAS, which means KRAS mutations that can happen in any codon or exon, or even the K RAS wild type. Wild type KRAS means, normally there are two copies of each single gene in our bodies. And one is mutated, the other can be normally expressed and and these molecules inhibits both of them- each copy of the protein in our body, even if it is KRAS. And I think this is relevant because, which I will touch on later, some of the resistance may be developing because of RAS wild type being amplified.

Dr. Ibrahim Sahin 13:33
So the Pan- KRAS refers, possibly that all K RAS mutations are being inhibited and also the KRAS wild type by definition. That being said, some pan- KRAS inhibitors that I’ve seen in trials are not inhibiting all K RAS mutations. They are just more, not allele specific, rather more inhibiting most of the KRAS mutation, but missing some of them. So it is important really make sure that specific RAS mutation is included in the trial. when you guys are looking for a trial and also talking with your oncologist. Pan-RAS is even more comprehensive. In addition to the K RAS, we have a gene in our body that can turn into an oncogene, which is called NRAS. And NRAS is also a molecular alteration we see in colon cancer up to 4 to 8% and pan RAS inhibitor inhibits NRAS in addition to the KRAS, so they are even more comprehensive. And they also inhibit anything about NRAS including wild type NRAS, which is normal NRAS. And they inhibit also HRAS, which is somewhat less relevant because we don’t see a lot of HRAS mutations. So anyhow, so the pan-RAS in general means it’s even more comprehensively inhibiting everything about RAS, that doesn’t mean always it is better because we don’t still have that answer, and I’ll touch base later on why, whether inhibiting everything about RAS or KRAS is the way to go, as compared or as opposed to the specific inhibitors. Important again, I think I’m trying to emphasize with industry, whenever I work with them, or whenever I go to their ad boards that EGFR blockade should be implemented early in the course, just because as I mentioned earlier, that without the EGFR blockade, especially for allele specific inhibitors, the efficacy really gets limited, becomes limited. And the main reason for that is because of the of the specific molecular characteristic of colon cancer. We learned over the decades, not specific for KRAs, but also same for the BRAF, if we did not block the EGFR, the inhibition of KRAS or the BRAF, increased activity of that receptor, which creates a bypass, which is why what we see in colon cancer is very different than in lung cancer and even the pancreatic cancer. So those agents often time work okay in pancreatic cancer and lung cancer as mono therapies, but their efficacy is always challenged as a monotherapy in colon cancer, and we learned that on this two drug development–sotorasib and adagrasib, but also BRAF inhibition– encorafenib which are some of these BRAF inhibitors tested as a monotherapies, even in combination with chemotherapy with limited activity up until they are combined with EGFR blockade.

Dr. Ibrahim Sahin 16:55
So this is a recent meeting result which is pretty impressive. And happy to see this. It’s not in colon cancer yet. So it is this agent, which is Revolution Medicine molecule, which the other name is RMC 9805 and now new name is zoldonrasib. They have now a name. And they tested in different, different solid tumors and now they presented results in lung cancer and the response rate was 61%. We don’t have the colon cancer data yet, but I’m hoping from previous experiences, that whatever is found in other disease eventually will come to colon cancer. The caveat I seen, again, with RMC and probably other industry groups as well, that again, during the dose escalation, whenever they see the signal the most, they go to that area first. We have seen that in the story with the G12C as well, which is why we are behind in drug development in colon cancer as compared to lung cancer. And I’m trying to emphasize this again and again in multiple platforms. And I think the same thing happened here. And as monotherapy, the activity was more promising in the lung, and now they present it in the AACR 2025. This molecule has really potential for the future for KRAS G12D. And KRAS G12D is the most common KRAS mutation we see in colorectal cancer.

Dr. Ibrahim Sahin 18:52
So as you guys see, the title is allele specific versus pan KRAS. And the reason I shared that– and I put the question mark in previous, but I forgot on this one– because I just wanted to create an early question for everyone, including myself, but also for drug development purpose. So in this study, unlike the other one, a drug called RMC 6036, which is Daraxonrasib– so the same company– but this is a pan RAS inhibitor. So it inhibits everything about the RAS oncogene. The previous drug here, which is a specific inhibitor, which is KRAS G12D. So in this study, response rate was 61% versus in this study, response rate was 38%. Similar patient population, non small cell lung cancer in both studies, and which creates a question to us as an investigator, although pan-RAS inhibitors may be working, but maybe this allele-specific inhibitors may have more potency.So I can’t say that this is true yet. When you see the distinct outcomes, this creates a question in our mind for future drug development, but this was something interesting that I felt important to really put out as a potential question.

Dr. Ibrahim Sahin 20:23
Nonetheless, this also showed activity. All these bars reflecting how much the tumor were shrinking. And here, every patient experienced tumor shrinkage, but 60% of the patients experienced more than 30% shrinkage. Here it was, 38% of the patient experienced 30% or more tumor shrinkage. So overall, I think both are promising and some more promising signal, as of now with allele- specific inhibitors, but time is going to tell, and we’ll learn more. And again, this was also some similar observation of mine, that I’ve seen in pancreatic cancer as well. So this is again, the same molecule, RMC6036 the pan RAS inhibitor. So not allele-specific, butinhibits, everything about KRAS, and in this study that they presented– now this was, sorry, an ASCO presentation– and objective response rate, 29% and this is obviously great. It’s promising because in pancreatic cancer, it’s a very challenging disease, but what we learned with other G12C inhibitor molecules, the response rate was a lot more than 30%, we seen up to 50% response rates with the specific G12C inhibitors. So that again, creates the question, although pan RAS or pan KRAS activity may be more appealing because of it’s broader coverage, it’s inhibiting multiple alleles that may exist, which we see, which I’ll discuss a little later. But whether that’s more effective, I don’t know that answer yet, and maybe time is going to tell.

Dr. Ibrahim Sahin 22:21
So there was another interesting study, I think these studies are relevant, maybe not directly related to right now to practice, but future of the practice, learning what the resistant mechanisms, while the drugs are being developed. And again, as I mentioned earlier, the KRAS amplification, which means that– normal we have, 2 KRAS copies in our body. Mutation in one of them is enough for potential oncogenic activity, and the other one, which you call wild type, can get amplified, and we call it KRAS amplification in wild type gene, can cause resistance. And we see receptor tyrosine kinases, which are basically the EGFR receptors, sometimes MET, which is another receptor that has oncogenic activity in itself can increase the chance of resistance. Interestingly, RAS and RAF mutations–and I’ve personally seen it– I had two patients who were on trial, so I shouldn’t say much about the trial. And the patients were getting G12C molecules, and they had a great response, thanks to God. But then eventually, when we saw resistance, we performed molecular profiling, and one of my patients had a concurrent, another KRAS mutation in addition to KRAS, G12C. So there are some other reports, also BRAF mutations happening, or any RAF mutations that has oncogenic activity can create resistance. And in one of my patients interestingly I’ve seen HER2 amplification as a resistance mechanism after progression.

Dr. Ibrahim Sahin 24:10
So interesting knowledge coming, these are important because these are also for us to learn for future drug development. Knowing resistance mechanisms can give us more opportunity to do better in the future. And again, as I mentioned earlier, one thing that came up during the our experiences with the BRAF and also the KRAS inhibitors, mono therapies, hasn’t been so successful. And RMC9805, which is the Revolution Medicine agent, now, has a name. It has been studies and not surprisingly, there’s more data coming for lung and pancreatic mainly because the initial studies were in animal models. The original study was published in 2023 that showed the animal models had more signal in pancreatic and and lung cancer, as compared to the colon cancer, where monotherapy was less promising, which I think also led to what we are seeing now. The drug development has focused on pancreatic and lung cancer by Revolution Medicine, which I believe mainly driven by this process, again, because of mono therapies are not working. And I think it’s so crucial for the industry to recognize and that we need to implement anti-EGFR early in the course of therapy or drug development I should say.

Dr. Ibrahim Sahin 26:00
And another one. So this is study of Astellas, which was presented just last year, called molecule ASP 3082. it’s a KRAS degrader. It doesn’t inhibit specifically the molecule, but it degrades. So kind of remove the molecule from cellular level, it degrades it and results in dissolvement of the oncoprotein. And as we see here, in pancreatic cancer, activity was pretty promising, three out of seven patients had response, which was the most promising response after lung. And one colorectal cancer patient that studied in the response. All in all, the recommended dose, which was 300 milligram in this study will probably focus on pancreatic cancer, just because of early signals.

Dr. Ibrahim Sahin 27:04
Anyhow, so these are the challenges, and I think we need to really change our approach for patients with colorectal cancer during drug development. And I think there’s really unmet need for more emphasis for how colon cancer patients should be treated in trials differently than patients with other tumors, including lung and pancreatic cancer. And I think time is going to hopefully help us to really change this practice. Anyhow, moving on for other approaches beyond the EGFR and KRAS together, there is hope maybe KRAS inhibitors can be combined with immunotherapy. This was another interesting thing I found at AACR. I couldn’t make it, but this is one of the thing that I felt interesting from virtual search that inhibition of KRAS may actually give usan opportunity to use immunotherapy for MSS colorectal cancer. And this was always a question in my mind, and I’m so happy to see this in animal models. So these are very early phase animal models that seems to be holding a promise. In this study, investigators combined KRAS G12C inhibitors with anti PD-1 which are immune checkpoint inhibitors, and they’ve seen activity of the T cells with anti tumor response, and that results in a reduction in tumor volume as compared to mono therapies. Maybe in the future, immunotherapy with G12C inhibitors for colon cancer may have hope. These were combined for lung cancer patients, and we’ve seen some good responses, some had challenges due to toxicity. But I’m hoping similar approaches will eventually come in to colon cancer. And again, at that point, even with the immune checkpoint inhibitors, we still need EGFR blockade, I want to emphasize that again, for hopefully for the industry to understand that our patients are different than patients with other solid tumors.

Dr. Ibrahim Sahin 29:29
And there was another study with peptide vaccines. So we are trying to also understand– our new hope, especially in pancreatic cancer, maybe KRAS specific peptides and mRNA vaccines can trigger response. And this study tried utilizing a peptide vaccine, not mRNA and combined with nivolumab, ipilumumab. The response rate was modest, its not what I would love to see. It was 8 percent. Generally for us as a clinical investigator, would like to see that above 15%. Nonetheless, I think this shouldn’t stop us looking for more and more. One failure doesn’t mean the other molecules or other vaccines not going to work in the future. So these are some other molecules in the field. I didn’t put everything here because there are so many of them with different different tumors and the different different studies, different different levels. I just want to give key summaries here and where things are in terms of drug development, but very good news that we have these different molecules are that are in development and very happy to see industry is putting a lot of effort for KRAS inhibitors and I’m hoping this will revolutionize the care that we can offer our patients in the future, so that we can change really the practice and also the outcomes of patients. And again, there are allele specific inhibitors here as summarized, including Mirati drug, Lily drug, AZ drug and also Revolution Medicine. Obviously, Lily has a pan KRAS inhibitor that is in development right now. We are actually trying to open the study at our site. there’s a pan RAS inhibitor from RMC, which is 6236 which they opted to test in pancreatic cancer, which I suspect because, again, drug development favored other solid tumors over colon cancer, and there is some other molecules also in development. And as I mentioned, and tried to go over multiple times. I’mhoping to change our trial designs and how we can implement EGFR blockade at maybe even at dose escalation phase for patients with colon colorectal cancer. With that, I think this is it for my presentation. Thank you.

Betsy Post 32:10
Thank you so much. I know that we have some questions in the chat. I’m gonna do my best to pronounce this stuff. Just remember, I’m not a medical professional, just a patient advocate. So one of the questions that we have is how effective the adagrasib is for patients that are MSS,

Dr. Ibrahim Sahin 32:30
yes, so I’m able to see them too. So you did great on pronunciation, I can tell it. So yeah, that was effective and is approved, and there is actually approval, and patients who were treated were predominantly–I don’t think there was a patient with with MSI high– so they are highly effective for MSS. I think to my recollection, all patients enrolled in that study were MSS, so yes, answer is they are effective. The question whether adagrasib versus sotorasib, we don’t have head to head comparison. That being said, looking to response rate, it was somewhat more favorable for adagrasib cetuximab combination. Nonetheless, we won’t have the clear answerwhether one is better than the other, unless we have a randomized trial, we won’t have that answer. It will be more about discussing the side effects of each drug and also understanding head to head comparisons of this trial can carry challenges due to difference in inclusion/exclusion criteria sometimes we see and that may impact the patient population. But short answer that question, yes, very happy to say it’s for patients with MSS colorectal cancer.

Betsy Post 34:00
Great. The second question is, can you use NGS or ctDNA to track resistance to KRAS targeted trials?

Dr. Ibrahim Sahin 34:09
Good. So they are using ctDNA, collecting samples. They’re not reporting those right away. They are generally very eager to just get the initial efficacy data and also the toxicity. But I know they are also collecting researchlabs, and I’m pretty sure they will be looking for resistance mechanisms in those studies, and they will come later on. Yes, in daily practice, it can be used, in terms of resistance, which I did as a research question. I was talking to patients where I felt at the time of progression, I didn’t have a great explanation why the disease is progressing. We discussed and agreed on doing liquid biopsy, and we did and we had our answer so it can be done at the time of progression. And I know some colleagues are using ctDNA to understand, not specific for KRAS amount in the blood, rather ctDNA overall, which circulating tumor DNA as a surrogate of response, but in general, this is a surrogate rather than a definitive answer. And we don’t use ctDNA to make big decisions in terms of stopping or changing the treatment until we have clear evidence of CAT scans. And I would like to also emphasize, I see that ctDNA clearance is frequently being used in clinical trials. We are learning more andmore ctDNA temporary clearance or reduction may not necessarily correlate always with survival outcomes.And we are learning that also the treatment, even modest activity, can suppress ctDNA secretion. So therefore, I think, still a learning experience for us, and it shouldn’t be a definitive tool in our box to make decisions. Rather, it can give us an idea in clinical practice, but also in research.

Betsy Post 36:30
Thank you. The next question is, does the percentage of cfDNA of specific biomarker make a difference in determining treatment? i.e., 0.2% versus 40% KRAS, G13D in Guardant Infinity blood test.

Dr. Ibrahim Sahin 36:47
Yes, very important question. And thank you for asking that, and highly relevant, because I seen that happening in real world as well, pretty often. Some patients when I see my clinic that comes with liquid biopsies and and this mutation alelle frequency really matters, because we have to make sure we are really not targeting subclones that may be not relevant to progression of disease. So in that case, what I generally look overall cell free DNA load in the blood, let’s say the found a mutation. Just give you an example. P53 is 38% and there is only 1% of KRAS mutation in the blood that often time happens when we have a patient on EGFR blockade, we often see either KRAS or BRAF mutation emerging as a subclone, and they may disappear.So targeting 1% over 38% knowing the rest of them probably don’t have that mutation, may be important. So therefore most of the trials that utilize CT DNA, such as EGFR re challenge trials, such as CHRONOS trial, they always look for ratio of that mutation into into the total cell free cancer DNA. So therefore it is important and it’s highly relevant. It could what we call a subclonal event. Maybe some small amount of cancer may have that mutation and targeting that may not yield therapeutic efficacy, because, obviously, the majority of the tumor are not going to benefit, not going to respond to that therapeutic because they don’t have that mutation.

Betsy Post 38:53
Thank you. If you have been on sotorasib, can you then go on adagrasib after progression,

Dr. Ibrahim Sahin 39:04
Yes, as a question, we don’t have an answer for that. Yeah. I think first thing I would do in that case is to discuss with oncologist whether liquid biopsy can be done and see what happened since then, we have similar experiences. Re challenge therapies, I would say, because this is, in other words, we are re challenging with another KRAS G12C inhibitor. we had similar intents and work in GI field with HER2 I know, in gastric field, they did, and we did also in colon with EGFR, rechallenged those patients who progressed on EGFR, if they have RAS wild type disease were rechallenged and we’ve seen some responses. That being said, we don’t have that one in for KRAS G12C world yet. I know though, there are some Pan KRAS inhibitor and pan RAS inhibitor that are in development to allow prior KRAS G12C. So if there’s a trial that is available with Pan K RAS inhibitors that may be actually more relevant and more meaningful than trying another G12C inhibitor. Outside of that, it will be just experimental, and I don’t have evidence to say it will work.

Betsy Post 40:40
Thank you. So our next question is understanding a lot of things are coming, but what should patients, for example, that are MSS, G12D with no response to standard treatment options, as we know FOLFIRINOX, FOLFIRI. What would you recommend for treatment options today?

Dr. Ibrahim Sahin 41:01
Is this referring to a frontline therapy or option? If this is referring to frontline therapy, obviously for G12D, we don’t have available FDA molecule or drug to using daily practice. But again, as I mentioned, there are drugs in development. I think G12C is one of the most developed molecule in development, I should say, and any of those trials will be meaningful in a chemo refractory setting. In terms of front line, whether starting with FOLFIRINOX versus FOLFOX versus FOLFIRI, I think it’s a discussion. I think for patients who are fit and who are interested in aggressive approaches, understanding three drug regimen is going to have more side effects than two drug regimen. It’s certainly reasonable to consider three drug regimen based on the study that we have from Europe which is called the TRIBE trial. In that study, the most benefit with three drug regimen was seen among patients with BRAF mutation, because they unfortunately have real aggressive disease, and using all the drug available upfront helps to control the cancer more readily. Thankfully, KRAS mutation are not as challenging as BRAF mutations. But that being said, for patients who want aggressive therapy, certainly triplet regimen is reasonable based on overall slight improvement. It wasn’t proven, but there was slight, I think, slight benefit, I should say, in this TRIBE trial with overall survival. So therefore practice pattern hasn’t switched totriplet for all. Rather, it is a more a discussion for each individual patient and those who want to be more aggressive up front, certainly reasonable to consider FOLFIRINOX or FOLFOXIRI, or those patient wants to focus on more quality of life and less aggressive approach, then doublet regimens are also reasonable.

Betsy Post 43:27
Thank you. What KRAS trials are you part of and are you finding there is a lot of patient interest? Are there limited slots?

Dr. Ibrahim Sahin 43:37
So yeah, very important question, we do have our trials at UPMC, and some of them are active and running, G, 12, D, trial is just activated. It’s still for dose escalations level, which means we are still trying to find right dose to be tested in expansion course, also in phase two. And the question regarding limited limited slots, it’s very big problem, which is why I’m trying to advocate that we should open it in more institutions. And obviously there are challenges due to opening multiple trials at the same time, and it is competing, but I think for KRAS trials, that should be an exception, because there’s huge unmet need, and we have a lot of patients with KRAS mutation in colon, in pancreatic cancer, obviously. And finding open slots in dose escalation phase is a big problem, because you have to fill certain slots and see the safety before you move into efficacy in the next dose and until then they don’t open slots– like a randomized trial will obviously have a lot more available slots, unlike the early phase trials. So early phase trials do have that challenge. Some of the molecules, like RMC 6636 is moving along to phase two, but they are in pancreatic cancer now then makes for that randomized phase a lot easier, because dose is defined and first come, first serve, versus here unfortunately, when there’s a dose escalation trial happening, then you have to wait to fill those, make sure they are safe before moving into the next dose. And then we have also pan-KRAS inhibitor of the Lilly company. It’s not active yet. We are trying to activate the study.

Betsy Post 45:53
Thank you. The next question is, if a stage four patient has progressed on first line, is enrolling in a clinical trial, a good option, for example, a targeted trial in combination with an EGFR inhibitor.

Dr. Ibrahim Sahin 46:09
So I think especially if there is a strong biological reasoning, and as long as the patient has understanding, there’s a standard of care approach is available, yes, and I think that happened with the BRAF targeting when we look the development of BRAF Beacon doublet has been tested in second line plus, although it could have been just FLOFOX, FOLFIRI and third line, I think it was smart. I think it was right thing to do, because, especially for the BRAF, because it’s a biologically challenging disease, and there are patient who kept making the third line, but KRAS is obviously relatively less aggressive, thanks to God. And nonetheless, I think as long as there’s a strong biological reasoning and and there is obviously engagement of the patient in terms of understanding risk and benefits, and especially if there’s already signals that molecule is active, certainly can consider going on a trial, where this opportunity may be available. And I think the reason I’m saying that, especially if there’s biological reasoning, finding available, slots in those trials may be challenging. And if the opportunity is there, trying to get benefit, maximum benefit, from those agents that have some signals, and then having the second line drugs, which will be available anyway, using that another time certainly makes sense. But again, I think there has to be some good reasoning for that.

Betsy Post 47:54
Thank you. And I have a question on Are there any trials for KRAS G 12V?

Dr. Ibrahim Sahin 48:00
So good question. I don’t think there’s to my knowledge. I have to emphasize that, because now this whole thing is expanding so rapidly. Maybe there’s some drug hidden somewhere in animal models that I don’t know, not specifically G12V, but the pan KRAS inhibitor. And pan RAS inhibitors possibly have an activity on G12V. I know the Lily drug, Pan KRAS does include G12V mutation. I’m pretty confident on that, because I was looking it up a few days ago. So that pan KRAS inhibitors covers dwelling with the Lily. I know they cover, but I’m I can’t say for everything, although some of the pan K RAS inhibitors possibly inhibiting all K RAS mutation, they may not be but I know that Lily drugs do cover G 12V mutation. I don’t think there’s allele specific molecule for G12V mutation itself, though.

Betsy Post 48:59
Thank you so much!

Dr. Ibrahim Sahin 49:00
My pleasure.

Betsy Post 49:02
Those are all the questions that I see. And I just wanted to see if you have any parting words for us, anything to say to the patients, to the COLONTOWN community about KRAS, or, you know, anything you think as far as with regard to what they’re doing with their oncologists, or questions they might ask, no pressure, but anything you know, any words of wisdom for this community, anything you’d like to say in that regard,

Dr. Ibrahim Sahin 49:33
I think, to be honest, not individual level. I think at patient advocacy level, there’s unmet need –work for COLONTOWN. And I’m part of this. I consider myself, because my own cousin had colon cancer at the age of 26 so colon cancer is dear to my heart, and I think there’s significant unmet need for advocacy, for drug development. And. I was trying to really put headlines and do on with large letters, trying to make sure, I think the message is passed that we really need to make it clear to industry that colorectal cancer has specific characteristics, and that has to be implemented early because that’s impacting their evolution. Drug evolution,they are gonna continue to see more activity with monotherapy for other tumors, and they’re gonna try to prioritize other tumors, just because they see more signal with mono therapies, and unless they start using anti EGFR very early, even maybe at dose escalation level, this pattern is not going to change. So we’ll have to really keep pushing and pushing and pushing the industry to make sure they understand we really have a different type of disease. We really need to make sure we are not ignoring the fact that we’re not going to see good as good responses in colon cancer unless we use anti EGFR early in the course, and this shouldn’t delay drug development for patients with colon cancer.

Betsy Post 51:14
Thank you so much for that. I really appreciate it. And a couple people have said thank you so much for your advocacy. So just know that your work is very appreciated in our community, by all of us, but especially, of course, by those in the K RAS community. So thank you so much for being here with us tonight and for sharing this with us. Thank you to all the patients and families that joined us live. We really appreciate your time, and thank you all for being here and have a great night.

Dr. Ibrahim Sahin 51:41
Thank you. It’s been an honor. How wonderful.

Betsy Post 51:43
Thank you. Good night.

DocTalk

2025

Dr. Sahin

KRAS

In this DocTalk, Dr. Ibrahim Sahin discusses targeting KRAS mutations. Recorded in May, 2025.

KRAS G12C trial

DocTalk

2024

Dr. Parseghian

Dr. Parseghian discusses the KRAS G12C trial with PALTOWN Scientific Director Dr. Manju George. Recorded in September 2024.

Transcript

Manju George 0:00
Hello everyone. Welcome to Doc Talks. I’m Dr Manju George, the Scientific Director at PALTOWN Development Foundation, the nonprofit that supports COLONTOWN. Today, we have Dr. Christine Parseghian with us, and she’s going to talk to us about her new trial. But before we get into this, I would like to ask Dr Parseghian how she got into GI oncology, and what are some of the areas that are of interest to her? And again, to remind you that a recording of this talk will be posted in COLONTOWN University. We will first cover a this trial, and then we will have a question and answer session. So welcome, Dr Parseghian.

Dr. Parseghian 0:39
Thank you so much, and thank you for having me. It’s it’s a pleasure to be here. So a little bit about myself. I’m one of the associate professors of GI Medical Oncology at MD Anderson. My focus of interest is not only CRC, but particularly patients with colorectal cancer that are resistant to first and second line therapies, and so I have a strong interest in anti EGFR rechallenge, KRAS G 12 C therapy, and KRAS G 12 C rechallenge as well. So subpopulations of these patients that have the more unfortunately, the more aggressive biology, and trying to improve outcomes. In terms of how I got into this field, it’s fairly straightforward. When I was 13 years old, my mom was diagnosed with colon cancer. I was young, and she was very involved in my schooling, and so she did not want to get adjuvant chemotherapy, because she wanted to be there to support me. And of course, I did not know enough to try to persuade her. So she did not get adjuvant chemo. She then went on in and of course, when a few years later, because she did not get adjuvant, she was higher risk for recurrence, and indeed, she did, she had metastases to her liver. Luckily, she was in Boston under the care of Dana Farber and MGH physicians, and she was able to get a curative hepatectomy, and now two, almost three decades later, she is well. And at that point, when I was only 16 or 17 years old, I decided to make more of an influence and be someone to try to persuade someone like my mom to have gotten adjuvant chemo, and, more importantly, other therapies in the metastatic setting. So I promised her, and I promised myself at that point that I would go to medical school and I would focus on oncology, and particularly, CRC.

Manju George 2:58
Yay. Wow. Thank you for sharing your personal inspiration of how you are in this field now, and I’m sure that you can really identify with a lot of patients that come to you, and to be able to provide them the care that they’re seeking. So thank you very much.

Dr. Parseghian 3:17
I wanted to give a little bit of background on why we’re doing this trial. So as many of you probably know, KRAS G 12 C mutated CRC is relatively rare in colon cancer. About 2 to 4% of patients have this mutation. Unfortunately, of those that do, it is more of an aggressive phenotype. The biology is more aggressive, patients compared to G 12 C wild type patients, do kind of relatively more poorly and are nonresponsive to other therapies to the degree that other wild type patients are. So thankfully, we are constantly looking for directed therapies against K RAS. So there was a G 12 C inhibitor in fact, multiple now that has been developed. One is adagrasib and in combination with anti EGFR such as cetuximab, and another is sotorasib, another G12C inhibitor that has been combined with panitumumab. Both have shown very nice responses in a patient population that is very heavily pretreated, in these patients that were on, for example, third line therapy. otherwise their options are a clinical trial versus standard of care, as many of you know, lonsurf plus Avastin, fruquintinib now with the approval or Regorafenib. And as we know, the response rates to third line therapy range anywhere between 2 to 7%. So we knew we had to do better, and thankfully adagrasib and Cetuximab, for example, has done just that. So Kopetz and colleagues just presented the data from Krystal-1, which is basically a combination of different kind of patient populations that they looked at together who had KRAS G, 12 C mutation and received adagrasib and Cetuximab. They have found, kind of the most dramatic response, I think, of the combinations that have been kind of evaluated to date, the objective response rate that was found was 34% with a disease control rate of about 85%. I think that objective response rate, again, 34% is is tremendous, in combination with, in basically, in relation to other third line regimens. Further, not only was it effective, it was deemed to be quite safe and potentially even less toxic than known third line therapies. So based on this data, you can kind of go on to the next slide, based on this data, and then also prior data that has come out of here at MD Anderson with Dr Morris and colleagues, and also, Dr. Corcoran from MGH, we have found that in other highly mutated and aggressive tumors, such as the BRAF V600E population of CRC, that the combination of, for example, the Braf combination, in addition to PD 1 or immunotherapy, has shown a significant improvement of objective response. So, for example, we all know the Beacon trial by Kopetz and colleagues that was, that was presented at and published in NEJM in 2019. This is an exciting trial, because these BRAF patients have an extremely aggressive disease, and so we were very excited, even with a 20% objective response rate, but we knew we could do better. So just recently, at GI ASCO, Dr Morris and colleagues presented very exciting data showing that, in fact, when you add an immunotherapy or checkpoint inhibitor, in this case, it was nivolumab, the objective response rate went from 20% to 50% which is just tremendous. So we use that as a little bit of hypothesis building for our own trial. And we know based on preclinical models that, similarly to BRAF, what happens in this KRAS G12C population is that we’ve shown, this like preclinically in mouse models as well, that adagrasib when given, enhances and basically reconditions the tumor microenvironment to then basically improve susceptibility to immunotherapy. So the hope that adagrasib and cetuximab looks great. It’s much better than third line therapy in this population of patients that are potentially able to get this regimen, but we can certainly do better than 34%. So our protocol that was just activated is a multi center phase IB/II study. It will be at MGH in Boston and MD Anderson here in Houston. It is a combination of adagrasib which is the G 12 C inhibitor, in combination with Cetuximab, the anti EGFR, and then, in this case, the checkpoint inhibitor, or the immunotherapy drug is Cemiplimab. This study will be in patients with metastatic or advanced colorectal cancer, who have a KRAS, G12C, mutation.

Dr. Parseghian 9:14
A little bit about what we’re looking for. We are looking primarily to ensure that this has an objective response rate. So a response rate we’re looking for, can we do better than the 34% that was seen in Krystal-1? And also looking obviously at safety and tolerability. There is a safety lead in with about six patients. So that’s the Phase 1b component. And then we will do a dose expansion with several more patients, with a maximum number of patients to be 31 divided essentially equally between MGH and MD Anderson. We’re very excited about this trial. I think it can certainly, hopefully help our patients, based on the preclinical data we have and based on the Braf story, which is just super exciting. And obviously this patient population is very biologically aggressive, and I think again, we can do better than 34% so looking forward to having patients come over. We are really trying to get patients with KRAS G, 12 C mutations in quickly, because of course, that biology is difficult to treat. So if we can get them on a clinical trial that’s very important. And and, you know, just to talk a little bit about inclusion, which I which I failed to mention, we are looking for patients, like I said, that have the KRAS G 12 C mutation, but have also had at least one line of prior therapy. So that would include at least 5FU. They will need to be microsatellite stable KRAS G12C mutated, like I said, but also would not have had received prior checkpoint inhibitor, like a PD 1 inhibitor, and not have received prior KRAS G, 12 C inhibition. So this is not a rechallenge study. It is an upfront treatment with KRAS inhibitor in combination with immunotherapy. Thanks so much.

Manju George 11:25
Okay, thank you very much. So now that we have the slide here, maybe we can start with questions about this. So you’re saying that it can be they need to have been exposed to 5FU. But do they need to get a certain amount of cycles containing 5FU or?

Dr. Parseghian 11:45
No, so the the inclusion would be, progression on 5FU based therapy, or intolerability to at least one line of therapy. So if you got FOLFOX or FOLFIRI and did not tolerate it, and your local oncologist had to take you off, then you would still be considered for the trial

Manju George 12:09
Okay. And then I also noticed that prior exposure to cetux or EGFR inhibitors is not an exclusion.

Dr. Parseghian 12:17
Correct. That’s right. So two sites open at MGH and MD Anderson being the two sites. So it will be 19 patients, but potentially up to 31 based on if we see any toxicities, etc, dose expansion. So yes, we, you know, this patient population is, like I said, rare, but we’re seeing them come through our doors. And you know, we anticipate this, this will be kind of a highly sought after trial, because we really are trying to get these KRAS G, 12 C patients early so that we can improve the duration of response, not only response rate, but the beauty of immunotherapy is it helps us with duration of response, and it basically allows your body to help you extend the duration of your therapy. And so if we can do that, that would also be a significant benefit for patients.

Manju George 13:25
Okay, what about early stage patients who have progressed on adjuvant chemo? Would they be eligible?

Dr. Parseghian 13:33
So if they’ve progressed on adjuvant I guess that would mean that they are metastatic. Yeah. So any line of prior 5FU based therapy would count,

Manju George 13:47
okay, okay. So that’s great,

Dr. Parseghian 13:49
Even if it was in the adjunct setting,

Manju George 13:51
okay, so, yeah, even in the adjuvant settings, so and again. Then the important thing is for patients to know if they are KRAS G12C, like upfront, so that you even when they’re starting first line therapy, this is something to keep in mind, because the moment they progress, they can get enrolled

Dr. Parseghian 14:08
Exactly, exactly, very important to stress, and I know we’ve probably talked about this at length, stress to the local oncologist, please get KRAS testing, BRAF testing and MSI at the very least, as soon as you’re diagnosed with metastatic cancer.

Manju George 14:26
Okay. And then this is also for rectal cancer, both colon and rectal,

Dr. Parseghian 14:30
Correct

Manju George 14:31
Yes, okay, And then there are no biopsies. It looks like you’re basically going to be looking at CtDNA like liquid biopsies. So no biopsies involved other than that,

Dr. Parseghian 14:41
No, there are. So there isn’t a pre- treatment biopsy, a tissue biopsy. But then there is an on treatment biopsy, and we are requiring them so that we can look at the tissue change over time, in terms of what is happening in the body and at a tissue level that we can do deep sequencing on to look at resistance in this population. And that’s how we’re really going to learn from this patient population. You cannot do that, the extent of that deep sequencing, the RNA sequencing, etc, on liquid biopsy, unfortunately.

Manju George 15:25
Okay, so then I would say that from a patient perspective, what is important is that they should have progressed on 5FU containing chemo. They should also have metastatic disease, which is amenable to being biopsied, if it’s a mandatory biopsy, that is part of it, right? So these are the two things for patients to remember, Okay, sounds good. And then what else? And the hope is that the ORR will improve from 34% to higher, following what you have seen with the strategy for BRAF, right? And you’re also saying that you would like to get patients by having this inclusion criteria, you would like to get patients relatively early in their treatment journey than somebody who’s much later and have gone through multiple lines. Okay, so I think those are three things that we could definitely talk about to patients when we are discussing this trial.

Dr. Parseghian 16:18
If you’re G 12 C, and you’re not local you could get the 5FU based therapy at home, no problem. But understand, there’s sometimes a delay getting into places like MGH and MD Anderson. So upon finding out that you have a KRAS G12C mutation, I might already reach out, even before you start any chemotherapy, to MGH or MD Anderson, just to get the foot in the door to start the process.

Manju George 16:48
Okay, okay, that sounds like great advice, yeah. And then, could you tell us a little bit about this, the immunotherapy, the Cemiplimab, it is a PD1 inhibitor, right?

Dr. Parseghian 17:01
It is PD-1. It has been studied in other tumor types already, such as bladder cancer, is very well tolerated with very minimal toxicities, similar toxicities to other immunotherapies, such as colitis, diarrhea in patients, pneumonitis, an inflammation of the organs, essentially. But we don’t suspect that, based on other data that we’ve had from Cemiplimab in combination with other chemotherapies, we don’t suspect that it is going to kind of worsen the safety profile in a significant degree should be very well tolerated in combination. In fact, we’re giving the the full dose of Cemiplimab, which has been approved.

Manju George 17:49
Okay, okay. And then can you also tell us a little bit about the the drugs, like so adagrasib looks like it’s an oral medication, and it’s twice daily every day, or is there a cycle like ?

Dr. Parseghian 18:01
No, its twice daily, every day, so that you could take at home in the morning and in the evening. And the Cetuximab is IV, and that you do come to the infusion center every two weeks for the 500 mg per meter square is the standard dose, and the Cemplimab is also IV. That’s a little bit of a different timeline. So the Cemiplimab is every three weeks IV, and the Cetuximab is every two weeks IV. So there is a two week period where you’re here more often, you’re my friend, more often, that is the way that it needs to be dosed for safety.

Manju George 18:39

Okay, okay, okay, that makes sense. I’m thinking, if there is any other question that I have, yeah. So the other thing is that, like I have seen, I don’t know how common it is in the US, but I have seen some, tumor testing reports which say, something like G12X where they don’t know if they’re G 12 C. So could those patients apply for the trial? Or they should they need, like, a already known G12C status? Or is there any way to get the testing done with you guys as part of the trial?

Dr. Parseghian 19:13
Yeah, you know, unfortunately, there are several G 12 mutations. So there’s commonly, more commonly, G12D mutations, for example. We are happy to run the test if you come to us, we can easily do that with the liquid biopsy. So just the CtDNA test to look at the molecular profile. We do not need to do biopsy for that. That will turn around in a matter of seven to 10 days. We will know the profile of the patient, and we can potentially get going on therapy.

Manju George 19:46
Okay, okay. Thank you very much. And then the other question that I have is when we come to know that there are G 12 C patients, would it be possible for us to give them your contact information, or, who would be the contact person say, for example, at MGH, that we could tell them, hey, email these people, and then you can get on it right away.

Dr. Parseghian 20:08
So if they could email me directly. And so my email address is [email protected], and I believe the contact at MGH will be Aparna Parikh. I don’t know her email address offhand, but she would be the contact or the lead PI essentially at MGH.

Manju George 20:33
Okay, okay, that’s great. I think we will be able to provide Dr Parikh’s email address as a contact information () and then, so I was wondering if you could say a little bit about, you know, the Stand Up to Cancer part of the whole project, and how it’s a collaborative effort, and what’s going on in the background?

Dr. Parseghian 20:55
Yeah, so they have been tremendously supportive, obviously, of this study and and all of the preclinical work that has led up to it and continues to be ongoing. The study would not have been possible without their financial, the grant support, and also the guidance, scientific guidance, that they have provided us along the way as well. So tremendously grateful. Really hope to make a difference in this patient population, and they were very excited and supportive of this. So we’re very appreciative of the funding and the support that they have given us for now several years.

Manju George 21:37
Okay, okay, I want to disclose here that I’m a patient advocate on this Stand Up to Cancer catalyst project. And for me, what has been exciting is the collaboration between Dr Corcoran’s lab at MGH and the MD Anderson group. So it’s like the top brains on looking at resistance combining together their expertise, and then having all, everyone in this field, interacting and collaborating. For me, that has been the most exciting part of this work.

Dr. Parseghian 22:12
Thank you.

Manju George 22:13

Is there anything else that you want patients to know about?

Dr. Parseghian 22:18
No, I don’t think so. I think just really trying to get patients the care that they need. And again, please reach out to me directly. If you’re having a hard time getting in. I’m happy to see you.

Manju George 22:32
Okay, okay. Thank you very much. What I’ll do is that once the video is posted, if people have questions, then I’ll bring them back to you. Before we end, I would like to ask you this one question. Do you have any advice for early stage patients who come to know about their KRAS status, about the impact of it on adjuvant therapy?

Dr. Parseghian 22:51
Yeah, unfortunately, we have no data for adjuvant I would say they fall into the same category of patients that would be subcategorized by specific stage, whether or not adjuvant chemotherapy would be recommended, just based on what we know so far per guidelines. However, I guess I would say, understanding that you are a KRAS G 12 C mutated patient, you unfortunately have a little bit of a different disease biology, which is a little bit more aggressive. And so if the local oncologist is recommending chemotherapy, I would highly encourage you to follow those instructions and go through with the adjuvant chemotherapy to at least reduce the chances of this coming back.

Manju George 23:41
Okay, okay, thank you. And when you were explaining about your personal exposure to the disease and how you got into this, I was a little bit anxious about when you said that your mom’s cancer had come back, but I was very happy to hear that she got timely help, and then, when it became metastatic, she has been NED for a couple of decades, and I think that is also a story that is hopeful for patients. And so I really appreciate you sharing that, and I think that’s it. And thank you very much for joining us and providing all the information about this trial.

Manju George 23:42
Thank you so much for having me.

DocTalk

2024

Dr. Parseghian

Dr. Parseghian discusses the KRAS G12C trial with PALTOWN Scientific Director Dr. Manju George. Recorded in September 2024.

Targeting RAS mutations in CRC

DocTalk

2022

Dr. Lenz

RAS

Dr. Heinz Lenz from USC Norris Comprehensive Cancer Center discusses targeting RAS mutations in CRC with PALTOWN Scientific Director Dr. Manju George. Recorded in October 2022.

Transcript

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Manju George 33:27
I think BREAKWATER.

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

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

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

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

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

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

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

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

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

Manju George 36:03
Thank you so much.

Dr. Scott Kopetz 36:06
Thanks.

Manju George 36:07
Bye

Dr. Scott Kopetz 36:08
Bye bye.

DocTalk

2022

Dr. Lenz

RAS

Dr. Heinz Lenz from USC Norris Comprehensive Cancer Center discusses targeting RAS mutations in CRC with PALTOWN Scientific Director Dr. Manju George. Recorded in October 2022.

KRAS therapies for CRC

DocTalk

2022

Dr. Kopetz

KRAS

Dr. Scott Kopetz from MD Anderson discusses the latest KRAS-directed therapies for colorectal cancer with Paltown Scientific Director Dr. Manju George. Recorded in April 2022.

Table of contents

0:00 Introduction
1:46 What is adaptive resistance?
3:45 Lessons learned from BRAF inhibition in CRC
4:16 Targeting MAPK signaling & adaptive resistance
5:19 Pathways to resistance
7:33 KRAS mutations by tumor type
9:00 KRAS G12C inhibition
11:35 Sotorasib in CRC
12:18 Adagrasib in CRC
13:00 Adaptive resistance to KRAS G12C
23:00 How to combat adaptive resistance?
25:45 CodeBreak 101
27:00 Common mechanisms of resistance to G12C inhibitors
28:40 Summary so far
30:04 Combinations with KRAS G12C inhibitors
31:52 Beyond KRAS G12C
33:05 Clinical development of RAS inhibitors
35:19 KRAS G12D inhibitor- preclinical data
39:15 Other approaches
42:49 Conclusions
45:30 Q & A

Transcript

Manju George 0:00
Hello Everyone, Welcome to DocTalks. I’m Dr Manju George, the Scientific Director of PALTOWN, the nonprofit that supports COLONTOWN. I organize DocTalks, which are Zoom video talks from expert clinicians from the field on topics that are relevant to colorectal cancer patients and caregivers. Today, we have Dr. Christopher Lieu with us. He’s the Associate Director of Clinical Research and the Co- Director of Gastrointestinal Medical Oncology at the Colorado Cancer Center. He’s also the Vice Chair of the NCI Colon Task Force. Very excited to have you with us, Dr. Lieu, and he’s going to tell us about CtDNA tests for cancer screening and about the CIRCULATE-US trial. Welcome.

Dr. Christopher Lieu 0:43
Thanks so much, Dr. George, and thank you so much for the opportunity to talk to you all today about circulating tumor DNA and an upcoming trial, or newly opened trial called CIRCULATE-US, where we’re trying to utilize this new technology to change the way we treat earlier stage colorectal cancer. So thanks for taking the time. These are my disclosures: I do want to mention that there is a contracting agreement between Natera and my institution, University of Colorado, and in regards to Natera, just mainly because they’re one of the companies that produce CtDNA assays.

Dr. Christopher Lieu 1:17
All right, so what are we going to talk about over the next 30 minutes? We’re going to go back. I know that you have already had great talks from Dr. Cohen and Dr. Kopetz in regards to circulating tumor DNA, and we’re going to build on that, but we’re going to take a little bit of a step back. I’m sure you’ve talked about circulating tumor DNA, or heard of it in terms of earlier stage, or even the utilization of this type of technology in later stage colorectal cancer. But what about screening and primary prevention of colorectal cancer? What we mean by that is essentially anybody who hasn’t ever been diagnosed with colorectal cancer, we want to prevent those cases. So where can blood based tests really make a difference? We’re going to talk about screening just in general initially, and we’re going to talk about screening rates within the United States, but we’re going to start then to talk about where CtDNA may be appropriate in primary prevention of any cancer. Of course, this includes colorectal cancer, and of course we want to follow up with a discussion about what CIRCULATE-US is in regards to the utilization of CtDNA for stage III colon cancer.

Dr. Christopher Lieu 2:24
So this is going to be a big background that everybody already knows about colorectal cancer, because this group that’s listening to this talk is, – you guys are really the experts, but it is good to go back to the basics and talk about, what is the landscape of the epidemiology to risk factors and screening for colorectal cancer. We know that this is the third most common cancer diagnosed in the United States, and the estimates for the number of colorectal cancer cases in 2022 are over 100,000 new cases of colon cancer and over 40,000 new cases of rectal cancers. So this is a tremendously big problem, and certainly something that this group knows a lot about. And of course, the risk factors for colorectal cancer include risk factors for a lot of cancers, including being overweight or obese, having physical inactivity. A little bit different than a lot of other cancers is this idea that a diet high in red meats, processed meats, or cooking meats at very high temperatures, is a risk factor for colorectal cancer. And of course, these are some foods that a lot of people like a lot. So if you eat barbecue, it is a risk factor for colorectal cancer. This isn’t an announcement to say, “don’t eat barbecue”. But of course, it does mean that we certainly want to limit how many processed meats, or red meats or high cooked or high temperature meats we eat on a daily basis.

Dr. Christopher Lieu 3:41
Smoking and alcohol use are significant risk factors for a lot of different cancers, but of course, we always worry about genetic risk and hereditary genes impacting our ability to develop a colorectal cancer. But this still is a vast minority of cases of colorectal cancer that have a genetic component to it. Familial Adenomatous Polyposis is only 1% of the population. Lynch Syndrome, which is the most common inherited cancer risk profile for colorectal cancer, is only 2 to 4%. So these are some really interesting charts in regards to the incidence of colorectal cancer by age. And so when you look at the population that’s 55 and older, you can see these dramatic decreases in the incidence of colorectal cancer. And this really speaks to the power of primary prevention. This idea that if you screen for colorectal cancer, if you get a colonoscopy and remove polyps, you can really reduce the incidence of colorectal cancer. That’s the big take home message. Of course, this group is also very familiar with the fact of the incidence in our younger population. So what you’re looking at here are graphs from 20 to 49 and you can see this inflection point in the 1980s and the 1990s where the rates of young onset colorectal cancer really started to increase, and then it increased year over year. Many of the people in this group and listening, and certainly the physicians and providers, would tell you that seeing young patients with colorectal cancer is really obviously still devastating, but it’s becoming, unfortunately, more common.

Dr. Christopher Lieu 5:13
Another way to look at this data is to look at colorectal cancer incidence rates by birth cohort, and you can again, see this inflection point that those born 1960 to 65 and then onwards. You can see this incidence increasing. Now I do have to tell you that early onset colorectal cancer is, of course, still rare, but if it increases by 2 or 3% every single year, then you can tell that even though it’s still a rare event, it’s becoming, unfortunately, more frequent. The United States is not the only country documenting an increase in early onset colorectal cancer, and those countries highlighted in red are showing similar trends. So this is a worldwide phenomenon, and not solely restricted to the United States. So the first take home point that everybody here already knows is that the incidence of colorectal cancer, particularly rectal cancer in young patients, is increasing. And this figure that you see here shows the duration of bleeding of having seen blood in the toilet before diagnosis, and this is stratified by the stage of diagnosis. When you look at older adults, the onset of bleeding to diagnosis of cancer is usually about 25 to 28 days. Here, if you look at some of the patients that were diagnosed with stage IV disease, on average, they were waiting over a year between the time that they had their initial symptoms and the time that they were actually diagnosed. And the longer that time takes, the more likely it is that you’re going to have advanced colorectal cancer, as opposed to an early stage colorectal cancer. So how do we prevent colorectal cancer? We don’t always talk a lot about screening as oncologists, because we’re usually taking care of patients after they’ve been diagnosed. But the problem with this is that there’s so many guidelines out there that it can be very confusing in terms of what patients should actually do. But of course, the American Cancer Society several years ago actually was very forward thinking and they actually decreased their age to start colorectal cancer screening from the age of 50 to 45 and I showed you the data as to why they wanted to change that. For people ages 76 to 85 the decision to be screened should be based on a lot of different factors, including how healthy that individual is. And the recommendation is that people over 85 should no longer get colorectal cancer screening.

Dr. Christopher Lieu 7:29
In terms of what tests that people offer, there’s stool-based tests and there’s visual tests. The stool-based tests include looking for blood in the stool, and that’s called a FIT Test or Fecal Immunochemical Test. We have this general fecal occult blood test, and there’s even a stool DNA test, which we’ll talk about. But of course, the gold standard is colonoscopy, because not only can you visually look at the colon, you can also remove polyps that may eventually turn into a cancer. There’s also CT imaging that’s available, and a flexible sigmoidoscopy looks at the first third of the colon, but cannot reach the last two thirds of the colon. The United States Preventative Services Task Force also has guidelines. This is our most conservative guideline group because their expectation for the level of evidence is quite high. So they really, really look at the data and say, well, the data doesn’t support certain screening, then they don’t recommend it. But if it does, then they do recommend it. Their Grade A recommendation is still for adults age 50 to 75, but the big update here in 2021 was a Grade B recommendation for 45 to 49 which means that these patients likely really should be screened. And, the more patients that get screened, the more we can prevent cancer. So your second take-home point: everybody should start screening at age 45 or 10 years before the youngest case in the immediate family. So if a first degree family member was diagnosed at the age of 40, then you would start screening at the age of 30. For patients 76 to 85: just consider the patient’s health. Then a colonoscopy is the gold standard, because it’s preventative and potentially treatable as well.

Dr. Christopher Lieu 9:10
Just a quick note from Dr. George that if you guys have any questions as the presentation comes in, feel free to put it into the chat. In all honesty, feel free to just unmute and ask the question even as I’m speaking. I’d love for this to be as interactive as possible. All right.

Manju George 9:26
Dr Lieu, then I have a question.

Dr. Christopher Lieu 9:28
Sure

Manju George 9:28
So my question is, what about polyps in the family, and how does that affect when you have to screen?

Dr. Christopher Lieu 9:36
So it really depends on the type of polyp. It’s such a great question, because I think that this really gets overlooked. If you have your typical tubular adenoma, and you get those things clipped off, and then the risk of having colorectal cancer, from a familial standpoint, is quite low. There are some times that patients have really, really advanced polyps, basically these polyps that have really high grade dysplasia and you can tell that in the next one or two years, you can tell that that patient is actually going to develop a colorectal cancer. And that’s why it’s actually so critically important to know that if you have a very advanced polyp that has significant malignant potential, we should treat those patients as if they already had a colon cancer. So, kind of complex. It’s certainly one of those things that when you get a colonoscopy, you get a polyp removed, it is good to ask, “Hey, was it a really benign polyp, or was this a really scary looking polyp?” And if it’s a scary looking polyp, then you go and tell your entire family. Great, great, great question!

Manju George 10:32
Okay, thank you.

Dr. Christopher Lieu 10:33
Absolutely! When you look at colorectal cancer screening across the country, there are disparities here. And actually, one of the questions I really wanted to ask the group was, well, what is the biggest predictor of getting colorectal cancer screening? You’ll find the answer as we go through the next several slides. But is it race and ethnicity? Is it income? Is it even geographic distribution? You can tell that your rate of colorectal cancer screening actually differs by by state. So if you’re living in Texas, for instance, then the rates are 62% which is obviously much lower than we want it to be. If you look into northeast: Rhode Island, Massachusetts, New Hampshire, Maine, they have 75 to 76% screening rates. And the goal here is, obviously would be 100% but in all honesty, even having 80% would be really, really, tremendously impactful, and you can see that there’s a difference across the entire country. Well, what about sex? So if you’re male or female, does that make a difference? In here, there’s a little bit of a difference between females and males, but for the most part, it’s relatively the same, and has stayed that way over time. What about age? It does make sense that as you get older, there’s increased use of screening. Maybe there are some other health factors, you’re seeing your doctor more frequently. But it is interesting that as you go from 50 to 64 and then from 65 to 70, there is a pretty significant jump in terms of who’s getting screened. What about race and ethnicity? It’s interesting because I thought that the disparity gap here would be wider. It’s not quite as bad as I thought there would be, but there is a disparity gap, and so even when you look at our Native American population and our Asian population, interestingly, those are some of lower rates of screening compared to some of the other groups that you’re seeing here. But for the most part, there isn’t a huge difference. But what I’ll tell you seems to be the biggest discrepancy, or disparity between colorectal cancer screening and groups is actually your insurance status. And I think that that’s actually one of the big take home points, is that if you’re insured, you’re going to get screened, and if you’re uninsured or underinsured, only half of those patients are actually getting screened. So it does tell you that a lot of these things, you can actually have an impact on. But it is interesting data.

Dr. Christopher Lieu 12:43
All right. Well, what about tumor DNA-based screening approaches for colorectal cancer? We’re here to talk about circulating tumor DNA, and we’re going to talk about — I see the question from Annie about right versus left sided primaries and screening methods. So that’s such a great, great question, and I’m actually going to answer that a little bit later over the course of the talk, because for these tumor DNA-based screening tests, you want to make sure that you can detect cancer on both sides. To go back to visual screening methods like flexible sigmoidoscopy and colonoscopy, if you have a left sided primary you should be able to see it on colonoscopy and flexible sigmoidoscopy, but because flex sigmoidoscopy only really looks at 1/3 of the colon, flex sigmoidoscopy is definitely going to miss the other two thirds, particularly the right side of primaries, because you’re just not looking. But of course, with even with colonoscopy, sometimes you can miss the right side of primaries because either the prep is not very good or, you know, because it’s just harder to get there, and sometimes you can’t even get the scope all the way that far. So the right side is a little bit harder in terms of detecting cancer even with colonoscopy, but colonoscopy is still the best bet to find it.

Dr. Christopher Lieu 13:55
All right, I do want to talk about the first ever DNA test approved for use for screening, and that is a stool-based DNA test. So we talk about circulating tumor DNA, but here we’re actually talking about stool DNA. And what you’re looking at here are the performance metrics between the stool DNA test and fecal immunochemical test, which is basically looking for blood in the stool. You can see across stages the multitarget DNA test does seem better for early stage stage I and II cancer, and then performs about as well for stage III and IV. That question about left versus right is shown on the right side of this graph, and so proximal cancer would be the right side and distal cancer will be on the left side, and then you can kind of see that this test does perform better than than the FIT test. What’s interesting about this is that you can actually even detect pre-cancerous lesions with the stool DNA test. Obviously it’s not as effective in patients with polyps versus cancer. But you can tell that there’s a certain amount of pre-cancerous lesions that the stool DNA test is actually picking up. All right, and that gets us to circulating tumor DNA.

Manju George 15:11
Dr. Lieu? I have a question. So basically, they’re looking for cells from the polyps that are shed into the stool. Is that what they’re looking at?

Dr. Christopher Lieu 15:20
So they’re looking at DNA shed from the polyps into the stool. You imagine that over the course of time, these polyps have some genetic alterations. We know that there’s some early events even like KRAS and RAS and BRAF mutations are kind of earlier events in the development of cancer. But you can actually detect some altered DNA, even in polyps, and you certainly can detect it when there’s a full blown colorectal cancer. So it is interesting that in some of the altered DNA, you can see in some of these higher grade polyps, particularly there’s high grade dysplasia. They are shedding altered DNA that can be picked up by these tests, which is kind of cool, right?

Manju George 16:03
Okay, thank you.

Dr. Christopher Lieu 16:04
Absolutely. I know that you’ve had lectures from Dr. Cohen and Dr. Kopetz in regards to what gets leaked into the bloodstream. When you have a tumor that’s in place, sometimes tumors can shed actual tumor cells that you can pick up and even sequence. They release these things called exosomes into the bloodstream, but when tumors undergo cell lysis, or cell death, they do shed cell-free DNA into the bloodstream. Now the way I always describe this to my patients is that if you have somebody who’s pregnant and you draw their blood, obviously a majority of what you see in the mom’s blood is their own cell-free DNA. These are just cells, normal cells that are just turning over, and there’s release ofDNA into the bloodstream, which gets metabolized by your body fairly quickly. And so that represents a majority of the DNA that floats around in the bloodstream. But a portion of that would be fetal DNA. So you can actually sequence out the baby’s DNA, the DNA from the baby that’s being circulating around the mom, that also gets metabolized very, very quickly. Well, the same thing happens with tumors. So in our patients that have a tumor, a majority of the circulating tumor cell-free DNA in the body is that person’s normal DNA, but there’s a fraction of that that can be circulating tumor DNA, or CtDNA, which can then be sequenced and detected. And that’s really the basis of a lot of the technology that we’re looking at.

Dr. Christopher Lieu 17:39
And certainly, circulating DNA has its advantages. It’s stable – you can actually do mutational testing on it. There are established biomarkers, and it’s a short half life. Why is that important? It’s because a lot of times we get information from tissue, and that just represents one point in time. What’s circulating in the body is happening right at that moment.It gives you this real-time look of what’s happening in the body at that moment. And there’s the potential to do even further genomic characterization from the fragments of DNA that are released into the bloodstream. But of course, the disadvantages are the ones that are critically important, especially when we’re talking about screening for cancer. So not all tumors appear to shed detectable CtDNA. We worry, if a tumor is too small and is not releasing at least enough detectable circulating tumor DNA to capture in the blood, then you may, at that point, not be able to detect CtDNA, even though a patient does actually have cancer. The methodologies for analysis are really complex and expensive andthis idea that you have to filter out a lot of noise. And so part of this is that that noise can even be that as patients age, they develop these mutations that exist usually in their white cells, in their bloodstream, that are not harmful at all and are not precursors for cancer. They’re just these altered mutations that are benign. But we call this clonal hematopoiesis of indeterminate potential, or we call it CHIP for short. And that is that sometimes, as we age, we develop these mutations that exist in some of our cells that are completely benign and have nothing to do with cancer. Well, what if we detect those mutations and say, “Oh, you have cancer”. That would be obviously a real problem. So your take home point, only a fraction of cell-free DNA is circulating tumor DNA, but CtDNA may provide a real time look at what is happening in the body.

Dr. Christopher Lieu 19:33
And so there’s a couple of points as we kind of go into this idea of utilizing a test to detect cancer for the first time. One of the things that people ask is, “Well, why don’t we just use CEA?”. CEA is a blood test, and a protein that we look for in patients with colorectal cancer. And sometimes we can trend CEA to determine if a cancer is getting better or getting worse. But a CtDNA is better than CEA. What you’re looking at here is CtDNA versus CEA positivity in different stages of cancer. What I want to show you is that, particularly in earlier stage colorectal cancer, CtDNA definitely outperforms CEA. You can see that with CtDNA being on the left and CEA being on the right. You can see that CEA isnegative in a lot of patients that actually have cancer, whereas when you look at CtDNA for stage II and stage III colorectal cancer in particular, it’s almost never negative. Which means that when it’s positive, there’s definitely cancer there.

Dr. Christopher Lieu 20:41
I want to talk about two tests that are currently under investigation. One is colorectal cancer specific, and one is just looking for cancer, period. There are companies that are certainly developing both of these right now. So this is a multimodal circulating tumor DNA test looking at the primary detection of colorectal cancer. This is called a LUNAR-2 assay. Essentially what both of these tests are doing is they are looking at something called DNA methylation. And aberrant methylation signals in tumor, versus benign tissues, are different. Therefore, if you see this methylated DNA, you might be able to detect cancer earlier. And this is the test case: There were 434 cases, 271 controls, and this is the distribution by age in the controls and in colorectal cancer. Really what I want to show you is essentially this slide. What you’re seeing here is the overall sensitivity for this assay for patients with colorectal cancer or without colorectal cancer. You can tell that the overall sensitivity is unbelievably high: 91%. In the age cohort 45 to 84 which is traditionally the group that we’re looking at to detect colorectal cancer, it’s 90%. You’re seeing this high sensitivity across stages: stage I and II, stage III. Specificity is this idea that if you detect cancer and if the test is positive and you do have cancer, what is the accuracy there? And it’s 94%. So the key here is that again, across stages, it’s a really, really highly sensitive test. That’s what you want in any good screening test. Then this question of left sided versus right sided, it’s actually detecting cancers pretty well, maybe even slightly better on the right side versus the left side. And then transverse, there are not as many cases. There are only 17 cases of colorectal cancer, but it was 82% sensitive in that case. So a really, really interesting test, and I think this is really interesting early data. What they did was, – the company, Guardant – has a trial where they enrolled 12,750 patients to detect colorectal cancer, and we’re hoping to get data in the middle of this year. We’ll find out what the performance of this LUNAR-2 blood test is in the individuals that would normally be screened for colorectal cancer, and we’re going to see how good of a test this is. But can you imagine, drawing a blood test to screen for colorectal cancer, as opposed to potentially either putting in for a stool sample or undergoing a flexible sigmoidoscopy or a full on colonoscopy. So, very, very interesting, and we’ll see what the data is as they as they come out later this year.

Dr. Christopher Lieu 23:39
All right. So we talked about colorectal cancer. I just want to briefly touch on a multi-cancer early detection test, and this idea that can you utilize the same technology that we were just talking about, but look for all cancers. So imagine a blood test to be able to detect any cancer, and obviously, hopefully at an early stage. We had talked a little bit about this before, but this focus on DNA methylation. The idea is to have a low false positive rate, and we call that “high specificity”. And this idea that if you have a lot of coverage over these methylated regions, not only would you be able to detect cancer, but if different cancer sites have a unique methylation pattern, then you could at least tell somebody, “Well, you may have cancer. We have no idea where it’s coming from”. You might be able to point people towards, “Well, this fingerprint is more suggestive of lung cancer or pancreas cancer or colorectal cancer”. And that’s what this really complex figure basically shows you, is that you can draw somebody’s blood, look at the DNA methylation, and then what they’re really trying to figure out is that, is there a tissue specific methylation fingerprint where a specific methylation pattern might tell somebody, well, we really need to look for lung cancer or liver cancer or colorectal cancer. Because, you can imagine as a primary care provider, if you just get this test back that says, “Oh, we think you have cancer”. That’s not only incredibly anxiety inducing from the patient’s standpoint, it’s also incredibly anxiety inducing from the physician’s standpoint, because then, what do you do? Do you do a colonoscopy? Do you do a full body CT scan? So you can see some risk involved with these tests as well.

Dr. Christopher Lieu 25:29
This is a 15,000 participant study at 142 sites, and essentially what they had was a discovery group and a validation group. Essentially they wanted to see if the test could potentially work in a smaller group of patients, and then look at a bigger group of patients. These patients, some of them had cancer, some of them didn’t have cancer. What this test shows you is two take-home messages. Number one, the sensitivity is not great. It’s 51.5% which means in patients that had cancer, sometimes the test was positive, sometimes the test was negative. The other take home point is that it was a highly specific test, which means that in patients that didn’t have cancer, if the test was negative, they really didn’t have cancer. And there are very, very few false positives, in other words, where the test was positive, but they did not have cancer. So it meant that basically, the test was negative. There’s an incredibly high chance that they didn’t have cancer, and that’s obviously a good thing, but the sensitivity rates across diseases, range very, very differently. So you can clearly tell on the left side of this graph that this test is not a great test for prostate cancer. 11% sensitivity. That is definitely not ready for prime time.

Dr. Christopher Lieu 26:48
Well, what about colorectal cancer? Here the sensitivity is quite good, 82%. And then if you go into liver cancer or even carcinoma of unknown primary, there the sensitivity is 93 to 94% so it’s a big spread. So I would say the data is very promising towards the right side of this graph. Very not promising on the left side of this graph. And I think the main question that you have to ask is, well, will the technology get better? Can we get all of these sensitivity rates really, really high? So again, this is colorectal cancer sensitivity looking at stage I through stage IV. It’s clear that as you go higher in stage that the ability of this test to detect cancer goes up significantly. It always seems like these tests have a harder time with stage I, but the moment you get to stage II and III and IV, it gets actually quite good. I wanted to show you that detection of other GI malignancies. There’s really one take home message, and that is, for all these GI malignancies, it doesn’t do great for stage I, but as you get further into the stages, it does quite a good job of being able to pick up the detection of cancer. But again, the main question that you want to answer is, can this test save lives? We’ll say, additional studies are needed. I think you’re going to see this technology really change the way healthcare is delivered in the future. Right now the question is, is it ready for prime time? And I would say we don’t really know the answer to that quite yet. All right.

Manju George 28:19
Dr. Lieu, I had a question. So, Exact Sciences had a large trial. Is that more like a multi-cancer, or is it more like the Guardant Health?

Dr. Christopher Lieu 28:29
Yeah, so Colvera is really focused predominantly on CRC, although I know that they have data on other cancers as well. It’s interesting, because a lot of these tests that I’m showing you are casting this really, really wide net. Colvera is very interesting in the sense that they’re really looking at two genes. But they found that those two genes really do a great job of predicting for colorectal cancer. So, a little bit different, but dissimilar technology.

Manju George 28:54
Okay, thank you.

Dr. Christopher Lieu 28:55
Absolutely. I’ll just wrap up on this with the last five minutes, because, well, we talked about primary prevention of colorectal cancer. We talked about screening. Well, what about in patients that do have colorectal cancer? What happens to CtDNA in those patients, either postoperatively after surgery, but even during adjuvant chemotherapy? What happens to CtDNA? Does it go up? Does it go down? Does it become detectable? Does it become undetectable? We call that CtDNA kinetics. I just want to show you data from the Japanese group. This is their GALAXY study where they’re utilizing CtDNA, and it’s really interesting data. What this shows you is that postoperatively all the way to 12 weeks, if you’re negative and stay negative, you’re going to do great. That’s the black line. And what you’re looking at here is disease-free survival. Basically, nobody’s recurring, right? So that’s good. Interestingly, if you’re CtDNA positive post operatively, and then you turn negative, that’s almost as good as just being negative from the get-go. So that’s interesting. If you’re CtDNA positive postoperatively, you’re freaking out. – I’m worried, you’re worried. But if you turn negative, then your prognosis is quite good. If you’re negative and then turn positive, then there’s a pretty high rate of recurrence. And if you’re positive and stay positive, these are the patients that here, you’re looking at almost 70 to 80% of those patients recurring even within one year’s time.

Dr. Christopher Lieu 30:25
And I do want to show you that adjuvant chemotherapy can clear CtDNA. Interestingly, there is a 10% clearance rate by doing nothing and it makes you wonder what’s going on in those patients. Are those patients just clearing it due to their immune system? But interestingly, there is a significant rate of patients that even if they’re CtDNA positive, they receive adjuvant chemotherapy, they can clear it. We also know that if in patients that are CtDNA positive and they receive adjuvant chemotherapy, that they do better. And so that’s what you’re seeing in stage II, stage III and stage IV. That if there’s CtDNA postoperatively, and they receive chemotherapy, that their recurrence rates are significantly less. So the real question that everybody in this group wants to answer is, are the findings of this test, which is very, very cool, but is it actionable? Because that’s how we’re going to save lives.

Dr. Christopher Lieu 31:20
So what do we know so far? If CtDNA is positive, the recurrence risk is extremely high. That makes sense. If we detect tumor DNA in the bloodstream, it means cancer is there, and it means that at some point it’s going to show up on a CT scan. If CtDNA can be cleared, in other words, with adjuvant therapy, then disease-free survival is significantly improved, and we know that adjuvant chemotherapy can clear CtDNA. And we also know that if CtDNA is not detected, and it’s not detected over multiple time points, we also know that those patients are going to do incredibly well. This is the overall problem with stage III colorectal cancer, and that is that we’re treating 10 patients with with stage III colorectal cancer to save 2 to 3. I’m going to go through that. Why is that? In 10 patients that have stage III colorectal cancer, 5 of them are essentially cured with surgery. They never needed chemotherapy. In other words, they’re getting treatment even though they never needed treatment because they were cured. There are 2 or 3 that get treated with adjuvant chemotherapy who relapse anyway, which means that we didn’t help them with adjuvant chemotherapy. They were going to have recurrence whether we gave them chemotherapy or not. So we almost gave them chemotherapy needlessly. So essentially, we treat 10 patients to save 2 to 3, which means that we basically treat 7 to 8 patients needlessly with chemotherapy, either because they’re going to be cured or because they’re going to recur regardless.

Dr. Christopher Lieu 32:45
The idea is, maybe CT DNA can tell us who we don’t need to treat, and maybe we can tell with CtDNA who needs to be treated even more aggressively. I want to highlight this study, because this study is now open to enrollment and it’s going to be open up across the entirety of the United States. Essentially the way this trial is designed is that if you have stage III colon cancer and you have no CtDNA detected post operatively, you are then randomized to receive standard of care chemotherapy, which is what we normally do, or surveillance without chemotherapy, with serial CtDNA checks. If you’re negative CtDNA and stay negative, you never get chemotherapy. But if you’re negative, and then turn positive, at that point, you get chemotherapy. You get randomized to either receive standard of care chemotherapy or an escalation of chemotherapy, where we try a three-drug regimen versus a two-drug regimen. We do this because we’re worried that our patients have a poor prognosis when CtDNA is detected. Postoperatively, if you are CtDNA detected from the get-go, you undergo that randomization: either the standard of care chemo, or this triplet combination which represents an escalation of chemotherapy.

Dr. Christopher Lieu 34:00
And so the real question is, is CtDNA ready for prime time? I would say, in terms of identifying alterations in the bloodstream, that it is ready for prime time. But what we’re really trying to answer is, this bottom one. In terms of the detection of minimal residual disease, this presence of cancer, even though we can’t see it on a CT scan. The answer is possibly. Is it ready for prime time? It’s clear that CtDNA can detect cancer, but are the results actionable? And so the idea being, we know that this is an incredibly prognostic tool. It can tell us whether somebody’s going to recur or not, and we know that getting serial testing helps, but will it alter clinical practice? What happens if you get a positive result? Do you increase surveillance? We don’t know the answer to that. Will these tests save lives? So in other words, will a clinical trial like CIRCULATE-US end up showing good data in terms of well, can we use this test to determine who should and shouldn’t get chemotherapy? Can we use this test to determine who needs more chemotherapy? I’m hopeful that we’ll get the answer to that as time goes on.

Dr. Christopher Lieu 35:11
So I know that’s a lot of information in a short amount of time, but happy to – , I know Manju, you had to step aside for a little bit, but wanted to see if you guys had any questions? I see Julie has a question, can you talk a little bit little more about patient selection in CIRCULATE for stage II? Yep. So, I was trying to keep it a little bit simpler, but Julie’s asking a really, really great question, and that is the trial enrolls lower risk stage III, so if you don’t have a ton of lymph nodes involved. But there is this thing called high risk stage III, if the tumor is aggressively moving into other organs, or if a lot of lymph nodes are involved. There is also high risk stage II, where there are features of the tumor that are really concerning for the clinicians, and that’s usually related to how angry it looks under a microscope, or that tumor is actually invading into other organs. You can actually enroll into CIRCULATE if you get outside testing and that test is positive for CtDNA. You can actually enroll into the CtDNA-positive arm. We just want to give those patients the ability to have a chance of getting more aggressive chemotherapy. So if you’re high risk stage II colon cancer, or high risk stage III colon cancer, you don’t traditionally enroll into CIRCULATE, but if you have outside testing that you got as standard of care and you’re positive, then you can enroll. Annie’s asking, “The trial is only in this location in NRG?” Yes. So essentially my hope is that it’ll be open at more than 400 sites across the country. This is a collaborative effort between all the cooperative groups, which includes NRG, so this trial should, honestly, it should really be open within, my hope is 30 miles from every patient, but the reality of it is that it should be open in every state and in most, if not all, major cities.

Julie Clauer 37:13
So in terms of, you know, we have a lot of patients that come into COLONTOWN who would qualify for CIRCULATE-US, but they’re not necessarily looking at clinical trials at that point, because, they’re not high stage. They’re just recently diagnosed. Can you talk about what that conversation could be in terms of, how do they talk to their doctor, about, “Hey, I heard about this trial. What is it? Is it interesting?” Because the timing is, they might be post-surgery, but pre-adjuvant chemo, and so that’s good timing. So talk a little bit more about that, just because it seems like a quick turnaround has to happen, but it’s not necessarily people that are poised to have that quick conversation.

Dr. Christopher Lieu 37:58
So yeah, I think the timing of this is the most challenging part of the trial, and that is this idea that, if most people get seen by medical oncologists, usually a decent amount of weeks after their surgery. Capturing these patients early and getting CtDNA testing so it can inform which arm of this trial you go on is critically important. And so, I think where COLONTOWN and PALTOWN have been amazing is number one, it’s a resource. People are told they have colon cancer, and obviously, understandably, they’re freaking out. So I think the information that’s provided on COLONTOWN University is absolutely incredible. And then honestly, the earlier you can have the conversation, the better. So even before surgery, asking about it, “Is it available? Can I talk to somebody about it?” would be huge, because then everybody knows as soon as surgery is done, that they’re going to start thinking about the study, and they’ll know whether or not it’s even available at their site, or if there’s a practice closer, or within close proximity that they can enroll in. And so I think, honestly, COLONTOWN will find patients way before medical oncologists will. I think just getting the word out would be really cool, because I think, – but it’s a tough conversation, because people are just now getting introduced to this technology, and then they’re talking about clinical trials, and it’s a complex clinical trial. So having that information available and even people to talk to, I think, makes all the difference in the world for our patients but, can also help with a clinical trial accrual.

Julie Clauer 39:41
So let’s say it is available at their location. Would they connect then to the PI, or would they have CtDNA done before?

Dr. Christopher Lieu 39:54
Yeah, so I honestly would connect either through ClinicalTrials.gov, which would show the sites. Honestly, the easiest way to find clinical trials, and this is just in general, is to really ask the doctors in that area to see if, –because if they don’t have CIRCULATE open, I’m sure that they’ll actually know who does. But then also contacting the PI even like Dr. Dasari or myself, is always, I think, easy, because we’ll happily direct people to the right place.

Julie Clauer 40:26
Great, thanks.

Dr. Christopher Lieu 40:29
And then, can either a Signatera or Reveal test qualify for high risk stage II? It’ll need to be a Signatera test.

Julie Clauer 40:37
I have an unrelated question, but it drives me nuts. So now we have a lot of awesome tools that are using blood tests, like, you can get your biomarkers from a liquid biopsy, you have CtDNA to detect whether you have cancer, whether you have MRD, but it gets really confusing in terms of what to call these tests if you don’t call them by the brand name. So it’s like trying to explain to a patient like, “Oh, no that’s a liquid biopsy, but it’s a different liquid biopsy than the one…”. So is there an easy terminology of what to call these different tests? Because you say a CtDNA test, and some doctors still don’t necessarily differentiate between the different tests. So anything that can help on that end, because it gets super confusing.

Dr. Christopher Lieu 41:25
Absolutely, I think we’re all learning this new terminology, right? And I would say whenever you’re talking about: ‘is there cancer or not’, we should just call those MRD tests or minimal residual disease tests, that’s probably the easiest way. And if we’re looking for mutations in patients with stage IV cancer, we’re just basically looking for – we wouldn’t call those MRD tests or minimal residual disease tests, we would call them, I think maybe the easiest way to describe it is almost like a liquid biopsy to look for mutations. That’s essentially what you’re doing. And so I think the easiest way to kind of think about is, hey, if it’s trying to determine whether cancer is present or not, MRD is probably the way to go. And then the question, is this for rectal? Well, so CIRCULATE-US is only for colon cancer. Rectal cancer is a little bit tough, because a lot of times patients are getting a lot of therapy even before surgery. In fact, they’re getting almost all their adjuvant therapy before surgery. So this study is only for colon cancer, but these assays can be used for rectal cancer as well as colon cancer. And then Annie mentioned that for those over 70 with a high immunoscore. Yeah. The question is, is it only CtDNA? Could it be a combination of immunoscore and CtDNA? And I would love to see those collaborations in the future, because it may not just be “it’s one test to rule them all”. Maybe it’s a combination of different factors to help us make these determinations. But we’re starting with CtDNA, and then we’ll have to look how immunoscore may be added to this to help our decision making.

Julie Clauer 43:03
In terms of sensitivity. So we know this sensitivity is really high for for MRD tests, but there seems to be some things that tend to be more questionable, right? So lung mets, or maybe, the location of mets, if you’re stage IV. And I know we’re not necessarily talking about it in terms of stage IV, but a lot of patients are doing it or age or things like that. So is there any kind of good understanding of where, within colorectal cancer, how the sensitivity changes by either location of tumors or age or other facors?

Dr. Christopher Lieu 43:39
Yeah, we had talked about the age and the fact that sometimes patients have mutations that don’t have anything to do with cancer, so that can be a confounder that we have to be very careful about. But then, this idea that maybe we’re missing small lung metastases or peritoneal metastases, where they’re in the lining of the abdomen, I think that’s what keeps us up at night, right? And this idea that, are we going to miss patients that may benefit from chemotherapy? Are we just going to miss patients period that have cancer and we just can’t detect it? I think we mitigate some of that by having serial testing. Testing that’s done over the course of time. And so if patients are negative and they stay negative, that’s good. If they’re negative and they turn positive, that’s what we worry about. But I think that therein lies the risk. We want these tests to be perfect, but no test ever is. And so the question being, is it good enough? And that’s what we’re trying to answer. And then the testing is on site. I think for the study, they’ll get collected by the teams, and then they’ll be sent off, but oftentimes, these companies do offer at home blood draws.

Julie Clauer 43:42
It is very compelling, for patients from a trial perspective, and is in terms of cost. All those testing costs would be covered as part of the trial.

Dr. Christopher Lieu 45:00
That’s correct. Great question, Julie, that’s correct.

Manju George 45:04
This is about CHIP. So a test such as Signatera, you don’t have to worry about CHIP, right?

Dr. Christopher Lieu 45:11
Yeah, because it’s a personalized assay, and this idea of testing it, getting a personalized assay developed off of that really does help us with a sensitivity. It really does.

Manju George 45:26
Okay, thank you.

Dr. Christopher Lieu 45:28
Guys, thank you so much for taking the time. These are phenomenal questions and you guys are way more informed than even some of our practitioners. It is so fun to talk to you guys, and you guys are asking all the right questions, and really appreciate your interest in this, and hopefully patients will enroll, and they’ll find it interesting. The hope is that we’re going to change the way we treat stage III colon cancer. That is the hope. But at the least, at the very least, we’re going to learn a lot, and we’ll do better, and we’ll be better. So thank you guys. Really appreciate it.

Manju George 46:03
I want to say that we will have the CIRCULATE-US as a feature trial in COLONTOWN University, and our hope is that patients in COLONTOWN are, in general CRC caregivers and the patients in the public will be able to access it and find more information. The video of this talk will also be linked there, so we are hoping that this will be a great educational resource for everyone involved. Dr Lieu, thank you so much for your time, this is excellent.

Dr. Christopher Lieu 46:32
Thank you everybody. Have a wonderful day.

Manju George 46:35
Thanks everyone for attending. Take care.

Dr. Christopher Lieu 46:38
Bye bye.

Manju George 46:38
Bye

DocTalk

2022

Dr. Kopetz

KRAS

Dr. Scott Kopetz from MD Anderson discusses the latest KRAS-directed therapies for colorectal cancer with Paltown Scientific Director Dr. Manju George. Recorded in April 2022.

Table of contents

HERKULES-3 trial for BRAF and RAS

DocTalk

2022

Dr. Lee

BRAF

KRAS

MSS

Stage IV

Trials

Dr. Michael Lee of MD Anderson discusses the HERKULES-3 clinical trial for BRAF and RAS-mutated GI cancers. Recorded in December, 2021.

Transcript

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Steve Schwarze 42:38
Thank you. Bye bye.

DocTalk

2021

Dr. Lee

BRAF

KRAS

MSS

Stage IV

Trials

Dr. Michael Lee of MD Anderson discusses the HERKULES-3 clinical trial for BRAF and RAS-mutated GI cancers. Recorded in December, 2021.

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