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AllyCon 2020: Advances in Precision Treatment and Therapies for Colorectal Cancer

Jun 09, 2021
Well, it's a real pleasure for me to be here today to talk about one of my favorite topics, which is how we're advancing immunotherapy for our

colorectal

cancer

patients, and over the next hour I think we'll be talking about a lot of things. of really interesting areas of research for new

treatment

s for patients, but I'm really excited to be able to talk about immunotherapy in particular, so these are my revelations and as we get started, I think one of the first things I want to emphasize is that Immunotherapy is actually not just a thing in the last five to seven years.
allycon 2020 advances in precision treatment and therapies for colorectal cancer
Immunotherapy has become synonymous with a group of drugs called pd-1 inhibitors, which are drugs that we give to stimulate immune cells, but that's just one class of drugs that immunotherapy can also. Being a vaccine-based therapy, we are giving people cytokines, which are proteins that our body produces that stimulate the immune system, we are administering them to patients to stimulate people's immune system, we can actually administer immune cells as an infusion to patients. I mean, your own immune cells that we activate or other people's immune cells or genetically modified immune cells, there's a lot of things we're doing as far as immunotherapy goes.
allycon 2020 advances in precision treatment and therapies for colorectal cancer

More Interesting Facts About,

allycon 2020 advances in precision treatment and therapies for colorectal cancer...

Today we are going to talk predominantly about pd-1 therapy because it is the most advanced. When we talk about this class of drugs, I just want to mention that there are many different areas that are very interesting when it comes to using the immune system against

cancer

and similarly, colon cancer is not just a disease and we all know that. . Everyone's cancer is different, but what I want to emphasize when it comes to immunotherapy is that there are actually two large groups of cancer when it comes to

colorectal

cancer that act very differently when we think about the immune response to some of these. medicines. a small cube of five percent of metastatic cancer patients and that group of people are called microsatellite unstable or msi high cancers and again that's only five percent of patients, but in that group of patients the DNA in their tumor is actually unstable, that's what msi means and because of that, a lot of mutations are generated, so an msi high cancer will have hundreds of mutations, while an mss or microsatellite stable cancer will actually only have a couple of dozens of mutations and each mutation is one more opportunity for the immune system to recognize that that cancer cell is different from the rest of its cells and because of that, cancers with high msi have been shown to be sensitive to immunotherapy and, in particular, what I'm talking about is pd-1 therapy, so pd-1 drugs are drugs that were first tested about a decade ago and you can think of pd-1 drugs as a disruption in the immune system, so what pd1 when it is on one cell and it binds to a pdl1 receptor on the other cell which disables the immune system. system is a break and so the pd-1 inhibitors are basically lifting off that break and so your immune system can actually attack the cancer now at the highest msi cancers that we have shown and this is a work that came out of Johns Hopkins from some of my friends and colleagues, dr. lee and dr. diaz, they say that pd-1 drugs are exquisitely sensitive when it comes to patients who have msi high disease and can receive pd-1 therapy, so these drugs and specifically pembrolizumab and now nevolumab are just cousins ​​to each other, They are now approved for colon cancer patients with high msi, but they are approved for people who have already had metastatic disease and have already received chemotherapy, but this year we have a new immunotherapy approval for colon cancer, so this was a really exciting piece of work that came out earlier this year and it was a trial that was again done by a similar group of people led by Dr.
allycon 2020 advances in precision treatment and therapies for colorectal cancer
Diaz and this is the 177th lead study so it was reported just a few months ago and it was again msi. tall people, that five percent of patients with metastatic disease, but now these patients had never received chemotherapy before, so they were diagnosed with a new diagnosis of metastatic cancer and they were randomly assigned to receive immunotherapy, which is pembrolizumab, or receive chemotherapy with our standard chemotherapy options and they followed these patients and what they found that they just reported is that the people who received the immunotherapy, which is this teal curve here, did much better in terms of how long it was controlled their disease, we call that progression-free survival, so progression-free survival: the time a person can receive

treatment

before their disease progresses was significantly longer than those who received chemotherapy, which is this brown line and even at the two year mark, half of the patients were still on that treatment and had none. growth of your cancer, really interesting data.
allycon 2020 advances in precision treatment and therapies for colorectal cancer
This is what we call a waterfall chart and each of these bars represents a single patient and when the bar goes down it means that the tumor is shrinking and what you can see is that there is significantly more tumor. reduction for patients who received pembrolizumab than patients who received chemotherapy and if they had tumor shrinkage, this is how long it lasted even at two years. 83 of the people still maintained disease control and reduction, so there is really interesting data and this has led the FDA to now approve pembrolizumab in the first line for our patients with high msi and metastatic disease, but I don't want to forget the biggest problem that we're facing right now when it comes to immunotherapy and colon cancer and those are our other 95 patients who have microsatellite stable disease or mss, so that's what the whole colorectal cancer immune apparatus is working on now, what can we do to that mss patients make immunotherapy work, so I have included this very complicated number.
Actually, just to be able to talk about the complexity of what we're dealing with when it comes to generating an immune response in colorectal cancer, what you see is a cluster on the right versus the left of the many proteins, genes and substances different chemistries. that our body secretes that both activate the immune system or interact and depress the immune system and we even have factors that are on both sides of this because depending on the context the same protein can sometimes be good or sometimes bad when it comes to immunotherapy. Working like this shows how complicated the situation is and why we might really need something in combination to be able to overcome a lot of this complexity and one of the big areas that people are looking at is combining immunological drugs with drugs specifically targeting abnormalities. proteins in colon cancer and this could be particularly beneficial for patients who have a certain molecular mutation in the tumor DNA, for example, about seven percent of colon cancer have mutations in b raf, so my colleagues of the Harvard institutions, dr. corcoran, dr. parikh and colleagues have actually investigated the idea of ​​taking patients who have braf mutations, giving them a drug, a braf inhibitor that inhibits it, along with a mechanistic inhibitor, which is another class of drugs that works for those patients, and combine it with immunotherapy, which is pd. -1 drug that we have been talking about and here on the right I want to show you what we look at as scientists when we try to figure out what we should advance in patients, so this is a graph that shows tumors implanted in mice and these tumors had this braf mutation and the black line here shows what happens when the tumor is allowed to grow uncontrollably, but the other lines, especially the blue line here at the bottom, show how the tumor growth stops completely. when you are given a braf inhibitor in combination with a pd-1 inhibitor and a mech inhibitor and this type of data is what forces us to say "hey, let's go ahead and try this in patients," so the group of dr. corcoran did exactly that and they have enrolled a braf mutation positive study for patients with this mutation with that triplet of an immunotherapy drug and two targeted drugs, a b rap inhibitor and a mech inhibitor, and what they show is also quite compelling, this really early data only a handful of patients are right 21 patients have been enrolled, but this is the same type of waterfall graph that shows many patients who are experiencing tumor shrinkage or even some reduction or stabilization of the disease as they receive this type of strategy and here on the right, this is just one more way we show data where we show how long people stay in treatment, so this is the number of days and weeks that a person stays in treatment.
Each bar represents a patient and you can see that many of these patients stay on treatment for an average of about six months and that average means that many patients are doing better than they were at six months in terms of their disease doing well. with this treatment. I'm also a fan of this another example of a combination approach to immunotherapy. I'm a fan of it because it's something that we're postulating here at Johns Hopkins and again, why did we decide to take this particular approach of trying to combine a pd1 inhibitor with a drug called a pi3 kinase inhibitor?
Now pi3 kinase is a mutation that is present in about 15 to 20 cases of colon cancer and So a collaborator in Dr. Collins' lab looked at: could we predict what mutations that patients have could predict that they will be more resistant or more sensitive to immunotherapy? So again we took a group of mice and implanted tumors that have multiple mutations and then I looked at those mice and those tumors and we scored each mutation, that's what this graph shows and each mutation that had a pi3 kinase actually seemed more resistant to immunotherapy than other tumors and then dr.
Collins goes back to the lab and treats those mutations with a combination of a pi3 kinase inhibitor and a pd-1 inhibitor, and when treated without the pi3 kinase inhibitor here on the left, these tumors grow, the inhibitor The PD-1 is totally resistant, that's what the red line is, but here on the right. when you combine them with a pi3 kinase inhibitor and an immunotherapy drug, now the tumors do not grow, so, based on this, we are advancing a clinical trial for patients who have pi3 kinase mutations, giving them the inhibitor of pi3 kinase copanla sib with nivolumab, which is one of the pd-1 inhibitors, just a different company than pembrolizumab, but this is an interesting trial that we hope to report next year.
Now there are other groups that are really excited about the idea of ​​using radiation to activate the immune system and the immune system. The idea here is that if you hit a cancer cell with radiation and rupture it, the inside of a cancer cell will spill out and the inside of a cancer cell are things that the immune system has not seen because it has been kept inside the cell and now These are the cells The immune system here, the dendritic cells and the T cells. Now those cells will recognize these internal components and they will activate, so more radiation is used because it opens up and allows the immune system to activate against the cancer, which is why this clinical trial led by Ted Hong, a radiation oncologist, has also been really exciting in terms of the data that has been shown looking at nivolumab and ippylumimab.
Both are immunotherapy drugs. Patients received six weeks of treatment and then received low doses of radiation again just to activate the immune system and then continued receiving immunotherapy. Then they saw some patients who had real responses, some tumor shrinkage that was durable for these patients, but the challenge in their trial was that for six weeks the patients received immunotherapy alone and we know that immunotherapy with these immune checkpoints by alone does not work in MSS colon cancer, so many patients left the study before they could receive radiation, so these were 13 of the patients who did not. we can get the immune system and receive the radiation, so it really compromises our ability to know because we have fewer numbers and now they are going to enroll more patients where they will receive the radiation from the beginning.
I'm very excited to get those results. where we can treat more patients with that type of strategy, the people who got answers really had a lot of time to be able to get their disease under control, as you can see here. The most signs show people who are still on treatment at the time this was reported,It's pretty interesting, a small group of patients, but I'm hopeful that with a larger study we'll see more and finally, before we wrap up, I really wanted to highlight some interesting vaccine-based approaches that have been advancing and really the idea. is: can we make a personalized cancer vaccine for a specific patient?
How do we select the right components to put in the vaccine? And so my colleague, Dr. Zeity, who will be on a panel in just a few minutes, has really been working on this concept in a way that I think is really exciting, so what she's proposing is to do a biopsy of a tumor, sequence that tumor to find out what mutations it has in the DNA. Look at the RNA, which is the part. of it which converts it into proteins and then a computer algorithm is used to predict which of the mutations in that tumor will be most likely to stimulate the immune system because some mutations are more likely to stimulate the immune system than others simply because of the way in which that mutation actually has that sequence and then a vaccine is created made from the mutations that are most likely to generate an immune response, and this was done in melanoma and they were able to show that when you create a personalized mutation it vaccinates the tumor of a patient that each of these small dots that you see here on the right represents a population of immune cells that is activated against one of these mutations and that is why it worked in melanoma.
Can we make it work in colon cancer and colon cancer? So this is Dr. Zaidi who you're going to meet very soon and she used a pancreas cancer model to show in the lab that this could be done, she sequenced a pancreatic cancer model and found that these 12 mutations were most likely to lead to an immune response and then created a vaccine and vaccinated the mice first, implanted them with the tumor and then they were vaccinated with this personalized vaccine along with immune checkpoint inhibition and here in purple what you see is when you receive the vaccine alone, That was not enough for the mice to have the tumors controlled, but when you started adding immunotherapy in each line.
Here it represents a mouse and a tumor. Now we're starting to see a reduction in those tumors and that increased when we added more immunotherapy, so this has been the backdrop for us to move forward with a trial that will start next year and hopefully in the year after that. three to four months where patients who have new metastatic colon cancer will receive a biopsy, we will sequence those biopsies, predict which mutations are most likely to generate an immune response, and generate a vaccine for that patient's tumor while the patient continues to receive their standard chemotherapy and after about four months, once your tumor is stable and we have a vaccine in hand, we will vaccinate patients with a personalized vaccine along with an immune checkpoint inhibition such as a pd-1 inhibitor, for example. what this trial is approved and We are in the final steps to optimize our process to manufacture the vaccine.
I'm very excited to move forward with this early next year. Dr. Zaidi has also activated a trial that we have been working on together to look for a k-ras vaccine and therefore forty percent of colon cancer has a mutation in k-ras. The doctor. zaidi has created a vaccine that, based on the six most common kras mutations, the vaccine is the same, so it is a commercially available vaccine, which means that each vaccine is identical, but it is only given to people who They have one of these six mutations and what we are doing is using this to help patients keep their cancer from coming back after they have had surgery, so in this setting the patients have already had their tumor removed, but they have a high risk of recurrence, this would be a patient who has had a metastatic tumor removed or has a lot of lymph nodes involved, so after they finish their chemotherapy, they will go ahead and receive this k ras vaccine in combination with nivolumab and ibulumimab. what are the immune checkpoint inhibitors and this will happen over the course of a year so they will receive vaccines and immunotherapy for a year and our goal is to show that they do not have any recurrence after that and so on with that.
I'm going to conclude, I hope I've shown you that, while we have a lot of complexity in dealing with the cancer that we have and trying to generate an immune response, there are a lot of interesting approaches that are being carried out right now and the most important thing is is that everyone who has the opportunity should look at clinical trials from the beginning and should do it frequently because we have many different strategies to try and the more patients who participate, the better chance we have of achieving it. Hopefully, we can find not just one, but multiple approaches that may work for patients.
Thank you very much and next we will have a really interesting panel on what's next in personalized therapy for patients with moderate colorectal cancer by Dr. Chloe Atreya from UCSF. Good morning and thanks. everyone for joining us I'm Dr. Chloe Atreya, associate professor at the University of California at San Francisco Helen Diller Family Camp Comprehensive Cancer Center uh in the gastrointestinal enterology group um gastrointestinal oncology group sorry, I'm moderating our first panel discussion on the What's new in personalization therapy and review recent innovations in biomarker therapy, including k-ras b-raf and general

precision

services. I'll start today with dr. niha zaidi, physician, scientist and medical oncologist at the sydney kimmel comprehensive cancer center at johns hopkins.
Thank you very much for joining us. Dr. Zadie and tell me what some of the recent

advances

are in

precision

immunotherapy for common mutations in colorectal cancers like chaoras. Thank you, Dr. Atreya, for the introduction. It is my pleasure to talk to you today about new precision approaches to targeting mutated k-ras. So what we know and what we've learned over the last two decades, although k-rest mutations have been known for a long time, is that k-ras are really drivers of cancer growth and mutations and k-rests They are drivers. of cancer growth and are really critical for cancer cells to grow and survive in colorectal cancer specifically, they are present in about 45 percent of colorectal cancer cases and generally in patients with advanced colorectal cancer.
Mutations in krafts confer a worse prognosis and resistance to treatment. standard chemo

therapies

and that is why really novel treatment approaches are desperately needed for this subset of colorectal cancers that have a qrs mutation and not only that, but we have also learned in the last 15 years or so that the presence of k-ras mutations It actually affects the treatment options that we, as medical oncologists, have to offer our patients and it has now become standard practice to test for k ras mutations along with similar types of b rath mutations, of which you will hear later and it is a standard of care. redo this test in patients with advanced disease and this is because certain k-ras mutations in patients with advanced disease do not respond well to a class of drugs that are commonly used in metastatic colorectal cancer and these are anti- egfr, so no Qs only tells us a little about the prognosis in patients with advanced cancer, but it also helps us understand what treatment options we have based on the presence of certain k-rest mutations, so the tests performed in advanced diseases are actually a standard of care. so keras itself is a protein that is expressed by mutation mutated k-ras is a protein that is expressed in advanced diseases and until recently it was thought to be non-pharmacological and numerous attempts to block or inhibit this protein have been tried in laboratories and clinical trials, but they haven't actually been very successful for decades and this is really due to the physicochemical properties of this protein that have made it very, very difficult to find pharmacological success and this has been until recently and not really until the last two years.
For years there have really been promising results in k-ras inhibition and I'm giving you one of two or three examples that have been looked at recently, one of them is a k-ras g-12c inhibitor and this was data that was they recently obtained. published in the New England Journal of Medicine, but these inhibitors were tested in a phase one clinical trial that looked at the safety of this drug at various doses and this was tested in lung cancer, which also has a high prevalence of k- mutations. rest. such as colorectal cancer and several other solid tumors and what was found was that this drug was safe and in fact showed some activity and mainly in lung cancer but also a little bit in the colorectal cancer group, so this was really the first. promising study we've seen for years where k-ras has been successfully inhibited in terms of colorectal cancer, specifically recent studies have looked at why it works so well in lung cancer and why it doesn't work as well in colorectal cancer and a recent study has suggested that we may need to combine this k-ras g12c inhibitor with other inhibitors to get a more successful result, so I think we will see a lot more in terms of drug combinations to successfully inhibit k-rafts than until It was recently thought to be a non-drug target for colorectal cancer, so this has been one of the most promising studies to come out in terms of k ras.
Additionally, although they are not specifically kras inhibitors, there are other medications that appear to be more sensitive in patients who have a k-ras mutation and one of these is a plk-1 inhibitor and this appears to be preferentially more effective in patients with colorectal cancer. advanced that have a krs mutation and are currently being studied in the second line in patients with metastatic disease and have shown some initial safety data and some anticancer activity and finally, I'm going to take the last few minutes to talk about my personal interest, which is to exploit the immune system to attack k-ras.
So instead of directly inhibiting k-ras, what we want to do is educate our own immune system to recognize the mutated k-ras as a foreign body that needs to be detected by the immune system and eliminated, and then, we have I learned a lot about how we can manipulate the immune system against cancer and one of the first studies that has exploited k-ras specifically showed us proof of concept that we could actually use our own immune system to attack cancer cells that express k- ras. And very briefly, this study was done at the NCI and it was on a colorectal cancer patient where scientists were able to isolate T cells, which are the most important part of our immune system for killing cancer cells that were specific to k- mutated ras.
They were actually able to isolate them out of the patient, expand them, and then reinfuse them into the patient and what you're seeing in the images on the right are CT scans of lung lesions or metastatic colon cancer lesions. that have pushed back on this type of therapy, so this was one of the first proof-of-concept studies where maybe we could target krafts using novel immuno

therapies

and since then, we and others have looked at vaccines that correspond to k proteins -rest mutated to actually educate the immune system like we do with the flu vaccine or other vaccines against viral infections to recognize the mutated k-ras as foreign and to kill these k-ras that express cancer cells and our particular group has combined a vaccine that we've developed with immune checkpoint inhibitors that you may have heard about in the last session that actually disrupt our immune system because what cancer can do is, so to speak, hide from the immune system by cause these disruptions that checkpoint inhibitors can eliminate, so we think we probably need a two-step process first with something like a vaccine to educate our immune system to recognize uh k-ras as foreign and then the second step is to effectively activate these T cells to actually go into the cancer and kill these cancer cells that have a k-rest target, so this is something that is actively being developed and I think both inhibitors and immunotherapy approaches can be used. to target mutated k-ras, which previously again was a very difficult and non-drug target, so I would like to thank everyone for their attention.
Thank you, Dr. Zadie, for sharing this exciting new research on targeting k-ras mutated colorectal cancer. Now I want to introduce you to Mark Delaney, a surviving patient who is currently undergoing treatment for colorectal cancer.metastatic. Mark. Thank you for joining us today to share your story as a patient who went through this. Can you tell us how biomarker testing has impacted your treatment? trip, what do you want our listeners to know? Thank you very much for the question and thank you very much for inviting me to participate. As a patient undergoing treatment, it's always hopeful and somehow, you know, it gives you comfort.
You know that doctors and scientists are aggressively looking for options to help those of us who are in treatment again. My name is Mark Delaney. I was diagnosed with stage four colon cancer in October 2016 with metastases to the liver. and you as a patient, when you go through that, you know obviously you get the diagnosis, it was, uh, momentous, to say the least, uh, and then you know immediately that it's okay, well, they're doing all the tests and one of the first things. What I had done was I had a liver biopsy and I had all the tests done for Lynch syndrome.
Microset micro satellite uh instability uh and uh the biomarkers and I came back with k-raz, a wild guy, uh, which the doctors will keep me honest here. I think it means I didn't have any uh uh mutations uh and at the time you know it didn't really mean much to me uh you know I didn't understand what the benefit or lack of benefit would be having just the wild type of k-ra so I they operated in 2017, I finished my first cycle in the summer of 2017 and then in December 2017, unfortunately it came back to my peritoneum and at that time I went to my oncologist, uh dr saltz. to sloan and he said well look you know the fact that you have this k-res uh wild uh actually it's good because we have medications that are applicable to that uh I mean the brands are avastin and uh vectabix uh and so again the convenience to know that there was an option, as a patient, you're obviously terrified because you know you read enough in dr. google what I like to call and you know you don't want to go through the lines of therapy too quickly and there's only a limited number of lines and you know the prognosis, uh, obviously, I'm stage four, so it's, you know, a therapy. palliative at this point, there's no cure, so you want to understand what the longevity is, uh, and your options, and you know in At that point, Dr.
Salt said, Well, look, we can use Avastin or Vectabix, and that's it. you know, he said he didn't really have a particular preference and he asked me, and does Vectobix have a rash associated with it so anyone who has it obviously knows or if anyone is planning on having it and then he said, let's start with avastin and that was January 2018, fast forward As of October

2020

, I have had 44 rounds of avastin satisfactory, I believe the way They classify my disease. I have a receptive disease, which means that when I'm on treatment everything shrinks, everything goes well and then when I finish my treatment, things start growing again, so the keras, you know, the ks go wild, ya You know, in retrospect, obviously, it was a small blessing in my cancer journey to know that I had the wild type, as Dr.
Zaidi said before. I know that previously mutations had no options and had a poor prognosis, but k rat has impacted me quite dramatically, I feel very lucky to have wild type k res and incredibly lucky to know that there are drugs and I even still have another option for that with the vectabix uh uh whenever I hope it won't be too long when the avastin uh and full fury combo seems to stop working so that's been my journey uh, you know, uh, and you know it right now, for me, kras has been kind of a lifesaver in terms of knowing that biomarker, and so at the time I got tested in 2016, you know I had no idea what it was.
I know no one thought much of it, but now, looking back and understanding where I am and understanding your biomarker, it's probably a requirement for every cancer patient. Thank you so much, Mark, for sharing his story and for giving hope to our listeners. It certainly sounds like that. You too have been living this cancer journey, which I think should also give you hope for life during this treatment ahead. We have Dr. Rona Yeager, associate attending physician at Memorial Sloan Kettering Cancer Center. Thank you very much for joining. us dr yeager dr yeager what new therapies are available for listeners who might have a braf v600e mutation or another b raft mutation thank you very much, it's a pleasure to join the panel and provide an update on the treatment for colorectal cancer with a braf mutation, so which I just wanted to start talking about first about what is the frequency of alterations in the bureau within colorectal cancers, so so far we have heard this morning about the mutations in k-ras and inside the brass and here you can see a Pie chart with the frequency of mutations in wrasse fish. or buraph and what you can see is like Mark said, many patients are wild type for mutations in ras or braf, about a little less than half of the patients are wild type and about 45 percent of colorectal patients have mutations in k-ras or n-rats, so the ras genes and that leaves about 10 percent of colorectal cancer patients who have a braf mutation in their tumor, the majority of those mutations are the biraci 600e mutation, which is what we call a hot spot because it currently occurs in human cancer. colorectal cancer, as well as other cancers, about a quarter of the respiratory mutations we see in colorectal cancer occur outside the v600e site, so we consider them non-v600 braf alterations.
I wanted to take a moment to talk especially about braf v600e. Because it has unique clinical characteristics and there are now approved treatments for braf b600e mutate a colorectal cancer, first some of the clinical characteristics, so Bureau v600e colorectal cancer patients tend to be older, it is more common among women and It is more common on the right side of the colon what that means is that the colon is like an inverted u that starts at the bottom of this type of inverted u and the right side is the first half and what we call the left side is the second half and We've talked about and you may have heard about that there is an increasing incidence of colorectal cancer among young patients and actually these are mainly tumors that are very distal, what we call the left side or rectum, while right-sided tumors tend to occur more. commonly in older patients and there is a clear predominance of the keras mras and vraf um mutations on the right side compared to the left sided tumors, which I assume probably has the mark and which tend to be wild type for those biomarkers which also we see.
An association between b raphi 600e and microsatellite instability means that the tumor has more mutations and tumors and microsatellite unstable may respond to immunotherapy and approximately one third of colorectal cancers with brfv 600 mutations are microsatellite unstable, so those patients would have the option of being treated with immunotherapy and potentially nice responses to that, most importantly, when we think about braf e600, it is associated with more aggressive disease, it tends to be a marker of poor prognosis in contrast to when we were talking about having a wild-type ras tumor, but hopefully, as we propose treatments, we will see that changing the braf v600d mutation is associated with abdominal spread with involvement of the peritoneum and with the possibility of having fluid in the abdomen, so patients can distend and have obstruction, so that's something to think about, especially because the medications I'm going to talk about are all oral and if a patient waits to start taking the medications until they are very sick and have received an oil treatment before, sometimes it's a problem that you may have some intestinal symptoms already, so I'll go over some of the data, but most of these medications have been developed in patients who have already received a line, which means a type of chemotherapy, so often at the time we think it's a good option.
It's time to use targeted therapy, so to think about these medications, I have a cartoon that explains to us what Braf is doing and includes some of the actors we've been talking about so far, but understanding this path will help us see What are the objectives? that we are hitting normally in our cells we have the outside of the cell that detects if there are nutrients and that will give a signal to the cell that walks from the outside surface through the inside of the cytoplasm of the cell to get to the nucleus says this this is a good time to grow this is a good time to proliferate and the cells should survive this is a program that is involved in cell growth so it is often co-opted by cancer cells and is often abnormal in colorectal cancer and In fact, we heard about it today when we talked about what a rast mutation is, so that's the protein that is activated when we have these growth signals from the outside that will activate the signal to say hey, it's a good time to grow and the braf mutations do the same thing and also turn on the same path normally, this goes through this progression from the outside and what Ross does is it causes Raf Biraff is a type of envelope that binds, so here we see the two separate Roth molecules that bind together, allowing the raft to turn on, so what the braf b600e mutation does is that it is on all the time, no matter what is happening outside the cell and it gives a continuous signal of growth and the way it does it is the ebraf v600 can signal as a monomer which means a single protein that no longer needs to pair and it no longer needs rats to get it to pair and that's why it's on all the time um and that it's um uh and we think that in patients who have that mutation that's a driving force for cancer that we've heard of, you've heard of vectabix, which is an egfr antibody, so in patients who don't have mutations in this pathway we can target here and target egfr, but in patients that already have activation we have to attack what is activate or decrease um to stop that growth signal, so initially when drugs would be developed for braf, those drugs seem to have binding-based efficacy preferentially to raf when presented as signals as a monomer, which is that only protein that allows them to enter patients. and they have fewer side effects compared to if they hit all the rats with all forms of anger and when some of these burap inhibitors that you may have heard of, like remyorafenib or carafenib, they were found when they were tested in cancer . types to high activity in certain settings such as melanoma, but surprisingly in colorectal cancer with the v600e mutation, the same mutation was observed to have low activity and it was initially unclear why this was an area that became a big focus of research and now As we understand it, there are many more of these receptors on the surface of the colon, so it is not enough to give the drug braf, you have to activate b raf and the receptor together and, usually, now and after this many tests have been carried out.
When considering giving a braf drug along with an egfr blocker, not only do we need to give the drugs to block the pathway better, if we have the receptor working this leads to activation of ras and then we get this anger pair where the braf drug does not It doesn't work as well because it works better when braf like v600ab raft was signaling as a monomer, so it works better when it's in monomer form, so based on this data, trials have been done that have shown better activity when it's in monomer form. combines the receptor inhibitor with the braf inhibitor we set the stage for the beacon trial the beacon trial was a phase three trial, meaning it got FDA approval and is a three-arm randomized study in which patients who had metastatic burat b600e colorectal cancer that had grown at least who had progressed or at least one line of chemotherapy were randomized to receive the standard therapy which is an egfr antibody cytoxamab or herbitox along with chemotherapy or receive the egfr antibody along with a bra with the braf inhibitor and carafinib or with encorafini plus a mech inhibitor and the study found that the primary endpoint they were looking at was whether giving the targeted therapy helps patients live longer.
They found that doublet or triplet targeted therapy helps patients live longer than standard chemotherapy with the egfr inhibitor, so just a moment about these treatments, so they're targeted therapies, they're a little bit different. to our standard chemotherapy, as Mark commonly mentioned, patients can develop a rash when given these egfr antibodies, targeted therapies tend to work quickly, so patients who start treatment and have pain inside can often feel improvement within a few days if they are responding to treatment, they have unique side effects, sowhen we do these combination treatments like braf inhibitor and egfr inhibitor, we found that the braf drug acts differently in normal cells where we don't. having that single braf monomer has an opposite effect to the egfr antibody, which is why we still see rash, but the rash tends to be mild.
Other common side effects would be fatigue, which is also usually mild, and some GI effects, such as nausea and diarrhea, so overall it has been a great achievement that we now have an FDA-approved treatment for patients with biraci-mutated colorectal cancer. 600e. However, not all patients respond and the response often, um uh um, although it may be a clear symptomatic improvement, um, does not last forever over time. The patient's tumor finds a way to outwit these drugs, so there is a lot of research now to understand what is happening, how we can help patients respond better and longer and perhaps with new drugs help more patients. respond, so I want to take advantage of my last moment to talk about braf alterations that are not v600, so we talk about braf v600e that signals as a monomer and that the b-raf that is not v600 can be dimmed, they can come out as a pair no activation required for ras and there are two groups, some of which simply dimerize on their own so they are activated all the time and some bind more tightly to the fish to cause further activation so we are hopeful that some of these new braf inhibitors may have activity regardless of whether braf is a monomer or paired as a dimer and there is also the possibility that some of these braf mutations may affect the response to known drugs, such as egfr antibodies. , so those that bind to rats more closely and are activated due to a signal coming from egfr may respond better to the egfr antibodies, so knowing what mutation is in your tumor can help guide what treatments to receive and also open up options for clinical trials.
Thank you very much, Dr. Yeager, for that excellent discussion. I want to add a special plugin for clinical trials. combining Braf targeted therapies with immunotherapies and also to encourage any patients who may be listening who have stage four metastatic colorectal cancer to have their tumors tested early for k-ras and ras and b-raf mutations b600e, as well as mismatch repair. or microsatellite instability to determine what standard of care and clinical trial options you may be eligible for, and then we have Gary Gregory, CEO of Perthera, a healthcare artificial intelligence company that

advances

precision medicine. Doctors and patients use biomarker information to combat colorectal cancer.
How could Perthera's precision medicine platform help improve outcomes and ultimately save lives? Thank you, Dr. Atreya, for the presentation and for the opportunity to speak alongside several prominent doctors and also a patient in In the midst of a courageous fight against colorectal cancer, I would like to congratulate you for your bravery in your battle and also for giving coming forward to raise awareness among other patients who are in a similar effort to fight colorectal cancer and achieve a positive outcome in their life is truly an inspiring story and your efforts here are noteworthy as well as the efforts of these oncologists who lead efforts every day to get patients doing well again in the battle against colorectal cancer.
Today we're going to tell you a little bit about prothera, we have an exciting announcement about our work with the colorectal cancer alliance and you know we're excited to give you an overview about prothera as a company and our partnership with cca and perthera is focused on empowering doctors. and patients with precision medicine and our goal is to help both doctors and patients take full advantage of cancer care opportunities using precision oncology to demonstrate outcomes and patients' lives a little in prothera. We are a precision oncology results company, this is how we are being known and seen in the market with 10 years of experience.
We have been used by over 250 cancer centers nationwide and over 10 percent of practicing oncologists have leveraged the prothera out platform and the great thing about this is that it has been shown to improve treatment decisions and patient outcomes. , as we'll talk a little bit about today from an Overview, you've heard in this review this afternoon, great ideas about the power of precision medicine and to sum it up, sometimes it's good to take a step back and say what medicine is of precision and really what our advantage is is an approach that enables patient care where doctors select treatments that are precisely tailored to patients based on their molecular profile and the doctor's understanding of their disease, the patient's individual disease and For us, at prothera we seek to combine the power of scientific medicine and data to advance the use of precision oncology from a broader perspective.
What our prothera precision oncology platform does is allow oncologists to make highly informed decisions about precision medicine to help patients achieve the best outcomes and there are certain things on our platform that we do that mesh with some of the things That brand talked about what they had and mentioned how they did molecular profiling testing and so, what? What does Prothera do? We are not a laboratory, but we integrate all available data and then return it to the doctor, the position and the patients for appropriate care decisions and direction of optimal outcomes and what we have in our platform that is unique is that we integrate the patient's medical and treatment history a multi-omics approach we will look at genomics proteomics germline new things like phosphoproteins we have a therapeutic engine that has been developed over many years that has artificial intelligence and machine learning an expert medical review or a tumor board, as it is often called, which applies to each and every patient, classifies the therapy recommendations that are provided and which give direction to the doctor.
That's not a long list of options that they're considering, but really ranked options that we'll talk a little bit about and last but not least, it's been tested and published to improve outcomes and we follow the patient longitudinally to make sure that We have support for you and your fight against cancer and we believe in that based on what we have seen from the company's perspective, in addition to the great work that doctors do, but as a company we are the only precision oncology platform that integrates all these elements, so it's really interesting to think about one thing as we approach the fight against colorectal cancer and as doctors take up that battle in a front-line position, is that when you look at different types of cancer there is a different test. that can be done, you can do DNA or genomic testing, you can do protein testing that is called proteomics, there are other test markers called things like RNA or phosphoproteins, and if you look at colon cancer, colorectal cancer , the use of genomics and proteomics, Depending on the type of cancer in the individual, the indicators vary from both genomics and proteomics and even some of these other markers are in the real term or in the short term horizon, for what to have the broadest profile when they test and evaluate it. in terms of their cancer, it is really something important for the patients and at prathera we make it easy that by following the direction of what each doctor wants to follow, what we do is that this slogan here implies that the doctor or the patient can also make that the test is ordered, you order the test and prothera does the rest and to give you a little bit behind the scenes of what we do, which is the rest, the first thing we do is coordinate it, a doctor will order a test and we will make sure that we get it again that multi-omics approach, genomics, proteomics, germline phosphorus proteins, whatever the doctor specifies and we certainly have recommendations because that's what we practice and what we work on every day, our patient coordinators will get all that information along with your medical history. and treatment history and then runs through our therapeutic intelligence engine, which is a computer system and a computational engine that has 10 databases, 50,000 plus heuristic rules and algorithms and artificial intelligence and machine learning that produce a set initial of range therapies and then what's really interesting is that we run those ranged therapies through a board of molecular tumor experts that is done for each patient every time we do a prothera analysis and we use both internal and external experts from all over the country, including doctors like those who are speaking on the panel today and will refine those classifications to make sure that we have an expert in the know looking at what has been essentially removed from our artificial intelligence computational engine and what that produces is a perthera report that will literally be ranked from the top to the bottom, the most favorable clinical trials and offline options and as mentioned above, clinical trials are very important in the fight against colorectal cancer and have been proven that our platform increases clinical trial enrollment five times the national average, so it gives you an extra step forward in your fight against colorectal cancer and the latest is that when you use this platform, it has been shown in publications that We will talk today that they have improved not only the overall survival but also the progression-free survival of the patients and we track the results of each individual. patient outcomes longitudinally and use those outcomes not only for their support and their care, but also with their consent, use them anonymously to advance scientific research and efforts to combat colorectal cancer, so that's the platform in few words I will give you. a quick look at our report, this report is different than what you would get through traditional molecular labs and again we supplement those you could still use some of the core labs or the labs that are located in a hospital that the doctor would run and normally I would order. but then what comes back is this report from Prothera that has literally ranked the options based on label, off label and clinical trials for the doctor to make decisions about your care, but the really cool thing about this is that with this engine Eighty percent of the time doctors will choose. our top three options and more than seventy percent of the time they will choose our top-ranked option as a care pathway and we can be very accurate and precise in this not only because we are taking this multi-agent approach not only because we are using our artificial intelligence and our engine computational, but also because we have an expert in the process and we're taking into account their past medical and treatment history, and that's how we create such an accurate roadmap that, in essence, it gives the doctor more of a GPS than a rand mcnally roadmap that they could get from a lab report here in the lab report there everything is integrated in one place to help them make better decisions in precision oncology printed and to illustrate that this was a publication on lancet oncology and another form of cancer gi pancreatic cancer, which is one of the deadliest forms of cancer and in more than 1100 patients it is seen here that patients receiving Prothera compatible therapies report versus non-compatible or unbranded therapies, without biomarkers, we have a difference of a year, uh in uh. overall patient survival rates and a 2.4-fold increase in progression-free survival, so it's a dramatic impact and when we look at these large cohorts of patients, it's very clear that when clinicians leverage the prothera platform , patients frankly live longer and not better um, it's really exciting and something that we're very proud of and puts a lot of science and medicine and effort into over the years.
This is a small snapshot of the hospitals and biopharmaceutical companies we've worked with and who help who. ask us to help accelerate recruitment for trials and, most importantly, advocacy groups across the country who have said, show us how we can bring precision medicine to our patients and show the power and impact of oncology efforts from precision, uh, precision medicine at its core for patient outcomes. And with that in my last note here we wanted to announce today a study of the program of 500 patients that is beingworking with the colorectal cancer alliance to advance patient care and clinical findings and here we will deliver the Prothera report and platform to physicians across the country. to use and for patients like you, so if there is anyone who has been molecularly profiled or is about to be molecularly profiled, you can contact us, we will enroll you in the program, we will also contact your doctor and get you involved. them in the process and in our efforts we seek to not only drive better outcomes for patients as we have done in other forms of cancer, but also educate patients on how to use the power of precision oncology to match therapies and patient-specific clinical trial options. individual dynamics of cancer and last but not least dramatically advanced research and colorectal cancer as we aim to discover new avenues, many of which we are talking about today and the beauty of this program in working with cca is that we are doing at no cost to patients and oncologists across the country, so it creates a truly unique ecosystem that you can participate in and have a direct benefit in your own cancer care through the Prothera report in which we talk about our approach to your physicians for their utilization of the technology and also in impacting a larger study with 500 or more patients that we plan to enroll in this program and that will provide some really key findings for the physicians who are leading this effort initiated by the researchers under the cca efforts, so this is a quick overview on prothera, i hope i did.
We won't give you too much away, go too fast or too slow here, but again keep in mind that this program was just announced today. Registration is free. You can contact us at an email from Hope in perthera, a phone number here found on our website or if you visit our website, there will be a specific page describing the program and how it is available to cca uh members at this program and beyond. I'm very excited to have the opportunity to work alongside the panel today, talk a little. a little about pertheran, our innovative approach to advancing precision oncology for doctors and patients, and the great fight to address and end colorectal cancer.
Thank you very much for your time. Thank you. Thank you Gary for introducing the prothera integrated precision medicine platform and for this exciting announcement to benefit colorectal cancer patients. I want to once again give a special thank you to all of our panelists today dr zadie dr yeager and gary gregory for sharing what latest in colorectal cancer research and technology and to mark delaney for sharing his experience as a patient now, tune in to the next recorded segment on liver-directed therapy presented by andrea cersek and this panel will be available after dr. cersek for questions from the audience and we will try to provide answers.
Thank you so much. It is a pleasure for me. I'll be here today and I'll talk about liver-directed therapy for colorectal cancer. So when we think about any regional therapy, but especially liver-directed therapy, there are really three important things that we need to consider, one is why we do it and the second is when we will do it and the third, of course, how and these are the things I'll go over today: metastatic or stage four colorectal cancer, about 20 percent of our patients have disease that is limited to the liver, so the tumors have metastasized. or they spread, but they remain limited to the liver and we don't know why that is or who those people might be, but we do see that over time they are about 20 percent of our patients and for those patients, the tumors are susceptible. to surgery surgery is really the best treatment of choice, what is important, it is done in combination with chemotherapy because we always worry about microscopic diseases or small tumors that we do not see the goal of liver-directed therapy, so beyond After surgery, what are other regional interventions that we can perform?
What we can do is work with chemotherapy along with chemotherapy or after chemotherapy to help reduce control or eliminate the disease in the liver. When do we use it? So this is a complicated question and it really depends on a number of factors and, most importantly, the individual. patient and the disease of the individual patient and sometimes these things are difficult to predict in some patients we can use regional therapy to take them to surgery so that they have disease on both sides of the liver if we can reduce the disease with chemotherapy and then do one more therapy focused or directed at the liver, perhaps we can reduce the disease enough to lead to surgery in other patients.
We use it in combination with chemotherapy to allow the chemotherapy to work better to continue the response and be able to continue treating patients and in others we can use it if the tumors have progressed with standard therapy, so if we have used our therapies standard and the disease is still in the liver or primarily in the liver, this is another area where we think about liver-directed therapy, so how can we do it? We do this so that this is beyond surgery, so other interventions targeting the liver, one is intrapathic arterial infusion or hai therapy, the next is radiotherapy, so radiotherapy really includes radiation like sbrt or cyberknife , as you may know it, selective internal radiation using radio radio labeled with atrium 90. labels pearls or cert sirt um and then tumor ablation and there are a few different ways to perform tumor ablation, the most common one is actually radiofrequency ablation , but there are others like microwaves or intratumoral injection of acetic acid or ethanol, as well as cryotherapy, although they are used less frequently, so these are really the tools that we have available and the ones that we use really depend in part on the center, the academic center , some depend on the doctor's personal choice or personal choice. comfort the comfort of your institution, although they all have some data supporting them to some extent and I will go over each of these in this talk, so starting with hepatic arterial infusion therapy or hai therapy, this is really the idea here is that tumors in the liver get their blood supply from the hepatic artery, so we have a venous system and an arterial system and it is simply the way that blood flows through the liver and this was many years ago, actually decades ago, we learned that tumors in the liver actually get their blood supply or all of their food and nutrients from the arterial system, so the way the pump works is that it's placed in a subcutaneous pocket, so which is placed under the skin, usually just above the waist, below the rib cage.
See here in this drawing sometimes even a little bit higher up and on the left side of the body instead of the right side where the liver is and then a catheter is put in and surgically placed in what's called gastroduodenal. artery which is an artery that then leads to the arterial system of the liver so the idea here is that this is completely covered by the skin and that we put chemotherapy into the pump with a syringe in this pocket of the pump here which again is covered through the skin like a metaport, the chemotherapy is placed and then there is a mechanism in the pump.
The current pump that is most commonly used is battery operated and the chemotherapy continuously flows into the liver, which is this area here over a two week period and the good thing and really the basic principle of intra-arterial therapy directed to the liver with the hi pump is that the liver eliminates the medication known as uridine flux or fudr immediately, so that is really the job of our liver. to eliminate what we ingest, etc., so it eliminates this chemotherapy with what is called first pass metabolism and by doing so, it allows us to administer a very high dose of chemotherapy that only the liver sees and predominantly the liver tumors and there are very little absorption. to the rest of the body, so it's really a way of delivering very high doses of chemotherapy to those liver tumors and we use it in various ways, we use it in combination with systemic chemotherapy, we use it in patients who may have had surgery and all of its liver metastases are gone and then we are giving chemotherapy through the liver to try to eliminate any microscopic disease that may still be there because we know just from studies that statistically there is a high probability of microscopic disease.
That's called adjuvant therapy, liver-directed therapy and it's used in metastatic tumors that are on both sides of the liver where they can't reach surgery to help shrink the tumors and it works very well in that setting and then it can also be used. if the disease remains predominantly in the liver but the patient has no other treatment options, so those are really the main ways that this therapy is used. What is important to note about high therapy is that it really requires team experience, so the procedure is a surgical procedure, the pump is placed by experienced hepatobiliary surgeons.
When the pump is placed it is important to make sure that the chemotherapy goes only to the liver and not to the surrounding organs in the liver so it is very important to look at the blood vessels and we do this with the radiolabeled um substance where we basically look at a scan and we see well, it is only the liver that lights up, this is good, it works if we see that other vessels light up outside the liver. Then the patient usually has to go to interventional radiology, where doctors can intervene and tie off or embolize some of the vessels that might be delivering chemotherapy to other organs like the stomach, lymph nodes, or small intestine because that would be very dangerous if If those organs received that chemotherapy because, unlike the liver, they can't get rid of it right away, then they would really suffer the consequences of this very high-dose chemotherapy in those tissues. because it is a surgical procedure, there are surgical complications, there are problems that can occur with the pump or the catheter that really require expert management and then the other important thing to keep in mind with the pump is that we can deliver such a high dose. of chemotherapy directly into the liver, and although we are predominantly treating healthy liver cells, we are also delivering that chemotherapy to healthy liver cells, so it is very important to closely monitor liver function tests in the blood to make sure that the liver is happy that it is not stressed, that it is not inflamed and that the treatment is adjusted if that happens and there is a small risk, probably less than about five percent, that this inflammation will not go away and patients will develop what is called biliary sclerosis. or actual inflammation of the bile ducts, the very fine tubes that run through the liver, which might then need a stent to keep them open, so those are all very important things, it's technically challenging but can be quite beneficial for patients, as I mention. in several different forms of radiation therapy, so stereotaxic radiation therapy or sbrt is what I mentioned before, you may know it as a cyber knife and this is actually radiation, it is specifically targeted at a tumor, it is done, since all the radiation is through the skin, there is a kind of a mold made of the body and then these radiation rays go directly to the liver, but what can happen is that the small intestine is sometimes in the way and other healthy tissues, so which sbrt prevents because it is a much more focused radiation. but this is still something we think about when we consider radiation and really, in terms of treatment options, this is not at the top, we don't have such good data to say that radiation is really the way to go with tumors colorectal. some response, but the responses tend not to be as good as some of the other regional interventions;
However, in some cases, if only one tumor is growing, if the patient is not susceptible, if the patient cannot obtain resection or cannot obtain any of these other more invasive procedures then this could be an option and, as I mentioned, really the problem is damage to healthy cells, so why is 90 o cert another version of radiotherapy and this is a cool radiolabeled bead approach? which have a 90 atrium, so they are like very fine particles of radiation with the idea that they are introduced through the arterial system, similar to a cardiac catheterization where there is a catheter that enters through the groin. and then to the heart, this is the same idea: the catheter goes up to the groin and then to the liver and is placed under fluoroscopic guidance so the interventional radiologist can see where they arethe tumors and instill these radiolabeled beads directly into the tumor and The idea then is that the beads are placed there in the tumor emitting this radiation and actually killing the tumor, if you understand from the data, this treatment is really better in combination with chemotherapy , but the concerns here are that there is this potential for liver damage, because it is still radiation, it may not be as focused, there is a significant risk of liver damage, so again, this approach is also center-specific.
At Memorial, we tend to do a lot more hepatic artery infusion, however, we have an atrium 90 program, as well as at other institutions, atrium 90 might be the treatment of choice, because it is the most invasive type of liver-directed therapy or most aggressive that is offered. What we do know is that this approach is not recommended for patients with early-stage disease, so a study was done with newly diagnosed metastatic disease in the liver that compared chemotherapy alone versus chemotherapy plus atrium 90 and there was no benefit with the addition of atrium 90, but patients did have more toxicity, including liver. toxicity, so we tend to use it if we do it later when the tumors have progressed on standard therapies and then next is radiofrequency ablation or rfa.
I think this is also becoming more and more common and is one of the least invasive procedures that I have discussed so far is similar to a little more invasive than sbrt, but the patient here is almost like a biopsy and a needle is placed through the skin to the liver again under the guidance of a cat scanner or fluoroscopic guidance, um and and then the needle is inserted into the liver and then with thermal energy the liver almost melts from the inside and basically dies or it becomes necrotic with that mechanism. The problem with this one is that it is difficult to assess the margin of the tumor so you can.
I can't say for sure if you are getting the entire tumor as it literally starts to melt under the cat scan and the way we use this here is generally in patients who could perhaps have surgery but are not candidates for surgery. surgery or in patients. where we see that they have small tumors where we think that the surgery is quite aggressive, these are very small tumors, perhaps they are amenable to local control with radiofrequency ablation and it is really better for small tumors, in fact, not so much for larger tumors. most places will not consider this intervention unless the tumors are actually around two centimeters or so, but certainly less than three, and here also the possible complications include things like a liver abscess, there is literally a hole, so to speak, where the tumor used to be. so the concern is that that could get infected and cause an abscess, it's rare but it can happen, things like bleeding can also happen, which for the most part can be manageable, but again, these are important things to consider. with this procedure, so here we don't know with this regimen, we really don't know with this approach, ideally, based on studies, we don't know how to work on each one's treatment and I think this is where really the biology of the individual The medical history of the individual can help guide us as to whether or not this is the right treatment approach and then other options for tumor ablation are microwave ablation really is the main one.
There is actually much more experience in small tumors in hepatocellular carcinoma or hcc, but we are. I'm starting to see a little bit more of this used in colorectal cancer as well and then others that I'll just mention in case they come up in our discussion, but they're things like cryoablation, which is like freezing tumors or injecting ethanol or acetic acid. and I really think they're not used very commonly for colorectal cancer, so in summary, liver-directed therapy has a role in the treatment of metastatic colorectal cancer that affects the liver. I think the most important thing is that the main treatment, the initial treatment, should be chemotherapy because we always worry not only about what we are seeing, not only about the disease that we see in the liver, but also about possible microscopic disease in another part of the body, in the bloodstream, in the lymph nodes, so ideally we do chemotherapy and see how much of a response we can get and then we start to think if it's okay, depending on the scenario, if the response is very good and the disease is limited to the liver, can we do surgery?
If we cannot do surgery, should we do some type of regional surgery? intervention and these are the nuances now, what will regional interventions offer us? Will they offer us the possibility of the patient living longer? That's an obvious choice. Will they offer us the ability to take the patient off chemotherapy because we can control the disease in the liver with some of these regional interventions or will they offer us the added benefit of a response that we're not getting enough of with chemotherapy alone, so all of those things are important considerations and, again, that's why it's really an important decision.
Think about each patient on a case-by-case basis and then consider all of these options to determine which is best for the patient, so clearly there is no right treatment, but we hope that with chemotherapy with the newer therapies that we're working on and these regional interventions that we're pushing the needle forward that we're improving outcomes for our patients with metastatic disease because that's really what it's all about, no matter what the choice is. , that's really all we want to achieve is improvement, improve treatment and improve outcomes for our patients. Thank you very much for your attention and I look forward to our discussion and welcome any questions you may have.
Thank you to all our speakers. Can everyone hear me? Maybe someone can raise their hand. Okay, I just wanted to make sure that this is working very well, so now we have time for our discussion with all of our speakers, our panelists and we are happy to answer questions, maybe let's start with some questions that have come up in the Chatee and I'm summarizing some topics that have come up rather than specific questions because we've gotten a lot of questions, which is great, so one question that's come up is about when to do tumor testing or germline testing.
I think there might be some questions about tumor versus germline testing, when it should be done, how often it should be done, what tumor tissues should be tested, Dr. Yeager is something he would like to talk about, sure. , Of course, thanks. I saw in the chat as well and it sounds.Overall the group is very informed, so we have been talking about various markers that we consider tumor tests. We look for alterations within the tumor tissue. It should be performed at the time of diagnosis of metastatic disease. We don't do it routinely. in early stage disease because it does not guide treatment, but as Mark mentioned, it can guide targeted therapy in patients with advanced disease, once performed it does not need to be repeated, it can be performed from the primary erectile colon tumor or from any metastatic site if patients receive targeted therapy sometimes genetic change there may be genetic changes, so your doctor may want to repeat it to look for resistance, but as a way to find massive therapy it is not necessary to do it repeatedly throughout the course.
Germline testing looks for anything inherited from mom or dad that may have put someone at risk for colon cancer and that is often done in younger patients or in patients who have a family history. We screen all patients for Lynch syndrome, which is the most common genetic syndrome and is usually done. at the time of diagnosis, it can be done on the tissue itself, so you do sort of a quick search for anything in the germline for the most common germline alterations. Excellent answer. Another question that has come up in various forms is how to find a clinical trial and when. the best time to look for a clinical trial.
I see Dr. Cersek in my speaker view. Maybe you could start by helping us address this question and then we'll come back to the therapeutic platform. Typically, the decision about the clinical trial is. It's done with the provider, the oncologist, and most patients, it really depends on what trials there are, the patient's interests, and motivation, so when we typically think of a clinical trial, it's often once the tumor has grown on all the standard therapy so the full fox full fury and even some of the targeted therapies including anti-egfr therapy or braf targeted therapy at this point since it's approved so we thought well about what could adapting to the patient is a totally different path.
There are some alterations, some of which Dr. Yeager mentioned, that could now be explored in a clinical trial, and most importantly, because the trials look at an experimental drug that we often don't know about the toxicity of, we don't know the toxicity of it. . Possible side effects that medications can cause, it is very important that patients are in good physical shape, which is why we always say that it is not a good idea to wait until the cancer has advanced to the point that the patient cannot tolerate a clinical trial. or the requirement to keep appointments and then not be fit for a trial, so it's an important window to think about and something to, if one is motivated for a clinical trial, mention what the oncologists are treating . then there are trials that are also in the early stages of first-line therapy, when that disease is first diagnosed and that's a different kind of question: we have good therapies, but can we do better?
So that's another thing to think about and I think it's really something where you need a motivated and interested patient to participate in a trial like that, but it's certainly always important because it helps advance science. Brilliant. I was also hoping to mention a couple of things to add to Andrea's wonderful comments. it's wonderful that perthera is doing this and that they're making this move to care for colorectal cancer patients, but there's no platform or clinical trial testing group or compatible service that gives you all the options, so, and I think that you know, even if you look at different areas of the country, people use different companies, there have been a lot of questions in the chat, like where you should get your tumor sequence, where you should send liquid biopsies and there are a lot of companies and each of the platforms is a little different but most of them are pretty good and it really depends on your particular doctor and what you might like or what you have so I really encourage it. people in the early stages of their diagnosis to contact an academic institution in the area because even if Hopkins doesn't have all the clinical trials, we have a big email thread between all the people on the east coast and we share our patients and we share our essays, etc.
We can communicate to someone with rona or with andrea because we are talking to each other and I think that getting into that system is really important and doing it in the most convenient way so that at least on that first visit it's not like you have to travel all over the country and go somewhere in particular, but just adopt that mentality, yeah, and uh, oh, yeah, go ahead, it sounds like a family of uh, it sounds a couple of things to add to the great comments already provided. One, it's been clearly shown in most forms of cancer and colorectal cancer participation in clinical trials definitely improves outcomes and that's an exciting thing, so the awareness of the patient group here to try to pursue those that I think it is quite remarkable and in most laboratory tests and to the point that I just offered, you know that various laboratories will offer various tests and we can say this clearly because Prothera, not being a laboratory, literally analyzes and works with every lab in the country, almost every lab in the country and Every lab has certain strengths and capabilities and your doctor is absolutely the right person to help direct and guide you, but what I would say is that it's also important to consult with your doctor to Make sure you are using the latest and greatest in technologies. and a lot of times we find that physicians may not be thinking about a clinical trial because they're just looking at a report that they get from a center or they may be looking at their internal reports that may not have uh clinical trial capabilities beyond their site and how they do it. offered previously by the two leading oncologists here, it's that mosaic approach that's really important to make sure you have a look at the clinical trials and off-label and as just one A parallel and somewhat detailed example, Prothera looks atall clinical trials listed nationally in our engine, which now has machine learning from hundreds of thousands of patients that have come through data and our own platform. a look at this in a way that empowers the physician to be able to make the right decisions and historically, patients don't go much further than 150 miles from their location, so it's that relationship between the medical oncologist and the information that comes together is really what is powerful in creating the path of care for each and every patient.
Excellent thanks. We're about to run out of time. I was wondering if you wanted to share any parting advice with other patients who may be listening today. Of course I'll do it. the place too much, I know, okay, first, you know again, as I mentioned the last time we were together, you know, it's incredibly comforting for all the patients and their caregivers to see all the great work that's being done and the hope . that we have for all doctors to be successful in their research efforts uh and you know, uh, the patients uh, and you know what I call my fellow fighters, uh, dealing with, uh, facing colon cancer, you know, uh, there's, you know like Gary, uh, you know, something like that. he said eloquently you know the combination of information is quite powerful you know I have learned a lot here you know just by listening to dr. cersek uh you know uh talk about uh well, I don't have a disease directed at the liver, it makes me ask questions about you know she eats regional diseases, so I'll ask Dr.
Saltz who is my beau about that, and you already know, so the information provides us with another degree of comfort, especially better than Dr. Google, which I spent a lot of time and Dr. Google doesn't give you really great information, but it gives you information, so you know, any patient that's out there. , you know, do your advice, talk to your oncologist, and you know, do your research. the academic areas that you know, obviously, uh, sloan, uh, hopkins, uh, md anderson, all those that you know, uh, you know, I live outside of the Philadelphia area, so I immediately went to sloan and he definitely changed the treatment program that I was going to receive and you.
You know, I'm a little vocal about anyone I know who has cancer of any kind going to one of these identified national cancer centers because you're the ones setting the standards, you know, instead of the community hospital, like that. which, I encourage everyone, obviously, knows that they should know their biomarker status. uh, you know, that sounds like something like I mentioned in my little speech there. I didn't know at the time it was important, but now. It's basically allowed me to live at least three four more years just knowing that and it gave me an incredible amount of hope and you know, it's a comfort to know that oh, okay, you know I'm not at the end of the line, here's a there treatments available, so you know, so those are the two things that you know, thanks to the doctors, you know, guys, you know, as I mentioned, uh, you know, the patients are in the stands supporting you, cheering you on, waiting for you. know.
We will encourage them as loud as we can to help them look at all the options they have and all the things they are thinking about to help us and it is incredibly covered to see how brilliant they are. and how much you are, how hard you are working with us, to help us, since we can't really help ourselves, you know, I'm in marketing, that doesn't really help me fight my illness, but you do. and I appreciate it and my family appreciates it and the world of cancer patients appreciates it and all the patients know that we are all capable, I say this all the time, we are much more capable than we realize and In this fight there is never a reason to give up, especially when you have a team of doctors like you, so thank you very much, thank you all for joining today, no one will give up, everyone, stay safe and in touch, thank you. thank you all very much thank you for the opportunity

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