CRC trials in Canada: Dr. Loree (2021)

This is an automatically generated transcript.

Manju George 0:00
Hi everyone. So for this DocTalk we have Dr Jonathan Loree. He’s a medical oncologist at BC Cancer, and he treats cancer the gastrointestinal tract. And he’s an assistant professor at the University of British Columbia, and completed his medical school and internal medicine training in the universe at the University of Alberta, and then completed his medical oncology fellowship at DC cancer. Then he had a translational research fellowship at the University of Texas, MD Anderson under Dr Scott kopits, and we are really excited to have him today with us to talk about clinical trials in Canada. Welcome, Dr Loree.

Dr. Jon Loree 0:38
Thanks so much. Appreciate you having me. So it’s always a pleasure to interact with everybody from COLONTOWN. It’s a great group. I’ve got some slides that we can go through, but if anybody has questions as we’re going through, feel free to put them in the chat or unmute yourself and bring them up, and then we’ll have kind of some open discussion at the end. Our kind of objectives, kind of split it up into three sessions. We’ll kind of discuss a little bit of an overview of, kind of how clinical trials are organized in Canada, review, kind of some recent or historic trials that you might have heard about, and then highlight some ongoing trials that are going on in Canada. We’ll go from there. So across Canada, you know, in the US, there’s a number of different cooperative groups, and depending on which Cancer Center you go to, they might be aligned with different cooperative groups. In Canada, there’s really one main cooperative group that all of the cancer clinics are part of. They are part of some of the other US cooperative groups as well certain centers might be so for example, BC Cancer, where I work, is also a SWOG site. But for the most part, all of the Canadian sites kind of collaborate in this one specific cooperative group, and it’s called the Canadian Cancer Trial Group, or cctg. And you can see the wide range of sites across the country. And so really, in every province, there’s representation, and trials tend to open. You know, some of the larger centers might have, kind of all of the trials, and some of the smaller centers might have some of the trials, and might have, might refer to other centers for some of those other sites. And to give you some ideas of about the trials. This is looking at 2018 we had in that one year, there were trials open at 84 centers across the country. So it’s not just in large centers, it’s all over the country that things are open. And so far in the past 20 years that CTG has existed, 14,000 patients have been put on trial. And in that 2018 year, there were 2400 patients. And it’s pretty stable over the years. Obviously, with COVID There, there have been some fluctuations across all the cooperative groups of what happened with clinical trials, and some going on hold, or some being a little bit easier or harder to do, but it’s been pretty safe, pretty stable or rising. We’ve had, you know, more opportunities for trials. There are over 85 institutions that have participated at any one point in time in Canada. But then there’s lots of international partners that we work with from up to 40 countries. It is part of this NIH NCI national cancer clinical trial network. So that’s really important and interesting. So there is this cooperative group mechanism. So cooperative group is basically a bunch of cancer centers that work together to do a clinical trial. So you know, any one trial might require a large number of patients to be on a trial before we’re able to learn about whether what was done in that trial actually provides a benefit. And so usually, centers will work together, because it’s hard to answer a question just by yourself. And so in the United States, the NIH NCI, this trial network, it kind of brings together all the cooperative groups. So that way there’s collaboration and cooperation, and so that way people don’t end up asking the same question. And so what happens is, someone may propose a trial that goes through their cooperative group, say swag or cctg, and then there’s this central mechanism where they review and see if there’s overlap, and there’s also a funding mechanism within that to support these academic trials that are really important. So that that’s one thing that’s a bit unique, is that CTG is part of that, although it’s outside of the United States, and you know, it’s it’s been ongoing for over 20 years now, and there’s been over 150 trials running concurrently, both kind of in the active phase, as well as follow up at any one point in time. So lots of trials happening. It does cover all different disease sites. So I’m going to talk today about colorectal cancer, but we do have trials that are in both solid tumors as well as liquid tumors and hematologic cancers. And there are mixture of kind of chemotherapy trials Re. Trials, surgery trials, we have some trials that look at exercise and some diet interventions. And so it’s a pretty big mix of different opportunities. The funding for the Canadian Cancer Trial Group, so it comes from a number of different mechanisms. So the Canadian Cancer Society in Canada does an excellent job. It’s across the country, and they raise a lot of funding that helps to support the Canadian cancer trials group. So they work together closely to help facilitate this and from that funding that helps to fund kind of a core center that I’ll talk about. So it’s in Queens, which is in Ontario, Southern Ontario. And so the kind of statistical center is there, and there’s funding that helps to support that. And then what happens is, if there’s a trial that someone comes up with an idea for, we do try and find other sources of funding as well that are leveraged. So there might be industry partnerships, so industry might have drugs that might be interesting, and might be an opportunity to try and explore and ask a question. We also apply for grants. So CIHR is a big granting mechanism in Canada, so we have something called project grants, which are kind of like the R ones, if anyone’s thinking about how does how to fund trials get funded? So these are funds that come from the government, kind of the national government, and candidates from CIHR in the US, they’re often our one is kind of this class of grants. And then we also work with other cooperative groups, and through the NIH in the US, or through these European groups. So there might be funding that comes from from various other mechanisms that help to pay for trials, both the drugs as well as the running of the trials, the types of trials that happen in in Canada. So we do kind of the full phase, all the phases of trials. So there’s phase one clinical trials. These are trials where we’re just starting to learn how to use a drug. So it might be the first time it’s used in humans, or maybe it’s the first time it’s being used for a bowel cancer or something like that. And oftentimes in these trials, we’re looking for the very you know, we’re looking to find the right dose to make sure it’s safe. We do like to see if there’s efficacy. We look early, but it’s not really the main goal of phase one. And so they’re often smaller trials, because what we want to do is find the right dose and quickly move them into phase two, where more patients will get the right dose. And that’s where we kind of take a look at, does it work? Well, what’s it look like? And then a phase three trial is where we look at, does it work better than what the standard is. So those are the three different phases that a drug has to go through in order to make it into the clinic. And I would say, you know, before phase one, there’s a huge amount of work that’s already gotten into a drug, to discover the drug and to make it safer, and to figure out how to how to give it effectively, and to turn it into a pill or something that might go in through an IV. In Canada, really, the easiest way to find what clinical trials are available is to go to Canadian cancer trials.ca, and to look on that website, and you can click, it’s nicely organized between kind of different trials that might be open if they’re through the cctg, and there’s a library there, and it’ll say things like, what, what are the requirements for that trial? What’s the question kind of trying to answer? And then from there, you’d be able to see what center, if there’s a center near you that might have the trial open, the centers in Canada might also participate in non cooperative group trials. So they might be on there might be trials that an industry partner might have. So suppose drug company y has a new drug, that they might be running their own clinical trial, and those might be available in Canada as well. Easiest way to find those is kind of the same ways in the US clinical trials.gov is where most of those trials are going to be registered and and clinical trials.gov covers really global registry for what trials are happening, as far as collaborative partners. So I mentioned there’s, you know, Canada does a lot of trials, but we tend to work together a lot with the US, those cooperative groups. We work quite a bit with unit cancer in France and agitg, that’s the Australasian gastrointestinal group in Australia and New Zealand. But depending on the cancer site, there’s been lots of other groups that we’ve worked with on these clinical trials to try and answer questions and try and move things forward. I’m going to show you a couple trials that you may or may not know happened in Canada, and just to give you kind of a flavor of the types of things that have happened in the past, and then we’ll move into some of the ones that are currently enrolling. So CF 17 was a really big clinical trial. This is the trial that led to Cetuximab being approved. So Cetuximab is an antibody that goes in through the IV and it basically grabs on to something on the outside of the colon cancer surface called EGFR. And. And the drug was first approved without any sort of biomarker. It actually this trial looked at EGFR over expression, and it was a positive trial which was exciting. This was a collaboration between Canada and Australia and New Zealand. And this trial led to, actually, the discovery of KRAs, Exon two mutations. And so, you know, the first trial was exciting. There was a little bit of benefit, but we like to use this hazard ratio, so kind of, how much does it improve? How well the drug works? So we dropped that from point seven, seven in the unselected group, 2.55 so it worked a lot better if you could identify patients who had a cancer that had that mutation, and in those patients, there really wasn’t any benefit to giving this drug, but when the if there was no mutation, we saw the benefit was even more. And that was also shown in a nice panetumumab trial, kind of around the same time. So that’s how we learned about this, this biomarker being important. So K RAs,

Manju George 11:00
Dr Loree, could you – in the previous slide, Could you explain what is wild type and mutant for people who might not know?

Dr. Jon Loree 11:05
Yeah. So what we do is, if someone has a new diagnosis of a metastatic colon cancer, what we’ll do is we’ll take the cancer and we’ll extract some DNA. And that’s like the the you can think of it like the book, the recipe book for everything a cell has to do, we extract the DNA that’s got all the recipes, and we make sure that they’re spelled right, that all the recipes have the right ingredients. And so if there’s a mutation in the gene called K RAs, basically the cancer cell is it’s got the foot to the gas pedal too much, and there’s it’s going to keep growing and growing and growing. And we know that this drug because it’s attacking that pathway, it doesn’t really work. And so we say it’s the tumor is K RAS mutant, meaning that there’s a mutation in the gene. And if we say wild type, that’s kind of a historic term, that just means there’s a normal version of K RAs and it’s not, it hasn’t been mutated yet. – Okay, K RAs, you know, when we think about the mutations, when we think of a cancer, there can be mutations in all of the cells that are the same, but quite often it’s kind of like an ecosystem. So what will happen is, over time, the cancer is going to mutate and change. And so there might be a mixture of populations of cancer cells that have slightly different mutations. And one question that’s come up is, if you have all of the cancer cells that have a mutation in K RAs, versus just some of the cancer cells that have the mutation K RAs, does that change? Like, are there some patients where there might be a very small population of cancer cells that have that mutation, maybe we can still use that drug. This was a trial called prime and they this is a forest plot, and it’s looking at that idea of how much benefit there is. You want something towards the left to show that this is better. And what they showed is that there were some new mutations in in a gene called N RAs and in other spots in K RAS that were important. So they were in different locations in the gene, in a different spot. But with new technology, we’re also finding that there’s kind of some rare there’s some tumors where maybe only a small portion of the tumor actually has a mutation in K RAS. This is a crystal trial, and when we see when there’s a smaller percent of the cancer that has that mutation, it looks like there might be some benefit to adding this anti EGFR drug. Now we say that there’s certain spots that we want to look at in K RAs and N RAS to find these mutations. And kind of we call them hot spots, meaning that’s where most of the mutations are. And we also say in guidelines that at least 5% of the cancer cells really have to have a mutation for us to say, yeah, that’s mutant, and we should the cancer has changed, and we shouldn’t use that drug. But the question is, what about less than 5% now that we have better sequencing, we might find some. We call these subclonal mutations. So in that same co 17 trial we recently looked at this, and we used a special type of sequencing called beaming. And so beaming is just a way of really being very certain that if you find a small number of the mutations that they’re they’re real, and they’re not just an artifact from the sequencing. And what we found is that you could make them the amount of benefit, it improved it by kind of another month. You could select patients a little bit better by looking at for more of those mutations. And we found that these low allele frequency mutations, so the ones that aren’t very common, there’s not very many of them, which, in and of itself, is important to know that it’s pretty rare. So only 2% of patients that were on this trial had this rare tumor, this rare mutation, and actually one out of the six patients who had a really low allele frequency mutation, so one were only part of the tumor had it had a partial response. So this isn’t enough to really change practice, but it’s enough to kind of give us an idea that this is a an interesting group that we still need to learn a little bit more about. And. Another recent trial that was done through cctg. So this is called the CO 26 trial. We always put CO, which means colon, and then the numbers, and they just keep going up in numbers. Each cooperative group has kind of a different way. I always say we really need to come up with some better names for them, because no one can remember co 26 or was that CO 27 or CO 28 but you need kind of a fun name, ideally, but this was a trial looking at patients who had used up most of the treatments that are available to us, and we didn’t have treatment options that would still work on the cancer, and they either received a combination of two types of immunotherapy drugs or supportive care, so they didn’t receive the treatment. And then we looked at how well these worked. This is important, because in patients who have a cancer that harbors micro satellite instability, this is the first line keynote study showing that immunotherapy for a lot of these patients. What you’re looking for is this is the number, the proportion of people have had their cancer grow, and you see that after about two years, there’s still half of people that their cancer hasn’t grown if they’re receiving immunotherapy up front. Now, this works really well for tumors that have mismatch repair deficiency or microsatelite instability, which means that the cancers, the spell check in the cancer is not working. And so those recipes we talked about earlier have lots of mutations. Those mutations are important because they let the immune system identify the cancer cell, because the cell looks weird. It looks different than what it should normally look like. So this trial was not specific to whether a tumor had micro satellite instability or not, but actually, only two out of the 180 cases had microsatellite instability. So it’s basically a mismatch repair proficient trial, and we found that, you know, if you were micro satellite stable is really the same amount of benefit. And this was surprising, because the trials to date, when we looked at immunotherapy and microsatellite stable tumors really had shown no benefit. You see, the curves are completely over top of each other. And so it’s kind of wondering what’s happening here. The other thing that was in the landscape at this time was tumor mutation burden. So this is the idea that as we spell more words wrong and the tumor looks funny, the immune system can identify it, and having more of those Neo antigens or problems, it’s something that the immune system will be able to monitor better. This has led to a label in the United States with the FDA based on the keynote 158 study, but there weren’t any colon cancer cells in there. And there’s quite a bit of debate about using immunotherapy for TMB, high colon cancer a lot of the time, high TMB. So lots of mutations corresponds with having something else that might be a reason to use immunotherapy, like micro satellite instability or something called the polymerase e mutations. That’s just a different type of proofreading, a different version of the word, proofreading, basically. And so it’s a bit unclear what to do in colon cancer. And so we looked at this in the trial. We looked at two things. We looked at something called a liquid biopsy. So this is the idea that cancer cells, or normal cells, as they die, will shed their DNA into the blood, and we can find the mutations, and it gives us a sense of whether the cancer is still there in the body. It only lasts for about two hours in the bloodstream before it breaks down. So if we find a mutation, it really means the cancer is there. It doesn’t mean that the cancer is is at risk of coming back. It’s probably there right then. And we can look and what we’re looking at is how much of the normal DNA is there compared to the part that’s mutated, because your normal cells also secrete this stuff. And we use some different measures of kind of how much of the bad stuff is there compared to all of the DNA. And so we looked at this liquid biopsy, as well as in the tumor itself for TMB. And this TMB is the number of mutations, really, that are in the cancer. And we shot in the tissue, there’s kind of a TMB that we expect. So there’s 6.6 mutations per something we call mega base, which is just the number of of individual DNA kind of letters that are used. But in the blood, we saw a very different number, and there was no correlation between the two. So it didn’t, you know, some people might have had a really high TMB in the cancer in the tissue, so the biopsy that was done when they were diagnosed, and in other people, the blood had changed. When we looked at the kind of how useful the the tissue was, it really didn’t help us to know which patients were going to have their cancer kind of be more well behaved if we looked at the tissue part, but if we looked in the blood, actually the patients who had more mutations in their cancer, those cancers tended to grow faster, and those patients didn’t live quite as long. But what we give those patients this immunotherapy, it actually seemed to help them, and it helped them more than the overall population that was in the trial. Remember, I mentioned the hazard ratio was kind of around point seven, five in the overall group, but it’s down to point three, four, which is a really good number. Actually, it’s quite a large magnitude of effect. And when we use tissue, there wasn’t really that same benefit. And this is important, because this is something that some people might use this tissue. TMB. Of over 10 to decide whether to use immunotherapy, and so the number was kind of around the same. There’s a bigger spread, and it looks a little bit more like kind of everyone else who received immunotherapy. It wasn’t really helpful to have that extra information about the tissue, TMB, and when we look at this, this is kind of looking at something called an interaction P value. So that’s telling you did the TMB actually predict that there was going to be a benefit of the immunotherapy as we move across the increasing level? And what you want to see is that it comes down and it stays low. So that way it’s not just some statistical phenomena. And when we see it go down and stay low, it says that once you get over 20, I think here it’s 26 it stays important and predictive, and that would make sense, right? If there’s lots of antigens and lots of problems in the cancer cell to be recognized, it makes sense that the patients who have a higher higher than that are also going to benefit. And so this was helpful to show that it’s not just kind of a fluke that we found this. So probably what’s happening is that as these individuals are being treated with the chemotherapy, their cancer cells are changing over time, and we’re changing the mutation burden, and normally the TMB is measured on the biopsy that patients might have had when they were first diagnosed, and we know that that, because that cancer can change over time, maybe using blood might be a useful test. And so we’re still learning more about how to use this plasma tumor mutation burden, but it’s kind of an exciting study.

Manju George 21:33
Dr Loree, can I ask a question, how much do you think the plasma TMB changes over the course of a person’s treatment. Do you have any guesses?

Dr. Jon Loree 21:46
I don’t know. We don’t have very many studies where we have, you know, many years of follow up. We often have kind of a couple of we might have them three or six months apart, and then we see how things change. And it what I can say is that it didn’t change very much for people while they were on this clinical trial. They were pretty stable between when they started the immunotherapy and three or four months afterwards. But you know, it’s the chemo therapies that are probably the parts that are driving the change in the TMB, and that’s been an exciting idea. There was a nice recent study where they looked at trying to use a drug called temozolomide, the Maya study to so that’s a drug that causes lots of damage in the DNA. They tried to use that to turn up the TMB, and it kind of looked, it looked exciting, like it might be doing something. It was a bit hard to find tumors that that happened in but I think there’s something to this that we change the tumor over time, and we need to start using what we do to it to make it susceptible to things.

Manju George 22:43
Okay, thank you.

Dr. Jon Loree 22:46
Another trial that was recently read out. So this was in at ASCO of this year was the CO 28 trial. So again, the numbers that we have, but it’s called the Neo trial. That’s the name for this one. And so this is a trial that’s looking at patients who have a very early stage rectal cancer, so there’s no lymph nodes that are involved. And if it’s near the sphincter, so it’s at the very end, those individuals would often need a surgery that’s going to take out the sphincter, and that leaves people with a permanent ostomy, which has a lot of quality of life issues for when you think about your day to day, activity, sexual health, body image, and so there’s, there’s been a move to try and do things, whether it’s with extra chemotherapy or with different types of surgical techniques, to try and preserve the sphincter. We call it organ preservation. Sometimes there’s different methods that we might use for that. The version that we did in this trial, we’re trying to use a different type of surgery. It’s a kind of a local excision. It’s called Trans anal endoscopic microsurgery, or trans an minimally invasive surgery. So what this is, is normally a surgery for rectal cancer might involve going into the abdomen, and there’s some ports, or it might be open. For this one, the surgery actually occurs through the anal canal, and the surgery happens that way, and it’s really impressive. Patients go go home the same day, and the recovery is very quick, and because it’s going in through the anal canal, they’re able to do it in a different way, where they can try and maintain the sphincter. One challenge is it doesn’t take out the area around the rectal cancer, so we don’t get lymph nodes to look at. But if we already know the lymph nodes are negative from the MRI or something, this might be kind of a good option. There have been studies that have looked at using for patients who have no negative disease, using chemotherapy and radiation. So the typical five and a half weeks of radiation and some pill chemotherapy called Capecitabine to try and shrink the cancer down and make it really small, so that way this trans anal type of surgery can be done. One of the challenges with that is that the chemo and radiation can make the sphincter not work as well. Even though we we preserved the sphincter, it might not be quite as good, and so people might have to go to the bathroom more often, or they might not get much warning before they go. And for younger women, it will put them into menopause. The. Radiation. And so trying to avoid that might be worthwhile. And so this trial was led by Hai and kenneki and Carl Brown, and we did it across Canada and a number of sites in the United States for patients who have a lymph node negative cancer, they received three months of chemotherapy, kind of traditional chemotherapy, and if the cancer is shrinking or staying the same size, there’s a local excision done, and then if there’s any high risk features, we would recommend doing the bigger surgery that’s going to potentially lead to a stoma. But otherwise, patients would go on to an observation schedule. Now the 58 patients that were on that, 56 out of the 58 were able to have just the excision, there were 10 that needed to have the bigger surgery, because there were some risky features that were seen. But we haven’t had any distant relapses, and there have been only two local, regional recurrences, and those have been operated on and cured. So it’s pretty exciting. I think this is, you know, it’s a really good trial. It’s very patient centered, and it was so rewarding to see people go through this and be able to at the end, have organ preservation so very positive. We do have some studies we’re doing on it where we have CT DNA, so we’ve got blood collected before the chemotherapy and then before surgery. And so the idea is, for those patients who might not have had their cancer shrink enough. Can we look in the blood and see if there’s signs that the cancer didn’t shrink enough, and for them, maybe we could do some radiation or something else to try and deepen the response and increase the chance that they don’t have to have the that big surgery and just got the results? Haven’t analyzed them yet, but they kind of just came off the sequencer recently, so should be exciting. Stay tuned. And then I just want to touch on a few trials that are open right now. And then we can go into kind of general questions right now. The trials that we really have in Canada, we have a trial essentially for everybody who has resected colon cancer, I’ll say So stage one colon cancer doesn’t really require extra adjuvant chemotherapy. Adjuvant chemotherapy is kind of an insurance policy. We give it after the surgery to increase the chance of cure. And then we have a couple of trials for stage two and three. The first one is called co 27 Iraqis is the other name. So this is a trial that candidate and France are doing together. What you’re looking at here is a graph that looks at all that we use T to stand for tumor, and then n is for the nodal staging. And all these patients in this study here are patients who have stage three colon cancer, but we’re looking at the chance of the cancer coming back here on the y axis, and you can see there’s a very big difference between someone in this group and someone in this group. And so here, you know, there’s a almost 90% chance of being cured. And here it’s, it’s, are we saying it’s less than 40% it’s a big difference, but we’re going to say they’re all stage three. So, you know, there we’re trying to tailor things. Now we’re doing a different duration of chemotherapy depending on the risk. But for people who are in this really high risk group with six months of full Fox, it’s still a really high risk. And so this trial is basically looking at adding an extra chemo, so the combination called FOLFIRINOX, versus a combination called FOLFOX, which is the standard, so it’s a more intense chemotherapy. And it’s looking to answer that question of this, the increased intensity will improve things. The other trials that we have are all looking at the this idea of CT DNA, so looking in the blood for signs of the cancer, and the idea.

Manju George 28:31
Sorry to interrupt. So if you go back that FOLFIRINOX versus FOLFOX, is this like stage 3c or what like?

Dr. Jon Loree 28:40
Oh good question: So it’s any tumor that’s t4 or n2 so t4 is basically how deep does the tumor go into the surrounding tissue, and then n2 means more than three lymph nodes have cancer. For anybody listening, so that’s those are the individuals that are the highest risk, and that’s who we’re recommending this trial for, or looking at having this as an opportunity, I wouldn’t say recommending, but it’s an option.

Manju George 29:07
Thank you.

Dr. Jon Loree 29:08
Yeah, thanks for pointing that out. I meant to touch on that next question, the next questions that we’re looking at are in the minimal residual disease space. So this is we take the blood test, and after a surgery, we can have a couple of different options. The blood tests can be positive, but there might not be any cancer around, or there might be cancer we can see on the CT scan. Well, ideally, individuals who are in this situation where there’s no cancer on a CT scan, if we give chemotherapy, we can try and cure them. But on the other side, there are some people who might be here where they don’t have any CT DNA and there’s no cancer, and right now, we don’t know who is going to have their cancer come back, and our guess is based on that TNM stage, and these liquid biopsies might help us be smarter about it, and so we might be able to tailor the therapy so those who are really high risk to come back, we give them more chemo, and those who. Lower risk, we might be able to avoid some of the toxicities. And the idea is, if this is a curve where we’re looking at the proportion who have their cancer come back over time, right now, we know about this black line, but if we could figure out who’s on the blue line, who are very low chance of the cancer coming back, they might not need all the chemo, and those on the red line might need more. So these trials are really trying to figure that out. We have a lot of retrospective studies so far that have told us this technology is very good. This is people who have CT DNA that’s positive. Most people will have their cancer come back in stage two and in stage three. Similarly, most people are going to have their cancer come back. But if they’re negative, if the blood is negative, then it’s very unlikely to come back. So the trials that we have, there’s one called Cobra, or CRC nine. This is a trial that’s open across North America, and it’s looking at patients who have a lower risk stage two cancer, who normally wouldn’t get extra chemotherapy because the risk of the cancer coming back is low, but patients are receiving the either standard of care surveillance or they’re getting the blood test, and if they have the blood test and it comes back positive, we do six months of full Fox. This trial’s been open for about a year and a half across North America, and it’ll be open for quite a while still. And then dynamic three is a trial that we opened just with about a year ago. And lots of centers across Canada have recently started coming online with this. This is for patients who have cancer that spread to the lymph node afterwards that on the trial, half of patients will do what they normally would do with the standard of care treatment, and the other half would have the CT DNA test inform what they’re going to do. And so we’re basically trying to use the CT DNA to help tailor the and personalized treatment. For those who are CT DNA positive, the risk is really high. So we’re going to go up on a ladder. We’ve got a ladder basically of all the different treatment options that someone could maybe have for stage three, because there’s a lot more decisions now for stage three, and we basically go up the ladder if it’s positive and down the ladder if it’s negative. And we’ve included a number of different options, so kind of the usual three or six months of full Fox or K pox. But for some people who might have other comorbidities, other health problems, or who might be older, they might only do Capecitabine because of the potential risks with it. And so we do have different options. So that way this is really open for everybody and anyone can participate on the trial. So this is open in Canada, Australia and New Zealand, all right, so a lot of presented a lot of things to, you know, the some of the stuff has been from some team members here, but we have a huge team at cctg, and it’s, it’s a, it’s a really, it is a really good group. And ideally, we have these trials that are open to everybody across the country. And there are still challenges with with having trials in smaller centers, sometimes just because it can be a little bit harder to open a trial if there’s only a few people who might go on to it. But we are working another big effort, and I know this is happening in the US as well. Another big effort is to try and make it so that way we can have remote trials and have people be able to participate in trials wherever they are, and in Canada, with our geography, that’s a really big challenge, but a really big opportunity as well. So with that, I’m happy to take any any questions, and thanks so much for your time.

Manju George 33:26
Thank you very much. Let me see if there are any questions. One thing that I often hear from people is like, what about for BRAF? Like, if somebody wanted to get on a trial, how would they go about it like, what can, what can patients and caregivers do to find out, you know, from their oncologist and to get on some trials? What? What advice would you give?

Dr. Jon Loree 33:50
So I think the first one is just asking about trials to your oncologist. So BRAF is a really good example of a drug that it’s nice to talk about the differences in Canada and the US. So we have encorafenib and cetuximab as effective therapy that’s coming forward in Canada right now. It it has, it’s going through the approval process for funding, but it’s kind of through an Access Program at the moment. And so there are drugs that are off trial that people can get that’s directed towards BRAF. But in Canada, instead of just having the FDA and then it’s approved and the drug companies quite quickly have it available to use through the insurance companies, in Canada, there’s a another step where it has to go through this economic evaluation and and oftentimes that’s a little bit later than the US. So a drug will get approved at the FDA, and then later on, it will go to Health Canada. And so we do have the first kind of option for BRAF directed treatments, and then for kind of after that first drug encorafenib and cetuximab has stopped working, then it really depends on the center, whether there’s a trial that might be open. One of the challenges we do have sometimes is that we are a little bit smaller in Canada, so our population basin, so we often focus on trials that are going to provide the most benefit to the most patients, because it might be hard for a smaller center to have a trial for every potential alteration or mutation. So it might be that if you ask your oncologist, they might say, well, I don’t have a trial here, but there might be a trial in Toronto or Vancouver or wherever. So those are potentials, and we do have some trials that might be basket or umbrella trials. So it might be that it’s not specific to colon cancer, but it might be for a drug that might might work.

Manju George 35:37
There’s a question about HER2 positive CRC, do you have Herceptin available for Canadians with CRC, off label?

Dr. Jon Loree 35:46
Yeah. So it depends on someone’s private insurance plan or if they’re going to pay. So we can potentially talk about off label drug use and and individuals can pay for things like Herceptin that are on the market. Sometimes patients their insurance plan. If we have extra private insurance will cover certain things, then it’s usually a case by case basis, where the physician has to kind of explain why it’s being used for HER2 amplifications in in Vancouver. Right now, we have some trials where they’re basket trials, so they’re not necessarily colorectal specific, but we have access to different drugs that might might be available, so each center is going to be a little bit different.

Manju George 36:26
Okay. Thank you. And I have one question, usually people ask me, like, if they’re in one part of Canada and there is a trial in some other part of Canada, how does it work? How do people can they do they have to move over to the other place and then enroll in a trial? Or is there like they can, they can only enroll in trials in their province. Is there something like that?

Dr. Jon Loree 36:46
I would say that it’s a little bit more complicated. If it’s out of province, if it’s in province, it’s really easy, because the way that the health insurance works, but it’s it is still possible to be part of a trial that’s in another part of the country, but that person would have to pay for the travel to get there. And then, obviously, COVID has made that a little bit more challenging from some of the travel perspectives, but it is still possible.

Manju George 37:09
I think the next question is about how to find out tumor mutation burden, like So would they need a biopsy? Or do you do plasma TMB?

Dr. Jon Loree 37:20
I would say that the plasma TMB is still investigational. We don’t, we don’t really know, and because we don’t know for sure, the drugs aren’t approved to match with it. So you often want to think about what, what gets you a result that you can also get drugs for. So I think that’s one that really depends on your local situation. So for example, in Vancouver, we have a trial where, if TMB is tested with a certain panel, that gets you access to a drug in this basket trial, but it only allows certain panels to be done, and that changes quite continuously, what trials are going to be open at each place. And so I think asking your oncologist about if there’s a trial, like, what test is going to be best for me? Because what I say today, you know, sometimes it’s because I like that test, and sometimes it’s actually more about the access to the drug, which is a really important part, whenever we’re talking about a test.

Manju George 38:15
Sounds good. And then what about all this, like, for example, I mean, I feel that I’m asking the wrong questions, being the US. But if somebody wanted to do like a MRD testing, like signature or guardant 360 I mean, how easy or difficult is it to get it done in Canada?

Dr. Jon Loree 38:30
So currently, none of those tests are available for commercial purchase. There have been some access program, but they’ve been very limited, I would say. And so if I have someone who wanted to get this testing done, I don’t actually, as of today, have a way of getting it done. I did have their companies have been helpful and given us some access tests, but not enough that everybody, unfortunately, we don’t have still access to it, and they’re still kind of learning how to provide it in a way that people could pay for it. So I’m not aware of any that we can actually order today, to be honest, unfortunately. So I think some people can. You know, we can. I think this will be something that’s going to change very quickly. And I know specifically that a number of those companies that you mentioned are looking into how to do this. It’s just they haven’t done it yet. They’ve been kind of focused on the US market.

Manju George 39:26
Okay, okay, sounds good. And then, so I think I’m going to basic question. So for example, when somebody is diagnosed with, say, stage four CRC in Canada, how does the process work? Like, you know, what are the basic like, immunohistochemistry testing or what. What is that? How does it work?

Dr. Jon Loree 39:45
So it’s a little bit variable depending on where you live. So there are some things that might be approved in one place and not in another place. We do most things are very similar across the country, but not everything. So if someone is diagnosed. Just, I’ll talk about BC, that’s just because that’s where I am. So if someone’s diagnosed in a hospital here, there’s a central BC Cancer kind of intake, and all cancer care, oh, not all, but most cancer care in the province is at these sites. So that way everybody across the province, in any location gets kind of the same access the referral comes in, and there’s certain tests that get ordered as part of the triage. So for example, a next generation sequencing panel that we do. We have kind of our own in-house panel that we do most people. So in where I live, everyone’s already had MMR testing because it’s reflexive. So we do that testing, both to give information for patients, but also because if we find patients who have that change, it has implications for their family members for screening. And when we think about a population, if we can find people who are young who we can prevent them from developing a cancer, that’s really helpful. So we’re lucky that we have that testing already available. So most of the time, all of that stuff is already done, and people don’t need to think about paying for finding their next generation sequencing test. It’ll just be done. Different cancer centers have different tests at each place, and so it’s hard to say what each depending on where you are, it might be different.

Manju George 41:16
So do they test for RAS mutations in general? Then if they wanted to give EGFR inhibitors, how would they know whether which to give?

Dr. Jon Loree 41:25
So we test, I would say, I’m comfortable saying that everywhere in Canada has expanded RAS testing and BRAF testing, and they also have MMR testing in Canada for the most part, whenever, once a drug is approved and paid for by the government, then it’s something where the test is also going to be approved and paid for. So HER2 testing is a really good point that was brought up by by one of our viewers, is that’s something where the drug is not necessarily approved and paid for in the public system. And so in some places the testing might be available, and in other places they might not do the testing because there’s no drug to go along with it technically.

Manju George 42:01
So the next question is, for the major cancer care centers, whom should be contact for clinical trial information? You’ve talked about asking our oncologist, what if our oncologist doesn’t recommend clinical trials?

Dr. Jon Loree 42:12
I mean, I think then it’s it’s having that discussion with them. There might be a reason that they’re not recommending. There might not be something that’s open at this time point. So I think clinical trials are really exciting and important, but oftentimes there are other treatments that might have more evidence or might be a better thing to do. So it really depends on the specific situation.

Manju George 42:31
Okay. The next question about, are there any special processes for Canadians to participate in clinical trials in the US without health insurance in the US? Or, you know, is there a just a regular visitor visa process?

Dr. Jon Loree 42:45
So I wouldn’t be able to guide you on the visa process, but I would say that if you’re doing any component of healthcare in the US, that’s something that’s not going to be funded by the Canadian healthcare system. So it would be kind of up to the individual and their insurance plan to identify the navigation for funding.

Manju George 43:03
Yeah, I just tried to there are a couple of people who are Canadians, who I know have been on trials in the US. So, I mean, if you message me, then I can connect you to those people, and they might be a good source of information on how the the actual process works. So how far behind is Canada in research for CRC, than the US?

Dr. Jon Loree 43:25
I don’t think there’s a difference. I think there’s different strengths in each country. You’ll notice lots of the trials that I’ve put up were things that were being done. So the COBRA trial, for example, is being done in US Centers for stage two. It’s being done in Canadian centers for stage two, the dynamic three studies that’s looking at CT DNA for Stage Three colon cancer that’s being done in Canada and Australia. The one in the US will be coming in a year or two, but it’s not currently open. And so that that might be something that we have open, but there might be more phase one trials that might be open in the United States than there are in Canada. So those are kind of new drugs that we don’t know how how they work. So at different times, there’s going to be different trials or different strengths in research, and ideally, we all work together. And it’s not that one is stronger than the other. I think we’re strongest if we’re working together.

Manju George 44:14
Yeah. So the next question is, trials in Canada for Stage Four colorectal cancer, what would you recommend?

Dr. Jon Loree 44:22
So it really depends on where you are and talking to your oncologist, because each center has different trials. So we have those cctg trials, which are the ones that I can say are across the country, but the industry trials, each center has to make their own decision about how many trials they can open. And as, as you probably know, you know, in everywhere in the in the world right now, there’s, there’s definitely staffing shortages, and so some trials have been slower to open than than would be ideal, because of everything that’s been happening.

Manju George 44:53
Yeah, and then you said that it’s Colon Cancer Canada trials, right? The website you had mentioned?

Dr. Jon Loree 44:59
Canadian Cancer trials. If you go on that website or cctg, they’ll have kind of the cooperative group trials, and then clinical trials.gov will have kind of any of the industry trials as well as the cctg trials.

Manju George 45:13
Okay, okay, thank you. I think I’m kind of familiar with the cctg because I’ve looked around different things, and then my other question would be, what about surgery and like radiation oncology, like trials, like they would also be listed in cctg?

Dr. Jon Loree 45:29
Yeah. So similarly, many of them will go through cctg, not all, so there might be some that are in the industry, but radiation trials tend to be academic quite often, so they’ll mostly be through CCT.

Manju George 45:41
I think the next question is, is there an increased wait time for resection surgeries due to COVID?

Dr. Jon Loree 45:47
You know, I think all kind of healthcare systems are dealing with strain from COVID. I think, you know, we’ve done a very good job, I can say, across Canada, of trying to prioritize cancer surgeries and other kind of very important surgeries that are time dependent. But I can’t give you kind of the exact wait times all over the country, so it’s been a bit variable, but I think they’ve done a very good job of trying to prioritize that both early on in the process of the pandemic as well as likely.

Manju George 46:20
Okay, so this might be more for my general understanding than, you know, dirty related trials. So is the first line chemo in general, in in Canada, like FOLFIRI versus how in the US, they do FOLFOX. Is that really true?

Dr. Jon Loree 46:35
Yeah, it’s really cold here in the winter, so we don’t like the oxaliplatin. Okay, I would say, honestly, everywhere except the United States, the first sign is FOLFIRI. So if you’re in Europe or in Australia, it’s also FOLFIRI. It’s just a, you know, there’s been a trial that show that the two are basically identical in outcomes, and it’s okay if you’ve switched from one or the other, but that’s just what happened in each community, and there’s been a preference. I do, honestly, I do think the cold, though, does impact treatment selection in Canada. So I definitely have that discussion with patients. If we’re around, if it’s the winter time, and we’re using oxaliplatin, depending on where you are, it does have more, you might be noticing it more. And there’s also, you know, there’s the fingers, but there’s also the component of, if you go outside and it’s windy out, and you get that gust of air on the back of the throat, you might feel, you might notice that. And some people can feel like they’re choking. That is a difference between, I’ll say, when I was living in Houston and when I was living in Edmonton.

Manju George 47:34
Yeah, Houston, I can imagine. So the other thing is that, like so we have in COLONTOWN, we have been, people have been doing this, what is called icing, yeah, which is basically like dunking their hands and, you know, or holding, like, ice packs in their hands, and then using cold socks for their feet, and for whatever reason, the theories that it causes vasoconstriction and less oxaliplatin, so they don’t have cold sensitivity.

Dr. Jon Loree 47:59
So it’s been interesting. I’ve had a couple of patients who’ve been doing that, and they it seems to work for them. You know, it’ll be something. We need to do a big trial of it and get it all out there and properly do it. It’ll be good.

Manju George 48:13
Yeah. So my other question is, so, for in general, for stage three, you know, for people who are not on the trials. Do you still do six months of FOLFOX then?

Dr. Jon Loree 48:26
So it’ll depend on the risk criteria, so for the lower risk, so if it’s not d4 and not n2 then most of the time it’ll be three months of capox. Obviously, it’s kind of patient specific, depending on other health issues and things like that. But I would say that that’s pretty standard across Canada. And then the six months is really for the higher risk tumors.

Manju George 48:46
okay, so for stage four, then they start with FOLFIRI. Do you add like EGFR inhibitors or Bevacizumab? When does that happen?

Dr. Jon Loree 48:55
Yeah. So it’d be the exact To be honest, most things were the exact same between Canada and the US. So we’ll add in the Bevacizumab or the anti EGFR, if it’s left sided, we’ll get wait for the panel to come back and make that decision. If it’s right sided, then we’re thinking Bevacizumab. There are some regional differences in funding for the anti EGFR first line, because it was the way the trials were done. It’s a little bit harder to to get that funding in place, but there’s often a way of getting first line n to EGFR, if that makes sense, and then we do the same. We kind of flip between them, and depending on the biomarkers, that’s going to change things immunotherapy. So for MMR deficiency, there’s an Access Program, and they’re going through the process of getting funding right now. We had to wait for the randomized trial that didn’t include immunotherapy before, because of the way we do our assessments for the finances.

Manju George 49:46
so and then, when? So when? If you’re stage four, and you start with FOLFIRI and add, you know, bevasicumab or EGFR inhibitors, and that’s generally till progression. Or do you do eight or 10 Cycles and then drop the irinotecan, Like, how is it practiced?

Dr. Jon Loree 50:03
I would say that we don’t need to drop as much in the first line because, you know, oxaliplatin, it comes on that you have to drop it. You have to dose reduce. And then, because we use FOLFIRI first, you can usually keep the dose a little bit higher, because there’s not the splenomegaly from the oxaliplatin. So I find that people who… some people, have a really hard time with irinotecan, but not everybody, and for the people who tolerate it really well, it doesn’t really accumulate the alopecia, so the hair loss does, but I don’t find that people get a lot more side effects in cycle eight than cycle four. For the irinotecan, whereas the oxaliplatin, it’s definitely cumulative.

Manju George 50:44
So it’s FOLFIRI until progression then, and then you switch to FOLFOX. Is that how it’s done?

Dr. Jon Loree 50:50
Depending on the patient, you know, sometimes, you know, we have a discussion, the tumors responded really nicely, and they want to be on a maintenance period. Or, you know, pre COVID People might want to travel, and then we might have taken a chemo break, but it is kind of patient dependent.

Manju George 51:06
okay? And then, like, once they go through FOLFOX, then is it like how it’s in the US? Do they get LONSURF and stivarga? Is that how it goes?

Dr. Jon Loree 51:15
Yeah, so if they didn’t get the first line anti EGFR, and they were RAS wild type, then we’d go over the anti EGFR and then to pirasil trifluorodine and regorafenib, are drugs that are in most provinces not funded because the magnitude of benefits versus the cost was not deemed to meet the bar for the health technology assessment, which is what we call kind of our central process. And so in that case, you know, we can apply to the company to see if there’s any kind of compassionate supply, as well as to patients, their private insurance plan, to see what they will cover. And then we kind of find out if it’s going to be covered, or if it’s going to cost, how much it’s going to cost, and have a discussion around whether it makes sense to do it or not. Okay.

Manju George 51:56
And then do people, like, recycle like, after they’ve had FOLFOX for some time, do they go back to FOLFIRI? Is that an option?

Dr. Jon Loree 52:04
I think it depends a little bit on how long it’s worked and how people are feeling, but you can go back to things if they worked before. I would say we probably don’t. If a drug has really properly stopped working, I think I wouldn’t be as keen on going back to it, as far as maybe trying to explore something different, as far as trials.

Participant Question 52:34
My husband has a stage four colon cancer, and then so the question is, they did the PDL one test, and then one test they’re saying the calculation they say is 0% and another one is they’re saying is positive. I guess they calculated that using including the immune cells and so just wondering, and we also did a foundation one, and he has four mutate tumor mutations. So I’m just wondering, could this kind of situation, he can join, like a immunotherapy trial?

Dr. Jon Loree 53:27
So this, I’m gonna stay away from commenting on specific cases a little bit, but I can broad, broad strength, Pdl-1 testing for colon cancer hasn’t really been something that’s been useful so far. It works for some cancers and not for others. And we, we don’t know, we don’t really know why it doesn’t work for certain ones, but for colon cancer, it hasn’t really been particularly useful. So I wouldn’t worry too much about the different ways of calculating it. There might be certain trials that say we’re looking for PDL one positive cancers for our new checkpoint inhibitor, or something like that, and that might be a different story, but for the most part, PDL one little bit less useful for colorectal cancer.

Participant Question 54:09
Okay, so because a lot of the immune therapy, they’re against the PDL one like this, they call that.

Dr. Jon Loree 54:22
You’re right, that’s, that’s the target. That’s what they’re going, yes, it’s their target. So you’re like, you have to be positive, and so you can, yeah, have this treatment to have effect is, but not using it depends on the type of cancer. So for colon cancer, the reasons that immunotherapy works is if there’s that problem in the proof reading for that deficient mismatch repair, or the other term is micro satellite instability, and we haven’t found any other biomarkers that say this definitely works. And so the other ones are all investigational, and we’re, you know, it doesn’t mean that we might not have something in the future, but right now, those are the only ones that work, and that’s only about five percent of cancers that have that abnormality depending on the stage factor,

Participant Question 55:04
So that means, if you’re even you you’re negative, you can still join those trials if they don’t have that cut off.

Dr. Jon Loree 55:11
Well, every trial will have kind of some different include, what we call inclusion criteria. So those are the types of things depending on the drug or what their question is. They might have some different rules, so each trial is unique.

Participant Question 55:23
Okay, okay, thank you.

Manju George 55:25
I think A. had a question about, what when is the best time to ask your oncologist about trials when you’re stage four? First line is working, so we’ve been asked to wait until we have we need to address options.

Dr. Jon Loree 55:37
Yeah, I think it’s always good to mention that you’re interested. And just because an oncologist doesn’t bring up trials doesn’t mean they haven’t thought about it, but sometimes we don’t always say that, “hey, I thought about it, but it doesn’t make sense for you to do” so you know some drugs, we know what works really well on the first and second line. We always want to make that better, but it’s it’s more common for drugs to be tested once the first couple of recipes stop working. So FOLFOX and FOLFIRI, despite being old, they tend to work quite well. And so we use them. And we don’t necessarily recommend doing something experimental if we’ve got things that work well. And so if things are going well, oftentimes an oncologist might say, No, I, you know, I don’t recommend doing a trial because you’ve got other things that make more sense that I think would work better. So it might be that that I think it’s important to say I’m interested in trials, but and say, let me know when, when it makes sense. But if they’re telling you that there’s, there’s a good chance either they don’t have a trial on the first line, or they’re thinking, your options are better to use kind of the normal things in the trial, and they’re trying to guide you that way. So think having a good dialog, and we need to do a better job of on call as oncologist, of saying, you know, I’ve thought about trials, and letting you know specifically we thought about it, but it just maybe there’s a reason for that suggestion.

Manju George 56:56
I have another question. Do you always check CEA, for patients? Is it checked when the diagnosis and through treatment. And do you also do CA 19-9 ?

Dr. Jon Loree 57:09
So I don’t, I don’t use the CA 19-9 personally. I don’t find it necessarily adds a lot of extra. I do do CEA serially. There are some patients who CA 19-9 might make more sense, depending on where they can, especially if it’s on peritoneum or something like that. But that’s kind of my practice pattern.

Manju George 57:30
This is another question about, like, you know, once they go through several lines of therapy, like, for example, in the US, you know, then they’re when treatment stops working, then refer to hospice or palliative care, right? How does that process work in Canada?

Dr. Jon Loree 57:45
Good question. So it is a little bit a variable depending on where you are and what resources are in place, but for the most part, we we have home care that’s funded. So hospice in the United States is a term often that’s very similar to, from my experience, that means kind of similar to home care. And so there’s kind of nurses, and there might be physicians who have more experience in managing symptoms and kind of building those supports around but I think in Canada, there’s probably a little bit earlier kind of the home we say we’re going to refer to that stream, but they might be not just kind of end of life care the hospital. When you hear that word hospice in the States, I think it, people often think of that and and sometimes when we bring it up in Canada, when I you know, I’m suggesting we’re talking about home care and these types of things. So we call it the in BC, we call it the palliative care drug benefit plan, the palliative Home Care stream. And people hear that, and sometimes it makes people feel uncomfortable or they’re but really, palliative care is about making people feel better and dealing with symptoms, and so similarly, you know, we make a referral, there’s nurses that might be able to come into the home and help out. There are limitations to kind of what’s available. So you know, around the clock nurse is not necessarily available for everyone you know, at the end of life, sometimes in the final days, that might be available, but not throughout the entire process. So there’s kind of certain availability, depending on where you are, and there’s there’s prescription plans that might cover kind of supportive meds, so things like opioids for pain or anti nausea pills, things like that, hospital care is covered. So there’s also hospice and there’s palliative care units. So if someone goes in through the emergency department, or sometimes they might go be in the home, and they might have pain that’s not well controlled, they might actually just get directly admitted to the palliative care unit, and there’s not really any cost or anything to that, hospice sometimes will have a little bit of cost. If there’s, like, food and stuff like that, that’s like different, or if there’s family that might be staying that’s kind of regional. It depends on the place, how much, but it’s usually something that’s very manageable, or they’re able to kind of work with people to make sure that things are covered.

Manju George 59:51
I think we are out of time. Thank you so much. This has been a great overview, and thank you very much for your time.

Dr. Jon Loree 59:59
Thank you for having me.