Genetics and Genomics of Gastrointestinal Stromal Tumors

MS. NEETA SOMAIAH, MD: Thank you, Kristie.Good evening, everyone.We hope this is going to be an informative session for all of you and hopefully we’ll be able to take most, if not all, questions that are coming in through the Q & A box.So we’d first like to start off the discussion talking about genetics and genomics, which is kind of integral to most of our discussions when we start treatment for just patients, talking about how to deepen response and prognosis as well.I’ll probably direct the first question to Dr. Heinrich about maybe explaining to the group about the importance of mutational testing and even CTDNA testing in patients with GIST.

DR. MICHAEL C. HEINRICH: Okay, well thanks Neeta, and thanks to the audience.So we’ve made a lot of advances in GIST therapy over the last 20 years, but all of our advances have been sort of with the insight that if we know what’s wrong with the tumor then we can develop a very specific therapy to try to fix that.And that was the beginning of what we call precision oncology and that way of thinking has been adapted to most of the common cancers, like lung cancer, for example.And, so we’ve known for a while there that GIST is not 1 actually type of cancer, that it’s multiple types of cancer.And so we have therapies that are very good for, say, 85 % of GIST using sort of the standard therapies.But we know that there are some nuances in that, like choice of drugs can be influenced in the 85 %.

And then the other 15 % of people our standard therapies are unlikely to provide any benefit at all, but alternative therapies might be highly effective for them and so we feel that it’s mission critical before deciding upon a therapy that the mutation be tested for in your tumor.So this could be done from a biopsy or a surgery specimen and it doesn’t really matter if the surgery was 10 years ago, most places retain their pathology for at least 10 years.And so we would, you know, encourage the patients to advocate for themselves for mutational testing with simple questions to their doctor like what type of GIST do I have?Is it a KIT exon 11? And hopefully your doctor knows what that means and if they don’t then you need to educate on your behalf and advocate for that type of testing.The other part of your questioning is circulating tumor DNA.

So circulating tumor DNA is based on the idea that all cells in your body shed some amount of DNA, it’s a normal kind of breakdown product.Tumors shed more than normal cells and with sensitive sequencing we can sometimes detect the mutation.So, in some people we could rather than, let’s say we didn’t have tumor or the tumor was really hard to biopsy or you’re on an anticoagulant that we couldn’t stop, we might be able biopsy or you’re on an anticoagulant that we couldn’t stop, we might be able to figure out your mutation from your blood using the circulating tumor DNA.But, you know, about a third of the time we don’t find the mutations, so not finding a result is not helpful.We can maybe later on circle back to other uses of circulating tumor DNA.

DR. SOMAIAH: Correct.And that’s what would be interesting to know is when do you use what?Gina, we talked about mutational testing on a tumor specimen, which I think is still the standard way of diagnosing what mutations you have, but I think circulating tumor DNA might have more uses as we go on and in further lines of treatment.So, Gina, when do you recommend?Because, you know, again, as Dr. Heinrich just mentioned, when patients are more and more asking about their mutational status, which is very encouraging, more than they used to before.So I’m glad that you guys are all empowered with this, but I think there needs to be more knowledge dissemination.So, Gina, guide us through when is it that we normally would recommend getting these mutation testing in patients.

DR. GINA D’AMATO: I think the first thing is with the mutation testing, the mutation status is important to know if you’re going to treat with medication, okay.We know the cure of the GIST is to surgically remove it and about 50 % of the GIST will recur.So, and we have imatininb that we give for patients with high risk, that if we were going to give it to prevent it from coming back.So if we’re not planning on treating it, we don’t necessarily need to know the mutation.If it’s a small tumor, we’re not going to give adjutant treatment we don’t necessarily need to know.But, if we’re planning on giving treatment to try to prevent it from coming back.We need to know if it is going to be sensitive to imatininb.

Now, most likely it will be, as Dr. Heinrich said, 80 % of the time it will be and we’ll use that dose.But there are mutations that will show that imatininb won’t be effective and then we’ll need to know that before wasting anybody’s time on the treatment.So definitely if we’re going to treat, if it’s already spread and we need to start on treatment, we want to know mutation status.Because we want to know if our treatments are going to be effective.Now, if a patient has been on a treatment and it is no longer working, it’s ideal to get mutation testing on that because we need to know was - did it develop a resistant mutation and what mutations and certain resistant mutations can help guide us for different treatment.So that’s ideal.

Now, it’s not always ideal to be able to get a biopsy, if the tumor has gotten worse and we’re trying to switch treatment.Ideally we can, because that’s more accurate.If not, that’s when we can potentially utilize the CTDNA.But again, most institutions that’s experimental, there are commercial testing available, but there are limitations in that.So that’s when I would recommend to get it.Number 1, if we’re going to treat initially and then 2, every time we have to change your treatment, ideally to test as well.

DR. SOMAIAH: Correct.Summarized, ask about your mutations and it’s kind of standard to do it before you start therapy.If you haven’t had it done before you have started therapy, they can always go back at the previous specimen and get the testing done at some point, say if you’re not responding to therapy.As Gina mentioned, ideally it would be nice to get new patients with every progression, but sometimes the progression is in multiple sites and each site might have a different mutation, so it is not considered standard to be biopsied.But if you’ve had a biopsy, for some other reason with progression or had a resection because of focal progression, that would be definitely a good time to look at mutations in that resected specimen.

And we can, if we have time, we’ll circle back to CTDNA which again I - it’s a very - it’s an upcoming technology, it’s useful but it’s probably still, you know, research or investigational, and done in certain centers.Marina, I mean this is one of the set ups where we inform people the importance of genomic, but what else would you recommend for patients?How should they inform themselves so that they can be better equipped asking these questions?

MS. MARINA SYMCOX: Yeah, I think the patients who are on the patient groups and GIST is fortunate that we do have very well organized patient groups, there is a high awareness about mutational testing, we discuss every day on our forums.The question is I think most patients aren’t in the group, so are there ways that the medical community could plant the message in other high traffic websites?An edu website, major cancer website that can be found on a Google search that to me is important.For a patient who feels perhaps a little uncomfortable or maybe they have just been diagnosed with a - -, I recommend that there are consensus treatment guidelines that you can access and printout.

We can go to a website, nccn.org, which what is it National Cancer Comprehensive Network, nccn.org.If you go to that website and in the top left there will be a menu for treatment guidelines.And you pull down the menu, you will have to short preregistration and after that you will - you can see the list and there is a set for gastrointestinal stromal - -.You can print, it’s a pretty long document, but it is the best stocks of standard of care.You can print it out, you can search it electronically through the keywords and you can take that into your doctor.If your doctor has not yet come around to - -, that’s something you could bring him and show him.And that will help. facilitate your discussion.

Also some patients do not really know the logistics and I have to say probably don’t either.Like what samples will I need?Do I have them on hand?Where will you send my samples and which genes will be tested?And how will it take before I get back a report?And how is this paid for?Will my insurance pay for it?You can come up with a checklist of logistical questions and answers to help patients feel more confident to bring the subject up with the clinician.

Finding the Right Team for Treatment

DR. SOMAIAH: Thank you Marina, I see that we have a lot of questions coming in.We will try to take them in the end unless there is one relevant to the actual topic, where I’ll try to scan them through.But we’ll move on to treatment because we are here, and we always, for most sarcomas, including GIST recommend that when you get a diagnosis of rare tumor you must seek out an expert or a center that specializes in the treatment of GIST.Because it takes a multidisciplinary team.Sometimes you don’t need everybody in the team, but it’s important, especially at initial diagnosis, to have input from the pathologists, the medical oncologist, the surgeon and often soon enough, we use interventional radiology colleagues all to chime in on how to manage the patients.

So if, Mike, if you could explain maybe what is the multi-disciplinary approach to treating patients with GIST?And how do these different factors play in?

DR. HEINRICH: Yeah, so it’s a good question.So a lot of times the multi-disciplinary nature plays out in what we call a tumor board.And so that’s the committee that most of our centers have and we actually, there are so many different kinds of cancer, we have a tumor board for melanoma versus lung cancer versus sarcoma.And so the participants at that are the pathologist to help us review the pathology, make sure we understand the diagnosis.The radiologist to pathologist to help us interpret the imaging.Radiation therapy, if their situation where radiation therapy might be used, which is not so much for GIST.

And then the medical oncologist and the surgical oncologists, which are to - here are situations even with - so in a primary GIST we generally would go straight to surgery, but there are certain situations where we think surgery might be excessively complicated and so we would want to actually shrink the tumor by giving a drug.So that’s a situation where we need to collaborate between giving a drug and timing of surgery.In some patients with metastatic disease we still envision situations where we might do surgery, so that’s pretty important.I would say, you know, outside of that, it’s the radiology or the interpreting GIST CTs can be a little subtle and so sometimes community radiologist might not completely interpret the same way that we would as to what’s going on.

Pathology for GIST is pretty good, but for any kind of rare diagnosis, like any kind of sarcoma, I would want it to be reviewed at our center before we would treat a patient generally.And so people at smaller institutions, you might want to have that pathology reviewed, just to make sure that the diagnosis is correct, because there is a lot of things that kind of look like GIST, that are not GIST, and we would treat them all completely different.So there is a lot of levels of sort of collaboration that are important.Getting to diagnosis right.Understanding if you’re responding or not responding based on the x-ray.Thinking about should we integrate surgery or not?

Or if yes, when would we do it?So there is a lot of ways that works.And in general kind of going back to what Neeta or Gina would probably agree with this, that having a center that specializes in this from the get go is generally better than having a medical oncologist here and a surgeon across the town and the pathologist is in a different city and nobody and nobody is really - and the radiologist is in Australia reading your x-rays on the internet.So having people in the same room or at least in the same institution, is often very valuable, especially trying to get records that everybody can look at.

DR. SOMAIAH: Yes, absolutely.And, you know, not everyone, probably if you’re not in a place that has easy or close access to a center that has all these specialists, is important to try and get to a center, early on in your diagnosis to get an opinion.Because, I mean as everyone in the panel would agree, we see a lot of patients who don’t necessarily stay in the area and then we’re able to give them good guidance and tell them when it’s the right time to come and see us again when things are not going well.

But they don’t have to necessarily move, but they can still continue their care local with the guidance of the experts.So it’s important and coming early on helps getting on the right treatment path for the future.So, Marina, you kind of gave good ideas for folks to approach topics about the genetic testing and how to be equipped with questions.But, and I guess the same way, if they feel their local oncologist doesn’t have much experience but is not recommending the patients to go seek a second opinion, how do patients approach that and try to get to a center with - -?

MS. SYMCOX: So is there a question with that?

DR. SOMAIAH: Yes, well I guess you know it’s kind of - what I would tell patients s go ahead, ask your local oncologist if you can get a second opinion.And if they’re not in favor, how do you navigate that to try and still go and get a second opinion at the center.Are there ideas that you have that you can share with patients?

MS. SYMCOX: I have never had a problem getting a second opinion.To me that that would be the warning for a local oncologist to not agree to that, to be honest.But, I do think as well as you can self-educate, is important.And the internet is really the place you’re going to do that.So learning how to search for reputable websites is important.So if you had a search term, I recommend that as you put in your search term, you might put for example .gov and that will take you to the NIH, NCI websites.You can put in your search term .edu and that will take you to academic university websites.So learning how to use the internet to inform yourself is really important.I really don’t have experience with the local oncologist declining for referrals, to be honest, unless it has something to do with insurance coverage.

Treatment Options for GIST

DR. SOMAIAH: Right.So, I think you know again, seek out a second opinion when you can.So we will move onto treatment.I know that’s most of the burning questions are coming in that category.So before we - and we will try to take questions as we do.But kind of to provide an overview, Mike do you what you want to get us started with reviewing the currently approved tyrosine kinase inhibitors for the treatment of GIST?

DR. HEINRICH: Yeah, there’s actually more than people might think.So again, kind of going back to our idea of genetics, let’s think about your GIST.So if you have KIT mutant GIST, which is the most common, they’ll be approved agents are imatininb or Gleevec, sunitinib or Sutent.Regorafenib also known as Stivarga and the newest one ripretinib, also known as Qinlock.And the order of treatment as they have been developed is Gleevec, Sutent, Stivarga, Qinlock.So that’s that pathway.Now, if you have a different type of GIST, PDGFRA, especially to the D8 42 V mutation, you will not respond to any of those drugs, or at least we don’t think so.

But there is a new drug avapritinib or Ayvakit, which has recently been approved, which is highly effective for that form of GIST.And so again, you don’t want to be on 4 drugs that aren’t likely - that aren’t expected to work at all, that have side effects before you get to one that works.So if - you need to have mutational testing, so we can branch at the beginning.There are more unusual forms of GIST that actually have, rather than mutations, they have chromosomal translocations that kind of bring together things.

And so there is an enzyme known as NTRK, N, T, R, K, and there is 1, 2, 3.And that is kind of similar to KIT and PGFRA, but it’s different, but it can be activated by translocation.And there is 2 approved agents for that.So that’s only like 1 % of GIST but again, the point is why would you want to take 4 drugs that can’t possibly work when you have 2 drugs that are highly likely to work?So kind of starting off on the right pathway.There is other situations like, again, rare things like BRAF mutant GIST.We don’t have a drug that is approved for GIST but we have drugs that work for BRAF mutant melanoma and we’ve had some success in that rare situation.

So there actually are quite a few drugs and again, making the correct selection and which pathway you want to be on is really helpful and mostly - well I would like to think that mostly we start off on the right pathway but I would have to say like from Gina’s institution, Dr. Trent who has studies that only according to the Medicare, kind of database, only 25 % of GIST patients in the US have tumor mutation testing, at least as of a few years ago.Hopefully it’s better, but I suspect not dramatically better.So you want to get going the right way from the beginning.

DR. SOMAIAH: No, that’s right, and I see a question in the chat box, and I don’t know if it’s for the adjuvant setting, which is after your tumor is resected.But they’re asking how long should a patient be on Gleevec?And you know if you have advanced disease and you’re being followed on - and you’re taking imatininb and there is disease and it’s disappearing, I basically keep you on imatininb basically as long as it’s working.So you - it’s pretty much there are patients that are on imatininb for 10 years because they had metastatic, just to start off with.And invariably when you stop they might be disease free for a while, but the tumor invariably comes back.

So if you have metastatic GIST to begin with, or advanced GIST that has spread to the peritoneum, liver, or elsewhere and you’re on imatininb and it’s working, you basically will stay on Imatininb or Gleevec, as long as it continues working.And I can direct the question to Gina or Mike in terms of the adjuvant setting, which is after your tumor is resected and we know that you have a mutation for which imatininb would work, and your doctor has identified this to be a high-risk situation for recurrence, the recommended this up to 3 years at minimum.But we’ll see what Mike or Gina would say in terms of what they do, because I think you both have different practices a little bit.

DR. HEINRICH: Yeah, it’s - maybe let Gina go first because I —

DR. D’AMATO: So, I think - you know the key is that really identifying what risk means.So there’s the 3 factors that we take into consideration, 3 main ones, but then also some other minor factors.So we want to see where the primary location is and that mitotic index right.So after was a tumor completely removed, had it spread anywhere?And what the size was, was it less than 5 centimeters?Was a less than 2 centimeters?The size and the grade, which is descriptive, how fast these cells are growing and dividing.And we defined the grade for GIST as the mitotic index.So basically the pathologist will count up how many cells are growing and dividing per the specimen and they can calculate that.

So based on the location, the size and the mitotic index that we can put in a formula and try to figure out how high at risk.So if it’s low risk, the chance of it spreading - well, you don’t need to be on additional treatment because why put your body through additional treatment if the chances of it spreading as low?If it’s high risk and usually if it’s high risk, like if it’s in the small intestine and it’s greater than 5 centimeters and it’s high grade, that’s very high risk.If it says high risk and it’s 90 or 95 % chance it is going to back, then I would out the patient - I would recommend imatininb indefinitely.I would put the patient, depending on how you’re going to tolerate it.

But the average, when the studies were done, initially the study was done 1 year you would take it, then they showed that 3 years is better than 1 year.And another study showed 5 years was good, but they didn’t compare it to 3 they just said 5 years was good.So it’s going to be dependent upon what your they just said five-years was good.So it’s going to be dependent upon what your risk level is, low, moderate or high, how you’re tolerating the treatment, whether you’re going to be on 3 years or longer or no treatment.

DR. HEINRICH: Yeah, I mean, I think this is really controversial.I mean, I agree with all that.Definitely breaking down the risk is very helpful, because some people probably don’t - we wouldn’t recommended it.I guess the main question we have not really figured out is does Gleevec kill off the microscopic cells or does it just put them in hibernation?So if you think about your garden, is Gleevec weed killer?So if you apply it you’re not going to have Dandy Lions?Or, is Gleevec winter, that dandy lions will not grow when it’s winter, but when you stopped Gleevec it’s spring and they’ll grow?We don’t really know.

Some of this kind of comes down to what your goal of therapy.So, if your goal of therapy is not to have a tumor come back in 5 years, your best strategy is to take it for 5 years, because the chance of recurrence on the drug is very low.Now, if your goal is I want to be alive in 15 years, what’s my best strategy?We don’t actually know the answer to that question.We don’t know does it really matter whether we treat you as long as we can and then if you get resistant switch or should we treat you for 3 years, stop and then restart if it comes back?You know, we don’t really know that.And that’s really frustrating, I think, to all of us not knowing the answer to that question.

I don’t know if they’re still doing the studies in Europe of 3 versus 5 and 3 versus 6.That might give us a little bit more insight.Generally, what I do is, for patients that are at least intermediate risk or higher, I discuss a minimum of 3 years with Gleevec and then let’s discuss it at 3 years and what do we know.If you’re at really high risk, like 95 %, I’d say let’s go 5 years because we have precedent for that and then let’s discuss it.Although my inclination is if you have 95 % risk that we probably, as long as you tolerate it and you’re willing, we shouldn’t stop it.

But there is limitations to what we know and different people interpret that differently.And then if you’re - if we get into the model that longer and longer is better than we want to be really careful on the front end, if you have a 1 % chance of recurrence, we don’t want to sign you up for Gleevec for 10 years because that makes no sense at all.And then where is the line?Is it 30 % risk, should we give you really 50 %, 70 %?I mean different people would draw the line.And if it was me and my body versus me counseling you, maybe the line and it looks different one way or the other.

DR. SOMAIAH: Yeah and that’s just very well said.You know that’s the discussion we have with all the patients.So, as we mentioned, knowing your risk.And I think most of us from a low risk, we wouldn’t recommend we will do the close watching.But for moderate to high risk we will definitely recommend.And it would be 3 years and beyond 3 years based on how you’re tolerating it, based on what your risk is, based on what your risk tolerance is.We will either do indefinite or we will stop and then closely monitor.So the key is if you have high risk and you’re stopping Gleevec, that’s - in the next 2 years you are at high risk of recurrence, so you need to be watched carefully.

DR. HEINRICH: I see a question that is relative to this point, so I just jump in.So the question is, if the guideline says 3 years, what about your insurance.Well, actually the FDA prescribed information does not say how long, it just says you should give Gleevec is approved after surgery, period without any limitation.I mean it’s a little surprising given how the studies were done, that, that they didn’t make them put 1 year and then switch it to 3 years.But the point of fact is if insurance is going to say prescribing information is the basis of their approval.Giving it indefinitely is consistent with the FDA prescribing information, so you could have an argument with your insurance company for sure.

DR. SOMAIAH: That is correct.Just moving on about what are the other treatments?So, we talked about, you know, imatininb, Sutent, Stivarga ripretinib or Qinlock and then Ayvakit or avapritinib when patients have the PGFRD 42d mutation.So there is a question is Qinlock the last line for this disease?So in - by approval standards for KIT mutant disease Qinlock is the last approved line, the fourth line approved.But as everyone on this panel and most treating GIST doctors know that people go through multiple IBs or TKIs interspersed with clinical trials when available in order to increase the lines of disease available.So there are a lot of patients who will come to our centers at the time when they’re running out of options.

So, you know, IBs that have been used and the other TKIs have been used after Qinlock, or even before Qinlock, because Qinlock was a recent approval, include nilotinib, pazopanib, which is also known as Votrient, there is cabozantinib.I mean there are multiple drugs, some are more easier to access.There was also a drug called ponatinib, some are not - and again the problem becomes, when you get to that line, most patients might have multiple mutations and it’s difficult to pick out which drug might work or might not.So we base that on the information we have and what drugs that are available to us, how the patient is doing.

And, whenever possible, access to clinical trials, which we can probably discuss next, is what I would recommend, because that’s where we get new therapies from and we’ve had very - some exciting trials with exciting data that have got us these 2 new drugs in the past year.So, we can start with Mike, do you want to list off some of the trials that you think are exciting and upcoming, or open right now for GIST patients?

DR. HEINRICH: So there’s a Daichi study which you’re participating as well and so that’s kind of a totally different idea.So rather than trying to inhibit the mutation, this is kind of - this is based on targeting a chemotherapy drug specifically to the GIST cells and not to the normal cell.So basically the antibody is like half of Velcro and the tumor has the other half of the Velcro. So as it slides by normal cells the drug will not bind but when it hits a GIST cell it sticks.And when it sticks it gets taken into the cell and the chemotherapy gets activated.So the idea is that the chemotherapy is only activated in the GIST cell and not in the normal cells.And we know that the toxicity from chemotherapy is from poisoning normal cells.

But we don’t - there’s a lot about - you know this is a phase I study, so we’re excited about it but we don’t know, does it target correctly.And we also don’t know will the chemotherapy kill GIST cells efficiently.So even if it targets correctly, is it correct chemotherapy.So there’s that approach.You know we still think there might be some immunotherapy approaches to this, but the ones that we have tested have been unsuccessful, but we need to continue to learn more.We also know that for the standard KIT mutant GIST that mutations, the secondary mutations can still defeat our drugs.So, can we come up with a 5th drug that’s better than the first 4 that takes care of all the mutations?

Or can we find a combination?I think that at Miami - I don’t know if Gina was there when they did this but John certainly was there when they did the combination of the Flexicon 9486, or some number like that plus sunitinib because they are complimentary drugs, they do different things and theoretically they inhibit all the mutations.So you know trying to be better against mutations, try to better with the immune system.Or just target the drug - target just with chemotherapy or there’s a radiation study that’s sort of a similar idea.You know again, I think the exciting thing is that more and more drug companies are still interested in GIST.

And you know Daichi had never been in the GIST space before and now they are with this study.SO I think that’s very exciting and we certainly appreciate all the patients that participate in these studies, especially the phasestudies.Because all of the drugs that we talked about, at some point, somebody was the first human and then somebody was the second human to every receive that drugs and that’s how we decide if drugs work or not.

DR. SOMAIAH: Yeah, correct.I mean, I was just going to mention Mike, I like your analogies and I’m going to steal some of them.The Velcro and then winter and the weed there.That was very good explanations.And I think there is also - and I guess the mech - so just as Mike mentioned there are a lot of new, newer drugs, or newer ways of targeting GIST, with immunotherapy and the Daichi drug, which target GPR 20.But also there are some combinations that have been looked at, just as Mike mentioned, with the Plexicon drug Sunitinib but I don’t think the trial is open, and hopefully there is time to develop it further.

And then there is the MEK in inhibitor which there is talks about, you know there is talks about in combination with imatininb.And the idea is will its delay resistance - - on imatininb and will the risk benefit be actually worth it.So that’s under consideration as well.Gina are there any other trials off the top of your head?

DR. D’AMATO: Yeah, so we’re going to have - so there’s a trial for SDH deficient or mutant with Zolamide.And then also we have one about to open or opening for, its ripretinib so Qinlock in combination with a diabetes medicine repaglinide, which to look at.It’s a phase I, it’s a look to see the combination and how it’s metabolized in your body.So that gives the patients an opportunity to get that drug sooner than4th line.And then we’re going to be having a trial called Intelligist where patients - we’re going to be collecting the CTDNA and then based on the mutation they will either get Sutent or Regorafenib or another, it’s possible maybe ripretinib.So that’s in the pipeline, so those were very exciting treatments.And again, we’re anxiously awaiting what’s going to happen with the Plexicon plus sunitinib.Hopefully, rumor is that the trial is in development.

So a lot of exciting - what I do is I go on, what I recommend if you can go on clinicaltrials.gov if you just type in GIST you get a little bit overwhelmed.But you can filter it down to recruiting and when you filter down to recruiting it definitely shrinks down the number.And then if you’re in the US you may not need to travel to China or whatever so you want to filter it to the US.Or you can say oh maybe I do want to go somewhere.And there are some exciting trials in Europe that I did notice a combination of Axitinib and avelumab but I think that was already reported.So definitely exciting things on the pipeline.But as Dr. Somaiah said, Neeta said, that actually we don’t just have 4 drugs we have a lot of drugs, that are not FDA approved, but the key is to have you on something to suppress that KIT receptor from being turned on.

DR. HEINRICH: And I would add to Gina’s great comments on clinicaltrials.gov is don’t be scared off if it says it’s in Texas or Portland.Because I know for the Daichi study, at least at our site and most of our studies, we negotiate travel into our budget so we will pay your travel and for a caretaker.And so, we know for GIST that for the early studies we generally only need 3 to 5 sites in the US.And so it’s more efficient to pay for the patients to go there than it is to open it at 50 sites, looking for 1 patient.So, you know you can always call and ask if there is travel and that can factor in sometimes.If it doesn’t matter to you, it doesn’t cost you anything to travel, you might be more willing to do something then obviously if it’s to fly to Texas every week on your own dime, it’s a great state, but you know it’s expensive.

Side Effect Management

DR. SOMAIAH: Very well, very very good point, Mike.We can move on to the last section that we’re going to talk and we’ll take as many questions as we can, it’s about side effect management.And, I know Gina, at one of our seminars, gave a really good talk on this.But, what is role of - how do side effects play into your treatment decision making and factor into the patient’s quality of life with the different treatments, in general?You can give a general answer.

DR. D’AMATO: So thank you, yes.So when we think about the side effects we have to again, when we’re on treatment, we have to think of pros and cons of things, and the risks and benefits.So we have to remember that everything we try can potentially have a side effect.And you know what’s why these television commercials are really funny because they say oh this drug is great and then they list all these potential side effects.And a lot of times when a patient tries the drug it’s something new and you may get more side effects and then overtime actually the side effects subside.And, there are a lot of different treatments that we can give to counteract it.

So for example imatininb, yes oh great we only have to take one pill a day, it’s only one pill.Actually it may wind up being 3 or 4 pills because you may have to have a nausea medicine, or you may have to have something to counteract the diarrhea.So, but that’s okay because the goal is to keep the cancer under control or prevent it from coming back.And because you have to remember that the cancer itself also can have side effects, right.

Cancer can cause pain, cancer can cause nausea, cancer can cause anxiety and bleeding.So you know you have to think about the side effects of the cancer.And so, quality of life is very important but we take that into consideration because quality of life can also be effected by if we don’t have your cancer under control.But we definitely have lots of different treatment options that we can do to counteract the side effects.And it’s very rare that I actually have to stop a drug based on the side effects.I usually can monitor someone very closely, be - if you, if someone starts you on a new medication and they give you an appointment in 3 months, okay I’ll see you in 3 months and we’ll get scans.No, you want to say wait, I usually see them at least once a week or twice - once every other week in the beginning to see how you tolerate it.

So you need to demand that from your doctor.Say you know you need to be followed closely.Usually when I start a patient on a medicine, I follow them very closely and then I release them.Okay, now I’m releasing my strings to you.And usually within the first month, you can get it under control.So you don’t want to give up and relinquish to these side effects, because again, they can be managed.

DR. SOMAIAH: Yeah, no that was very good.Exactly, I mean there are different side effects, I don’t know if we have time to go into all of them, but just as Gina said very rarely do we need to stop the drug completely.There is different dosing decreases that we can do and with aggressive symptom management we can usually keep you on your drug.I am getting a lot of questions here.I don’t know if we can take.

Q & A From Audience

DR. SOMAIAH: So there is one question about a clinical trial and whether it is open to outside the US or Canadians?So the problem there becomes for outside US patients is you need to have insurance that will cover you.Or else - even though the drugs are usually provided by the clinical trial, the standard of care costs then become out of pocket expenses if you don’t have insurance to cover you.So the trial, everything that is covered by the trial which is the drug or even travel reimbursement will be applicable to you.

But there’s a lot of standard of care treatments like your CT scans, your doctor’s appointments, that might not be covered.And I see this question about how do you find a trial?But we did kind of discuss that, so talk to your oncologist.But, clinicaltrials.gov just as Gina said, is a great site.But you need to filter it in for actively recruiting, GIST trials.And then if you’re in the US and want to limit it to the US, you can.And you will get a bunch of trials in there.There was also a question about, for Dr. Heinrich, about whether the trail was open only for all mutations or for KIT exon 11?I don’t know which particular trial that question was about, but I can just answer that - so Mike go ahead, you can go ahead and take that because it was directed to you.

DR. HEINRICH: Well, for the Daichi study it is not restricted to any particular type of GIST.So we think that what we’re targeting the Velcro is intrinsic to all GIST, so the mutation doesn’t matter.Although, we’re trying to figure out if that’s true or not.There is not a specific limitation.That’s a good question because some studies are very limited by what type of mutations you have.So, but this one is not.

DR. SOMAIAH: Right.And then Gina do you want to take this question?Is it possible for GIST on the stomach to metastasized?Which you know it is, but can it spread to the adrenal glands?

DR. D’AMATO: So, it is possible that GIST of the stomach can metastasize and it’s going to be based on the original tumor size, the mitotic index, how many cells were growing and dividing by their - and other factors.Whether it’s spread to a lymph node, which is rate but it’s possible.I supposed it can metastasize to the adrenal gland.I think it’s rare, I think most likely it’s probably around, close to the adrenal gland because you can - it can metastasize in that mesentery, which is like the abdominal area.And so it’s hard to say whether it’s actually in the adrenal gland or more like close to or attaching to it.So have that - I don’t know if anyone else wants to —

DR. HEINRICH: Benign lesions of the adrenal gland are super common, they’re called adenomas.So we could go scan a 100 people that are healthy and we would find some.So, you know again it could go to the adrenal gland, but most likely in GIST it’s probably a benign thing.And sometimes we, if you had an old scan from like 5 years ago, we’d see the same thing.So you know yes it’s possible but probably, adrenal mets are very rare.

DR. SOMAIAH: Right so if that’s the only site of some abnormality looking into it further, it might not be a met, that’s what we’re saying.So the next question, again, we can take it, is there any research being done about wild type GIST where there is no mutation exist?And what treatment options are available?I find that this is still my most challenging group of GIST patients to treat because just as Mike mentioned, there are other mutations.

So just make sure if you don’t have KIT or PGFR mutations you do the whole panel so you can look for this fusions or those rare BRAF mutations that we have targeted therapies for.Gina did mention there was the temozolomide which, this class of drugs the - - temozolomide have had some activity in wild types.There is an ongoing trial in San Diego.Mike and Gina do you want to add anything else, in terms of - and again, the GPR 20 trial you mentioned, again is mutation agnostic.So that’s also something that is applicable to them.Anything else?

DR. HEINRICH: These days, if you had a comprehensive panel, the - a GIST with no mutation would be less than 1 % of all GISTs.So intrinsically that’s the result, we would question the results and maybe no everything was tested or maybe what was sent was normal tissue and not the GIST.So, mostly wild type these days means well we only tested a few things and we left the 15 causes of GIST off the list and so we just don’t know about them.

DR. SOMAIAH: Correct, so we can move on to - and just with that the mutation from metastasis change from the original primary tumor and that kind of ties in with the CTDNA question a little bit.So we can talk about CTDNA - well one question is whether CTDNA predicts recurrence.Then we can go on and talk about it in the metastatic setting.So, Mike do you want to take that question?

DR. HEINRICH: Yeah, I actually think Gina’s institution is kind of a leader in this, so I don’t know if she wants to go first.(cross talk).

DR. D’AMATO: So yeah, I think right now the CTDNA, as Dr. Heinrich is saying, is not 100 % accurate.And the reason being is that it’s not sophisticated enough to detect a small amount of tumor.Right now if you have a lot of cancer in the body you’re more likely to be able to get a positive result on the CTDNA.So, we’re not at the level right now to be able to predict recurrence meaning that we can’t see anything on the scan.Now, hopefully we are doing - we’re trying to work on an assay and actually we have a PhD student that’s going to be working on an assay that’s going to hopefully be able to detect it at a different level and optimize that.

You know when they first came out with the cell phone it was this big honking thing and now it’s this little small thing.So hopefully we’ll be able to get to the technology.But, right now the only way we can predict recurrence is by looking at your scans, if it’s recurred.And then does the - does it mutate?Like if the original one and then it spreads, is it a different mutation?You have primary mutations that’s always going to be there in the primary tumor.If it’s spread and you’ve never been on treatment, and it’s spread, likely it will have the same mutations that we can detect.Now there may be some newer ones.

If you’ve been on a treatment and then you develop metastasis it’s possible then you may develop - you’ll still see the primary but you can have additional treatments - additional mutations.And probably Dr. Heinrich has some analogy that we’re going to steal from him to explain that.But I don’t know if I explained it - he explains things so good.

DR. HEINRICH: Well, to me - so you know the drug has to fit in exactly to KIT for PGFRA where the target is quite exactly.So I view it as a key in the lock.So you have the lock and so it’s you know it’s a quick change lock or whatever but then as the drug - as the tumor gets drugged it randomly mutates and so the lock changes and the key doesn’t fit, but you can sometimes find a different key that will fit into the lockThe kind of problem with if you have 20 GIST tumors and you’ve been on multiple drugs then you may have 5 different versions of locks and so choosing the drug is not easy to predict other than going 1, 2, 3, 4.

We’re hoping that in the future, circulating tumor DNA might sort us out because we might be able to sort of detect all the different locks in the blood sample and kind of make an informed decision.But we actually don’t know if that’s any better than just choosing the 4th drug over the 3rd drug, that needs to be worked out.

DR. SOMAIAH: Right.So there is a question about can a KIT mutation also have an - can also be NTRK positive?So my experience I haven’t found that yet.The NTRK fusions that we detected, again very rare, I know of 2 GIST patients, but it was in non-KIT mutated GIST.Another other comments, I mean from the panel?Have they seen that?I think they are mutually exclusive.

DR. HEINRICH: Agree.

DR. D’AMATO: That’s the standard of thought, yes.

DR. SOMAIAH: Yes.There’s also another question about 2 - like you know when you have repeated biopsy, and you still don’t get enough tissue for genetic testing, it can be quite frustrating.But the questions becomes if that’s the only site of your disease in one area then we kind of go to the panel and kind of go by a surgical approach to try and get enough tissue.But, often than not we are able to get specimen unless your mets or the disease that you’ve been left with is just very minimal.In which case, you can kind of wait until it starts growing and then you have access to more tissue.

Because if it’s not growing and say controlled on imatininb then the urgency of that mutation testing is not there.Because there are a lot of patients who come to us who already started imatininb, their tumors have responded really well and there is really dead tissue.So but if they have not had mutation testing upfront and we have no access to their tissue, we’ll probably wait until they progress before we try to get more tissue to get mutation testing.There is a question about how important is it to see a GIST specialist?Let’s see, Gina, can you put that into good words?If not we will get it to Mike again.Because we kind of talked about this, how important is it?

DR. D’AMATO: Very very important.I mean you know I think it’s just a matter of you want to have the GIST specialist evaluate you and be part of your treatment team.Not everyone has the ability or resources to, or ability to be that be your primary oncologist because you may not be able to travel to the location.But at least have them - have you - have someone be on your side, fully evaluated at an institution and then they can work with your local oncologist to help make decisions.And you know COVID sucks, we all know that, I’m not going to sugar coat COVID.

But it did come up with telehealth and telehealth has been a game changer for sarcoma experts in that we can reach more people now.Patients can come to see us for opinions and we can see them, get their scans, look - have their biopsies evaluated and we can help them.So, you do want to have someone that at least you’re in contact with, at least once a year.And a - -

DR. SOMAIAH: And that’s a very - oh I was just going to say that that’s very critical now. That’s one good thing coming out of COVID, telehealth.So I don’t know if Mike you have it too, but I know for Gina and us, we’re able to do tele visits for patients now.

DR. HEINRICH: I mean I would kind of go back to what Marina said, I think it’s important to advocate for yourself.So the first time you meet your doctor, if you have a list of questions that you have like; what kind of mutation do I have, what does of Gleevac should I be on, some sort of standard questions.And if your doctor seems unsure or intimidated by those questions, or you say well I’ve heard that there’s side effects I should get a follow up in 3 weeks and they say no 4 months is fine.Then you know even if they’re not a GIST specialist somebody else might be a better doctor for you to work with you.

So I actually like it when people come in with these sort of questions, because then it makes my job easier to educate them and work with them because they’ve already done a lot of thinking and so I just have to figure out what their questions are and work with that.So, seeing a GIST specialist is great.So you know the doctor that is knowledgeable about GIST even if they’re not a sarcoma specialist and that will work with you, that’s the doctor that you want.And that’s sort of like if I want to have back surgery and I did have back surgery, if I didn’t trust the surgeon answering my questions, I’m not going to have surgery.So, I think that the same principle applies, be comfortable with your doctor.

DR. SOMAIAH: Exactly don’t be afraid to ask questions.So there is a question about combinations, really, so different pathways, metabolic pathways if they are identified can they block the drug combinations.So I’ll just tart by answering that drug combinations do make sense in certain situations.We just talked about the Plexicon drug that was combined with sunitinib as Mike said, one targets the resistant exon 17 mutation very well the other one has activity against exon 13 - - mutations.So we feel the combination has activity in a larger number of patients because of that dual blocking being effective.

But, usually combinations are done as part of clinical trials and as we’re doing clinical trials with combinations getting tumor tissue and CTDNA to try and evaluate which are the populations where those combinations make the most sense are probably going to be a good way forward.But we don’t do it outside of a clinical trial.Mike any other comments on that?

DR. HEINRICH: You know combinations sound great and we think likely they make sense.But in people they’re difficult because drugs don’t always play with each other.So we give 2 drugs and we might find that both drugs become super toxic when we give them in combination while individually they are fine.Or, sometimes they oppose each other, one drug makes the other drug level drop and the other one goes high.So we have to test all these things out and sometimes it’s just not easy to figure a way - ways to combine them.So, you know it’s been frustratingly slow.And for most cancers it takes a while to get the combination treatment.

DR. SOMAIAH: Right, there’s another question, I don’t know if it will be our last.But, who qualifies for surgery to remove GIST?And Gina, I mean I guess you could tackle it in the localized setting but also in probably the advanced settings.So who would qualify for surgery?

DR. D’AMATO: Who - like who the surgeon is or who qualifies for surgery?

DR. SOMAIAH: Who qualifies for surgery.I think the question they are talking about maybe if it’s advanced.Because of course if it’s localized, the surgeon makes that decision and you should be eligible for surgery whether we treat before with imatininb or not.

DR. D’AMATO: Yeah, I mean I think that the main thing is if it’s a curable - if it hasn’t spread and it can be removed, obviously we want to get that tumor out.Now, with the exception is that there are some very small GISTs that are less than 2 centimeters that may be slow growing, you may not necessarily have to have those removed.As far as when - when the timing is, is going to be based on how you’re responding.We always want to start, unless it’s in - if it’s already spread we want to start with medication first, get the cancer under control, have it quiescent, have it not be active, not be growing and then we can consider surgery to clear out the disease and put you back on the medication.

But it is a case by case basis.So that’s why we really need that multidisciplinary approach where we have the surgeons and the medical oncologists and the radiologists and everyone involved making those decisions.So it’s a tricky decision making.

DR. SOMAIAH: Yep, thank you Gina.So I know this is - we’re almost up on the hour.So we might have to wrap up right nowBut I believe we can - if there is other burning questions, maybe they can bring it to us later and we’d be happy to answer as many as we can through email or send it back to you.

DR. HEINRICH: (interposing) Can I say one thing?

DR. SOMAIAH: Yeah, Mike, yes.

DR. HEINRICH: So we mentioned COVID, so the questions comes up every single visit, should I get a COVID vaccine?And I think for every single patient the answer is yes when you get offered you should take it and there is just almost no exception to that in the GIST world.You don’t have to stop your therapy, no therapy should keep you from getting COVID vaccine.So yes, get it when it’s offered to you.