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Check out the show notes for the application link. All applications are due March 25th. Hi everyone and welcome back to another episode about GIST with your surgical oncology team. Just to reintroduce ourselves, I'm Connor Cech. I'm a first-year research oncology fellow at Ohio State. I'm Lexi Adams. I'm a fifth-year resident at Brook Army Medical Center. I'm Beth Carpenter. I'm a fourth-year resident at Brook Army Medical Center.
I'm Tim Breland. I'm a surgical oncologist at Brook Army Medical Center. And unfortunately, the last member of our team, Dr. Dan Nelson, is currently an HPV fellow at MD Anderson. Couldn't make it today to record. We're excited to have him back for our next episode in May. All right. So without further ado, let's jump into our discussion today.
Our previous episode started off with a case review and discussion about the workup and management of a patient found to have a gastric gist. So if you didn't catch it in October, that episode is a great place to start for some context.
But we'll focus our episode today on the research that revolutionized the care of patients for these tumors, specifically molecularly targeted therapies, so imatinib. Dr. Breland, can you give us some context for the care of these patients prior to these therapies? Yeah, I think, you know, Matinib has been around for a while. So even in my career, there was no such thing as before Matinib. But I think the reality is it just is.
as we talked about previously, mostly a surgical disease, because most just are not going to fall into a high enough risk category that they would even get imatinib. I shouldn't say most, but a small majority. But there are these patients who present with metastatic disease or have a very large tumor, have a much higher mitotic rate.
And those patients really did not do well before we had adjuvant therapies for them. So short recurrence-free survival in the placebo arms. And the initial trials didn't show any real difference in overall survival just because this is... Not as aggressive as like an adenocarcinoma and things like that, but the initial recurrence-free survival or placebo arm in the first trial of imatinib was 83% at one year and then quite a bit lower.
more like 60 percent at three years so when you look at the follow-up data so ultimately there is a subset of these gists that present with rather aggressive disease and do very poorly without some sort of adjuvant therapy. So prior to imatinib, it was sort of surgery and then watch. Chemo doesn't really work for these things. So I do think in that regard, imatinib was really a game changer for GIST. So yeah, Dr. Wieland makes some really good points.
including the fact that in that ACOSOG Z9001 trial, it was really the first phase three trial of adjuvant imatinib for resected gist. They initially started out with a primary endpoint of overall survival, but then actually had to switch it to recurrence research because it didn't look like there was going to be a difference because so many of these patients do very well.
They had pretty clear evidence that there were some patients that were going to recur. And as we'll see in the paper we're about to discuss, a lot of these recurrences happen pretty soon after you end up stopping the therapy. Just one more thing to put.
this trial into context a little bit. If you look back at the recurrence-free survival curves from the initial trial, and we'll talk about the same thing with this trial, what you see is that the patients on imatinib did much better while they were on imatinib. But then... The curve almost looks identical between the placebo and the imatinib arm. It's just shifted one year over with imatinib. So as soon as the patients who were going to recur come off of imatinib.
they recur at roughly the same pace as they would have with the placebo. So that was really the driver to just give more therapy. Like if it's working, it works until you stop it. And then the patients who are going to recur seem to recur. So the thought is, well, let's just give it longer. And we'll talk about the results of this three-year trial kind of showing the same thing.
Awesome. So that's some really great background from both Dr. Greenland and Hunter Chick about journal article that we'll discuss today. So this article is titled One Versus Three Years of Adjuvant and Matinib. for operable gastrointestinal stromal tumor, a randomized trial. This trial was published in JAMA in 2012 by Jen Su and colleagues within the Scandinavian Sarcoma Group. Lexi, do you mind giving us an overview of the article?
Yes. So we already knew that patients with advanced GIST usually respond to imatinib or other immunotherapies, but most of those patients would have disease progression at some point. So at the time of this study, we knew that 12 months of adjuvant imatinib after surgical resection of kit immunopositive just prolongs recurrence-free survival, but effect on overall survival wasn't known.
If progression after one year of imatinib is common, the authors hypothesize that after three years versus one year of imatinib, for those considered to have high risk of recurrence of just following surgery could be beneficial. And that high risk of recurrence was measured by the modified NIH consensus criteria.
Between February 2004 and September 2008, patients who underwent surgical resection of KIT-positive GIST treated at 24 hospitals in Finland, Germany, Norway, and Sweden were enrolled in this randomized open-label Phase III study. The study did not include patients that had inoperable metastatic or recurrent GIST or those who received neoadjuvant imatinib. So, Lexi, can you remind us what an open-label study is?
Yes, that is a key concept when we talk about these randomized clinical trials. So open label means that both the researchers and participants know which drug is being given to participants, i.e. it's not blinded. Right. And then Beth? As Lexi mentioned, this is a phase three study. So what does that mean? Yeah, so this is another key concept when we talk about clinical trials. So there are four different phases of a clinical trial. Phase one studies aim to see if a treatment is safe.
how best to administer it, and this is usually with a small number of patients. Phase II studies are looking to see if the treatment works. So, for example, if cancer responds to a drug. Phase 3 studies like this one are testing to see if a new treatment, or in this case a longer treatment, is better than standard treatments or duration of treatments. And Phase 4 studies are aimed at determining long-term benefits and side effects.
So given that this was a phase three study, Lexi, what were the authors comparing? Yes. So in this study, the authors compared imatinib at 400 milligrams per day for one year versus 400 mg per day for three years. The primary endpoint of the study was recurrence-free survival, and secondary endpoints included overall survival and safety data. A total of 400 patients were enrolled and divided evenly between the two groups.
and median follow-up was 54 months. They analyzed survival between the two groups using Kaplan-Meier method. and patients receiving 36 months of imatinib did have longer recurrence-free survival than the 12-month group, and the 5-year recurrence-free survival of 65% versus 47%, which was statistically significant, as well as a five-year overall survival of 92% versus 81%, which is also statistically significant.
Regarding safety, while imatinum was moderately well-tolerated, 12% and 25% of patients in the one- and three-year group stopped treatment for reasons other than disease recurrence, and most of those safety reasons were considered mild side effects. Connor, what major takeaways did you have from this study? Yeah, so this is a really well-done study. It was adequately powered, randomized, met its primary endpoint in the intention-to-treat analysis.
demonstrated pretty conclusively that three years of imatinib improves recurrence for you in overall survival and is well tolerated with mild side effects in some patients. The authors do acknowledge this is the first randomized study to report an overall survival benefit associated with an oral tyrosine kinase inhibitor given as an adjuvant treatment for any cancer.
Beth, can you discuss some limitations of the study? Yeah, absolutely. So this trial was a great starting point. In my opinion, this is a well-researched and well-written study. But as with all studies, limitations have to be acknowledged. Firstly, in this study, over 25% of patients treated with three years of imatinib discontinued the treatment for a reason other than disease recurrence. This is a fairly high number, even if most adverse events in the study were characterized as mild.
Secondly, the authors acknowledge that tumor mutation type likely influences sensitivity to imatinib, so we should be cautious regarding generalizability of the results of this trial to all gists, especially as the data for tumor mutation type evolves. For instance, we know from the results of the ACOSOG Z9001 that there's a better response to imatinib for those with an exon 11 kit mutation compared to exon 9 or wild type GIST.
We also know from the ERTC 62005 study that those with an exon 9 mutation benefit from a higher daily dose than standard. And also, certain subgroups may be imatinib-resistant. So we talked about this a little bit in our previous episode, but those, for instance, with a PDG-FRA exon 18 D842V mutation...
or those with neither kit or PDGFR mutations, those can benefit from other therapies instead of imatinib. Finally, and Dr. Breeland referenced this earlier, but this study had a high five-year survival rate among patients administered three years of imatinib.
at 92 percent and this is compared to other studies there's a relatively small number of deaths in the trial additionally emphasizing the need for longer follow-up to confirm the results of the trial now just to add to that beth if you look at the forest plot from this trial you see that really almost all the benefit came from the exon 11 patients. And that's the majority of GIST, right? So if you look at the demographics, about two-thirds of the patients is trial at exon 11.
About two-thirds of GIST are exon 11. So this is a representative sample of all exons, or of all GIST, I'm sorry. But almost all the benefit of a 400 milligram a day dose of imatinib comes in exon 11. You could argue that maybe the trial would have looked even better if they had only enrolled Exxon 11, which if you were designing this trial in 2023 or 2024.
uh that's what you would do right you would only enroll those who had exile 11 mutations so arguably the effect may be even greater it's interesting you you talk about the 25 that dropped off because of probably intolerance to therapy There are some things to think about there, right? So this is a cancer trial, an oncology trial, where with chemo, like when you look at the toxicity table for a chemo.
you sort of ignore the overall adverse event rate and you only look at the grade three, four, right? So grade three or greater. When you look at this drug, grade three or greater adverse events, very low. you're talking like a handful of patients in the whole trial so this drug is extremely well tolerated relative to say chemotherapy but for chemotherapy you're talking about taking it for you know maybe six months something like that
This is talking about taking it for three years. So it's just a different perspective. The side effects are way less than chemo, but they have to be tolerated for many years. So that's what makes it harder, I think, to tolerate. So even if it's a... grade two adverse event but you experience it every day of your life for three years that's gonna wear on you and you're gonna want to stop so you know just a little bit different trial than our standard kind of chemo trials
And again, as more of these targeted therapies become available, that's just something to be aware of when you look at these trials is that patients may be on the medication for a very long time. So even a grade two adverse event becomes significant at that point. Yeah.
And even though this is an older trial, some of the longer term data bears that out as well. And I think Lexi's going to talk about this in a minute, but there was a U.S. trial called the Persist 5 trial that was a single arm study. that looked at five years of adjuvant imatinib for resectagist and when you look at the adverse event rates in that trial they did have a higher rate of grade three or four probably because you know with the longer time you're going to catch more of those
But very similar rates of dropout for those reasons, it was somewhere between 20 and 30%. Let's stop there. Being a soldier, it's exciting. You already know that. What you want to know is, what's in it for me? I wanted to learn leadership skills from the experts. I wanted to get paid to earn qualifications. I wanted more confidence. And now look, I'm on the radio.
That's what was in it for me. Get skills, get qualified, get confident. Army, recruiting now, search Army jobs. All innovation starts with an idea. A spark of inspiration that can take us to places we never thought possible. And Horizon Europe is here for ambitious businesses with big ideas. With an average funding award to UK businesses of over £500,000.
and the chance to build a network of like-minded collaborators horizon europe can help turn your ideas into reality get started today at horizon europe uk.org yes so Our surgical oncology community still has many unanswered questions about... just management. And one of those questions is, what is the best duration of therapy for imatinib? If three years is better than one year, then is even longer better than three?
Like Connor was mentioning, the Persist 5 trial is looking into that question. And the... The phase two trial was first published in 2018, investigating that five-year duration of imatinib for an intermediate or high-risk GIST, and their estimated five-year recurrence-free survival of 90% and overall survival of 95%.
But like Connor was saying, a very high amount of them dropped out of treatment at nearly half of the patients. And the current NCCN guidelines are pretty clear in stating that we don't know the optimal duration of imatinib after all.
yeah it's important to look at the you know if the listeners have the ability to look at this article i would recommend just looking at the survival curves because it's the same thing you saw in the one-year data it's like the recurrences all still happen you just shift it two years into the future so however long you stay on imatinib you're shifting your recurrence if you're going to recur that far into the future so if you're tolerating it well it's like why would you stop because
you know the data shows that a lot you know close to 50 of patients are going to recur after they stop therapy now You're sort of flipping the coin. Are you going to be in the 50% that doesn't recur even after stopping there? Because even in the one-year arm, it's not perfect, right? Because the Kaplan-Meier curve at five, six years is really an estimate.
The two curves come pretty close to each other at the end. So in some ways, you're not necessarily stopping your recurrence. You're just pushing it into the future as long as you're able to take imatinib. And then there's some percent of patients that may not recur.
right so you don't know which group you're in until you recur and then i guess you could always restart your imatinib at that point so that's another consideration like if you're having a lot of toxicity stop it until you recur and then just deal with the toxicity if you're having very little toxicity if it was me and i had a high risk gist and i was tolerating imatinib just fine i'd probably want to stay on it for the rest of my life but you know again that's going to come down to really
balancing that benefit versus whatever toxicity the patient's going to have to hammer that point home from that persist five trial they didn't have a single patient recur on imatinib, except for one who ended up having a PDGFR-alpha D842B mutation, and you wouldn't expect them to have great results with imatinib. All the recurrences in that five-year study happened after they stopped.
Yeah, and just to be very clear, everything that I just said is only true for exon 11, right? So for exon 9, they double the dose. And some patients do still have a clear benefit from imatinib, but you got to take a higher dose. And then for the other ones, it's really less convincing that they're going to have benefit. There is also some preliminary data that once you recur, maybe you're not some patients.
are not going to then respond to a mat even if they did before so that is a little bit of a gamble you know coming back on a little bit what i said there but i think it's a reasonable strategy if you're having a lot of toxicity So I think you bring up a good point, Dr. Breland, that I was reading about, which is the question of whether or not long durations of imatinib therapy increase the likelihood of secondary resistance to the drug.
yeah nobody knows the answer to that so i don't think we know the answer i think that if we can get some real randomized data on you know three versus five that will help but i think the general consensus is that for exon 11s probably that five-year group is going to do better. They're going to have a longer recurrence-free survival. Now, when you recur, are you going to be resistant to a mat-dib? Sure, right? Because you recurred on a mat-dib.
But does it make you more likely to recur by taking more imatinib? I don't think the doubt shows that at all. So again, if it were me and I was tolerated and doing just fine, I would stay on it. And just for those readers interested what those adverse effects are, they're mostly hematological anemia and leukopenia. And then other side effects that are commonly reported are diarrhea, edema, and fatigue.
One of the other points that I don't think we've brought up in terms of long duration of imatinib is the cost of the drug. So the cost of the drug is, I was reading, approximately $100,000 per year or so. Certainly staying on the treatment for long durations of time is not benign either from a financial perspective. Yeah, that's a good point. However, the new drug was developed for DA42V.
That one's real expensive, so it's awesome. You've got to put it all in perspective. Dr. Verland, how do you see this data play out in your clinical practice? Yeah, I mean, again, this is a great trial, right? It's hard to critique this trial. Three years is better than one. You know, it sort of boils down to that. So if you have an exon 11 mutation and you can handle being on for three years, you should be on for three years. I think this is not an overly complicated trial. I think.
when this trial was started right we didn't know all this stuff about the exons and i think that's where that's where the sort of educated clinician needs to be aware of things is you really should be getting exod analysis for every gist that you see before you make any treatment decisions.
Unless it's a straightforward resectable, just then just go resect it. I think we kind of boiled that down last time. But if you're trying to decide about neoadjuvant versus going to surgery, or if you're making any adjuvant decisions, you know, that should really be done in the context of...
exon analysis again with a low risk resectable gist just go cut it out and they don't need anything but if you're going to give them any medical therapy you have to check the exons because you know you may need to change the imatinib dose or you may know that imatinib is not going to work or you know that it has a lower chance of working you may still try it in those patients but you're just going to be you're going to have your antennas up that it's not going to work so
i think that this this paper along with the other things that have come out about gist really point to the idea that that you got to know the exons when you're making real treatment decisions and again the forest plot from this trial shows exactly that
All the benefit was in Exxon 11. One of the other interesting things about this trial that I think it illustrates is the difference between U.S. and European interpretation of data. So I think the NCCN guidelines say that duration... of imatinib is unknown, but I think a lot of clinicians will keep patients on it for as long as they can tolerate it, whereas I think the European guidelines are a little bit more definitive in stating three years is all.
yeah i think a lot of that comes down to how you pay for treatment right so in europe with socialized healthcare there you have to have good data to drive paying more money for a medication whereas In America, either, you know, I doubt a lot of patients are paying out of pocket for MadNib, but some would. And then there's just more of a push for Medicare to cover things that we think work better, even if there's not great data.
and you know there are people that argue on both sides of that argument right so some people would say it's a waste of money or we have data that there's one month difference in recurrence-free survival, and we spend a million dollars a year on this medication, and that only happens in America. So yeah, I mean, there certainly are differences between American and European healthcare.
I'm going to try not to make any comments on which one I think is better. All right, guys. Well, really great discussion. Any final thoughts or additional takeaways from the trial before we finish up? I think other things that are kind of interesting about this trial, if you look at the forest plot.
So R0 versus R1, does it matter? This forest fly would agree with basically everything we have. It doesn't matter. So I think that's one thing that confuses trainees. You'd never want to do an R2 resection of a gist. but it's okay to do an R1. And what that means is that a lot of times the gist is going to be pushing into the serosa of the stomach. And so you just cut that piece of stomach out. You don't have to do an end block resection of everything that's touching it.
And then the pathologist is going to say, oh, it's a R1 resection because there was microscopic tumor at the border of the resection. You're going to say, well, which border? And they're going to say the peritoneal surface of the stomach. And you're like, well, what was I going to do? Cut half their abdomen out?
So R1 resection is not important in gist, and this data would agree with it, right? So there was no difference between R1 and R0. Tumor rupture is a high-risk feature, but... it doesn't seem to matter for this so whether you have an extremely high risk or kind of just high enough risk to get adjuvant therapy three years seems to benefit you so you know you might think like
oh, well, I qualify for adjuvant therapy, but my tumor wasn't ruptured and things like that. Maybe I don't need the longer therapy. Most of the factors seem to point that you should still get it. The one that was interesting is the local mitotic count. those with the lower count had less benefit. Although on the central count, it seemed to be about the same, which is really interesting because you would think the central pathology analysis would be more accurate.
And so you would think that they would be the ones that would not show that difference. Anyway, just an interesting kind of random thing on the subset. Overall on GIST, you can really hug the tumor on these. Again, a lot of times you're wedging it out with a stapler.
Just don't staple through the middle of the mass, but you can hug it and have a R1 margin and it's fine. Thanks for those comments, Dr. Vreeland. And thanks everybody for such a good journal article discussion. It's easy to get bogged down in the weeds with some of the molecular things.
with gist but one of the reasons we selected this important journal article about gist is it illustrates some really great points about cancer research in general yeah i completely agree with that connor Well as a send off let's review just a few quick hits before we finish.
Some of these are a review from our last episode, but worth mentioning again. Others are just good trial tidbits to save for tumor board. So, risk of recurrence in GIST is independently predicted by size, mitotic rate, and site of the disease. Staging of GIST tumors differs for gastric versus other sites of disease and is dictated by the T, N, M, and mitotic rate. A highlight of GIST staging is that any N-positive disease is stage 4, even if no metastasis.
Some specific mutations help to predict response to TKI therapy. And then finally, some major trial takeaways. From the Z9001 trial, we know that there's a better response rate, progression-free survival, and overall survival to imatinib. if there's an exon 11 kit mutation. From the ERTC-62-5 trial, there's an improved progression-free survival with double the daily imatinib dose if there's an exon 9 mutation.
Finally, if your patient experiences clinical progression during the first six months of therapy, so this is termed imatinib resistance, you should absolutely review your exon testing. Certain mutations, such as the PDGFRA exon 18, D842V mutation may respond to alternative therapies. Thanks everyone for listening. Until next time, dominate the day.
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