GIST_JournalClub_15Jan

Hi, everyone and welcome back to another episode about just with your surgical oncology team. We'll just to reintroduce ourselves. I'm Connor check. I'm a 1st year surgical oncology fellow at Ohio State. I'm Lexi Adams. I'm a 5th year resident at Brooke Army Medical Center. I'm Beth Carpenter. I'm a 4th year resident at Brooke Army Medical Center.

And I'm Tim Breland. I'm a surgical oncologist at Brooke 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 with these tumors specifically molecularly targeted therapies.

Dr. Vreeland, 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 that gist is, as we talked about previously, mostly a surgical disease, because most gists are not going to fall into a high enough risk category that they would even get a matinib.

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 of 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 percent 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 just 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. Whelan makes some really good points, including the fact that in that ACASOG Z9001 trial that 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 resurvival 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 resurvival 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're 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 gonna recur come off of imatinib, they recur at roughly the same pace as they would have with the placebo.

So that that was really the driver to just give more therapy like if it's working It works until you stop it and then they 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. Vreeland and CounterChick about journal article that we'll discuss today. So, this article is titled One Versus Three Years of Adjuvant and

Imatinib 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 a matinib 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 matinib after surgical resection of kit immunopositive gist.

Prolongs recurrence, free survival, but effect on overall survival wasn't known. If progression after one year of a matinib is common, the authors hypothesize that after three years versus one year of a matinib for those considered to have high risk of recurrence of just following surgery could be beneficial.

And the, 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 3 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 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.

It's not blinded. Right? And then Beth, as Lexi mentioned, this is a phase 3 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 two studies are looking to see if the treatment works. So for example, if cancer responds to a drug phase three 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 four 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? Yeah, 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 five year recurrence free survival Of 65 percent versus 47%, which was statistically significant, as well as a five year overall survival of 92 percent versus 81% which is also statistically significant regarding safety.

While imatinib was moderately well tolerated 12 percent and 25 percent of patients in the one and three year group stop 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's it was adequately powered, you know, randomized, met its primary endpoint in the intention to treat analysis Demonstrated pretty conclusively that three years of imatinib is improves recurrence free and overall survival and is well tolerated with mild side effects.

In some patients, the authors do acknowledge this is the 1st randomized study to report an overall survival benefit associated with an oral tyrosine kinase inhibitor given as an adjuvant treatment for any disease. 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. So, firstly, in this study over. The 5 percent of patients treated with three years of a matinib 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 acknowledged that tumor mutation type likely influences sensitivity to a matinib. So we should be cautious regarding generalized ability of the results of this trial to all just especially as the data for tumor mutation type evolves.

For instance, we know from the results of the ECOSOG 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 ERRTC 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 PDGFRA exon 18 D842V

mutation, or those with neither KIT or PDHGFR mutations those can benefit from other therapies instead of imatinib. Finally, and Dr.

Breland referenced this earlier, but this study had a high five year survival rate among patients administered three years of imatinib at 92% and this is compared to other studies. There was a relatively small number of deaths in the trial additionally, emphasizing the need for longer follow up to confirm the results of the trial.

And 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 Exxon 11 patients. So, and that's the majority of GIST, right? So in the, if you look at the demographics, about two thirds of the patients this trial had Exxon 11, about two thirds of GIST.

Our exon 11. So this is a representative sample of all exons are of all just I'm sorry, but almost all the benefit of a 400 mg a day dose of matinib comes in exon 11. So you could argue that maybe the trial would have looked

even better if they had only enrolled exon 11, which if you were designing this trial in 2023 or 2024, that's what you would do, right?

You would only enroll those who had exon 11 mutations. So, arguably, the effect may be even greater. It's interesting. You talk about the 25 percent that dropped off because of probably intolerance to therapy. There's 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 3, 4, right? So grade 3 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 6 months, something like that.

This is talking about taking it for 3 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 experienced it every day of your life for three years, that's going to wear on you and you're going to 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, it'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 2 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 is going to talk about this in a minute, but there's, there was a U. S. trial. Called the persist five trial that was a single arm study that looked at five years of adjuvant imatinib for resecta gist.

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. I think it was somewhere between 20 and 30%.

Is so our surgical oncology community still has many unanswered questions about just management. And 1 of those questions is what is the best duration of therapy for a matinee if 3 years is better than 1 year, then is even longer, better than 3 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 percent and overall survival of 95 percent. 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. And 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 server survival curve because it's the same thing you saw in the one year data.

It's like the recurrence is all still happen. You just shift it two years into the future. So however long you stay on a matinib, 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 percent 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 percent that doesn't recur even after stopping there? Because even in the 1 year arm. You know, it's not perfect, right? Because the Kaplan Meier curve at five, six years is really an estimate, but 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 5 trial, they didn't have a single patient recur on imatinib except for one who ended up having a PDGFR alpha D842V mutation.

And you wouldn't expect them to have great results with a matinib. All the recurrences in that five years study happened after they stopped. Yeah. And that, you know, to draw just to be very clear,

everything that I just said is only true for Exxon 11, right? So for Exxon 9, they double the dose. And some patients do still have a clear benefit from a matinee, 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 matinee 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. Vreeland, 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 Exxon 11s, probably that five year group is going to do better. You know, they're gonna have a longer recurrence free

survival. Now, when you recur, are you going to be resistant to a matnib? Sure. Right. Cause you recurred on a matnib. So, but is it, does it make you more likely to recur?

By taking more imatinib, I don't think the data shows that at all. So, again, if it were me, and I was tolerating 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 a matinib is the cost of the drug. So the cost of the drug is I was reading approximately a hundred thousand dollars per year. 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 that was developed for DA42V, that one's real expensive. So it's all, you got to put it all on perspective. Dr.

Rylan, how do you see this data play out in your clinical practice? Yeah, I mean, again, this is like, it's a great trial, right? It's hard to critique this trial, like 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 it started.

Yeah. That's where the, sort of educated clinician needs to be aware of things is you really should be getting exon analysis for every gist that you see before you make any treatment decisions. Unless it's a straightforward resectable gist, 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 just 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 an Exxon 11. One of the other interesting things about this trial that I think it illustrates is the difference between US and European interpretation of data. So, I think the NCCN guidelines say that duration. 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 and 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 the, 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 magnet, 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. 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 plot 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. And 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 our one resection is not important in just and this data would agree with it, right? So there's there was no difference between our one in our zero tumor rupture is a high risk feature, but 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. Like 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 aging 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 a mat nib if there's an exon 11 kit mutation. From the ERTC 625 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 6 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.

?