IDH-Mutant Low-Grade Glioma — An Interview with Dr Patrick Y Wen on Current and Future Management Strategies

Welcome to Oncology Today, current and future management of IDH mutant low-grade glioma. This is medical oncologist, Dr. Neil Love. For this program, I met with Dr. Patrick Nguyen from the Dana-Farber Cancer Institute in Boston. In addition to this interview, there's also a corresponding video program featuring Dr. Nguyen's slide presentation.

To begin, I asked him to walk us through how gliomas are classified and where IDH mutant disease fits in that framework. In the past, these tumors were graded. two, three, and four based on the histologic appearance. And there was significant variability and this made conducting clinical trials very difficult. Because a grade two patient, some of them will do really well and some of them will do very poorly. I think the...

The identification of IDH and the incorporation of IDH into the classification of these tumors has been a huge step forwards because those tumors that have an IDH mutation... have a much better outcome than those tumors that are a wild type for IDH. Basically, even though if the tumor looks like a grade 2 or 3 glioma, and they don't have an IDH mutation, they are a glioblastoma. And so they have a much worse outcome. So the new classification separates these...

Basically, these glioblastomas from IDH mutated tumors. And so you have a much more homogeneous population to study. And this helps defining the appropriate treatment for these patients.

Can you just review the major histologic classifications of primary brain tumors and how often you see IDH mutations in each of those? The diffuse gliomas, which account for the majority of malignant primary tumors, are now divided into three groups. Glioblastomas, which are IDH wild type, account for over half of these patients and have a terrible prognosis in the order of 14 to 18 months.

The other two groups are oligodendrogliomas and astrocytomas. They are much less common than glioblastomas and occur in a younger population. Astrocytomas are more common than oligodendrogliomas. But they both, by definition, now have to have an IDH mutation. The oligodendrogliomas also have co-deletion of 1p19q. So they have an IDH mutation and co-deletion of 1p19q.

whereas astrocytomas have an IDH mutation, but they have intact 1p19q. So it sort of sounds like at this point, in terms of primary gliomas, The classification is completely biomarker driven, kind of like in breast cancer, you know, your ER positive, HER2 negative, et cetera. It looks like if you look at these two variables, you basically, that is the classification at the current time.

Yeah, it's now part of the classification. So you have to be able to look at the presence of IDH mutations, be able to determine 1p19q status. And then something that I didn't mention is that you also have to determine the presence of CDKN2AB loss because if you have... CDK into AB loss. If you're an astrocytomer, it immediately puts it into a grade four.

And if you have an oligodendroglioma, even if it looks like a grade 2, if you have CDKN2A loss, it's a grade 3 tumor. So all these markers, IDH, 1P19Q. and CDKN2AB loss are necessary for the full classification of these tumors.

Any thoughts in terms of pathophysiology of how these tumors develop about why you see this really dramatic difference in the presence or absence of IDH? I think that's one area where we really have very little information. We just know that IDH is one of the earliest mutations and an early driver. But the cause of these mutations is completely unclear. And also I was going to maybe talk a little bit more about the evolution. of therapy, specifically vorocidinib.

Can you talk about sort of how that sort of came about, its mechanism of action, and then the key studies? I know you went through these in detail, but more from a conversational point of view. what this agent is, how it was kind of discovered, and then sort of how it's sort of tracked through to end up with the FDA approval. So IDH mutations occur in...

as you know, in a number of cancers, in AML, cholangiocarcinoma, chondrosarcoma, and others. But for gliomas, it occurs with the highest incidence. And with the 2021 WHO classification update, it occurs in all astrocytomas and oligodendrogliomas. So it made it a very compelling target to find drugs that could inhibit that pathway.

The first in class drug was actually ivocyaninib, which is a proof of leukemia and a number of other indications. And that is an IDH1 inhibitor. But it was known that it didn't get into the brain very well. So vorocitinib was specifically developed to get into the brain. And this is something unusual because in drug development and oncology, very often...

companies will try to have the drug not get into the brain, to not have to deal with potential neurotoxicity. But here they developed a drug specifically to be brain penetrant, which was very important. And so in both the first one studies of ivocitinib and vorocitinib, there were a number of patients with prolonged stable disease, but there were very few responses.

And one of the problems with a slow-growing tumor, when you see prolonged stable disease, you're not sure that it's actually doing anything. It could be that it just takes you a while to figure out that the tumor is slowly growing. And so very careful imaging studies were also done to track the tumor size. And if you do that, then you can see true stability of the tumor and even some shrinkage in the phase one studies.

But that also led them to do the surgical window of opportunity trial because they wanted to know that the drug was really doing what they were hoping it will do. And so that trial, which is something that we should really do much more often in neuro-oncology, showed that vorocytin got into the tumor very well with a brain plasma ratio of over 2.1. But it also showed that it inhibited the targeted pathway, lowered the 2-HG by more than 90%.

So we knew that the drug got in, and we knew that it inhibited the pathway really well. Whether that translates into a clinical benefit was still unclear, but that led to the INDIGO trial. And that trial was stopped earlier than planned because there was such a significant benefit in the varazidine bomb. And that led to FDA approval.

Can you talk a little bit about the IDH inhibition? in terms of exactly how IDH inhibitors work. And do you see IDH1 or 2 in gliomas, or do you see both? It doesn't matter. We know for targeting IDH1, but what do you actually see with gliomas? So this is a small molecule inhibitor. It's very much like I was saying. Gliomas, probably 95% or more are IDH1. A small percentage are IDH2. Most of the IDH1 mutations are IDH...

R132H, 90% of them are that specific mutation. And that can be detected by immunohistochemistry. So when these patients get surgery, within a week, we'll know. for 90% of these patients, whether they have the IDHR132H mutation. But it means that 10% don't have that mutation. They have non-canonical mutations that require NGS.

And so in a young patient, if you stain them for IDH1R132H and it's negative, you're obligated to perform NGS to make sure that it doesn't have a non-canonical IDH mutation. And that can delay the final diagnosis. So if you find no evidence of IDH mutation, does that mean the histologic diagnosis is different? It's a primary glioma? Or GBM. Yeah, basically it's a GBM. There are specific criteria for other molecular alterations to call it a true GBM. But basically if it's a...

Grade 2 or 3 glioma histologically, and you don't see an IDH mutation. And they're IDH wild type. They're functionally a glioblastoma.

Can you go back, you know, in your talk, you had a really cool diagram, but maybe you can just try to verbally explain sort of what the mechanism of action is of IDH inhibition and, you know, what the normal... you know, pathway is and how IDH inhibitors or IDH mutation changes that, and then how do IDH inhibitors sort of reverse that? So normally...

IDH, it's present in all our cells and it converts isocitrate to alpha-ketoglutarate. In the presence of an IDH mutation, the alpha-ketoglutarate is converted to an oncometabolite. called 2-hydroxyglutarate, or 2-Hg. This accumulates in very high concentrations, in millimolar concentrations, and it causes epigenetic changes and tumorigenesis. And so the hope is that if you can block the mutinite age, you reverse this process, you lower the 2-HG levels, and you control the growth of the tumor.

So with conventional IDH inhibitors in AML, you can see differentiation syndrome. Do you see anything similar to that when you use IDH inhibition and gliomas? No, I think that's purely related to the treatment of leukemia. So we don't see differentiation syndrome or swelling or anything like that.

And maybe we can get into your cases that we can start to kind of clinically evolve into this. And starting out with your 30-year-old patient, what happened with this patient? So this is a 30-year-old female who presented with seizures and had surgery, but because of the location of the tumor, including in the insula, it was only partially resected. And this showed an astrocytoma, a grade 2 astrocytoma with the common IDH or R132H mutation.

Following surgery, the patient continued to have seizures that required treatment with two seizure medicines. And so the treatment options for this patient... Theoretically, it could be watch and wait with serial scans every few months. Radio chemotherapy, and because it's an astrocytoma, it would be radiation followed by a year of temozolamide. This patient, because she had a subtotal resection and there was residual tumor, would fall into the...

group of patients that were part of the INDIGO trial. And so one option would be to treat with furosyedinib. But in this case, the patient is having intractable seizures. And so in that case, even though vorocytinib can have an anti-seizure effect, it's not a very rapid effect. It can take a long time to manifest. And so to have more rapid control of the tumor, one might consider radio chemotherapy as a first choice treatment. This particular patient, however, did not want to have radiation.

tried on vorocytinib initially. But I think the more standard approach would be to go ahead with radio chemotherapy. It's a difficult situation for this patient because she's young. The radiation is in her dominant hemisphere. And so her memory area, for instance, will get radiated. And so the likelihood of sequelae 10 years or more out is not trivial.

So how was the patient treated, and what's her current status? So she was treated initially with furacitinib, and then she continued to have seizures. She had more surgery. And that helped the seizures. But then her scan started to show new areas of enhancement. And so we recommended that she proceed with radial chemotherapy. I think with anybody who goes on vorocytinib.

One of the critical things is to monitor closely because the standard treatment is radiation and chemotherapy, and you don't want patients to stay on drug. longer than they need to if the tumor is actually progressing. But the actual monitoring of patients on varicidinib is relatively simple. So apart from doing scans every three to four months, they just require blood tests initially every two weeks for a couple of months and then monthly. So the monitoring is not onerous on patients.

So how long was this patient on vorocytinib, and while she was being treated, any tolerability issues? You mentioned liver function abnormalities. So she didn't have any liver function problems. She was on it for between one to one and a half years. Her main problem is that she continued to have seizures that were not controlled by seizure medicines. And so we advised her to try to get...

additional surgery to try to control the seizures or go on radio chemotherapy. And she wanted to try to have the surgery first. In general, how often do you see liver function abnormalities? Do you typically hold therapy? How often do you have to actually stop therapy? So mild liver function abnormalities is relatively common. In 10% of patients, they get grade 3 elevation of liver function tests.

Treatment has to be held, and then often the dose reduced from 40 to 20 milligrams. In about 3 to 4% of patients, they have to stop treatment. In these patients who stop ferocitinib but whose tumor is not progressing, we've tried to get them onto ivocitinib. Because ivocitinib inhibits the pathway also by more than 90%. and it doesn't have the liver function test problems. So I think that you mainly, you showed the curve for PFS.

I don't know that I saw the overall survival. What was the impact in the trial on survival? Because these patients do really well, overall survival will take a very long time. The survival of grade two astrocytoma patients is probably 10 to 12 years at least. And for oligodendrogliomas, it's probably in excess of 15 years. So it's going to take a very long time to have an OS effect. And I think that was one of the reasons FDA...

approved this drug based on PFS. The PFS was centrally reviewed, and so that made it a somewhat stronger endpoint. I think the other problem, though, is that after the trial was stopped for efficacy, the placebo patients were crossed over to the virucidinib group. Right. And the majority of them chose to do that. So it could be that the long-term survival benefit will be diluted by this crossover.

Another thing I didn't see, and I don't know if it exists, I know it's difficult to do tumor measurements in gliomas, but I didn't see a waterfall plot. Is there one? And how often do you see people actually progress? So the response rate, especially initially, is quite low. So there were relatively few true responses in the vorocytic group compared to placebo.

In the surgical window of opportunity trial, with much longer follow-up, you begin to see responses approaching 30% to 40% in the vorocytinib group. So I think... With additional follow-up of these patients, we may start to see a much higher number of true responses, but it may take several years for that to manifest.

You know, it's interesting when you use that term window of opportunity, I was thinking that early on in breast cancer, they would call these trials window of opportunity. And then it just sort of shifted into the whole concept of neoadjuvant. systemic therapy. And is that something that you see occurring here in this situation? I mean, I guess when you use primary treatment.

In a sense, that is neoadjuvant therapy, if you continue it indefinitely, even theoretically. But is that the way you view this, that this is really neoadjuvant treatment? I think it's not. So much neoadjuvant because for these gliomas, significant resection of the tumor will make a difference to outcome. So we don't want to be avoiding or delaying surgery. The first step.

should always be maximum safe resection. Because if you can get a good resection, those patients do much better. And so this is following surgery rather than before surgery. So the idea of using pre-op treatment to maybe make the surgery less extensive is something that really doesn't apply here because you don't really see responses. Yeah, and also we need tissue, at least right now, to make the diagnosis. Right now, it's very hard to make a definite diagnosis non-invasively.

You know, we can't use blood biomarkers or MR spectroscopy. None of them are sufficiently sensitive and specific enough to allow a diagnosis without getting tumor tissue.

Speaking of biomarkers, are there any sort of cell-free DNA bespoke assays with gliomas? I think people are trying to do that. I think in the blood... It's still a challenge because relatively little tumor or DNA reaches the blood. The yield is higher in the cerebral spinal fluid, and so there's increasingly...

assays that have been developed looking in the spinal fluid. But the hope is that eventually the tests will become sensitive enough to get blood biomarkers in the same way it's being done for many other cancers. All right, let's hear about your 43-year-old man. So this is a patient who also presented with seizures. 80 to 90% of these IDH-mutated low-grade gliomes present with seizures. And the patient had a subtotal resection, as you can see on the scans on the right.

And so this is exactly the kind of patient that was eligible for the indigo trial. So the options are that you can watch and wait, and before the availability of our site end up. a number of these patients would be observed with serial scans. Because there is residual tumor in the previous high-risk, low-risk group, Many patients would be offered radio chemotherapy. But now this is an exact indication of varicidinib. And so this patient went on varicidinib.

This scan on the left is the post-optive scan, and the scan on the right is the scan three years later on vorocytinib showing stable disease. And the hope is that... This drug will work for a number of years and allow this patient to delay the need for radiation and chemotherapy. I have a patient from the original phase one trial that is now nine years out and still on drug. So some patients tolerate the drug well and can benefit it for a prolonged period of time. Thank you.

What are some of the key questions right now about vorocytinib that are being debated right now in terms of use clinically? And also, where do you see things heading with this agent? What kind of ongoing... trials are being done right now? So the FDA approval was actually more extensive than the eligibility criteria for the indigo trial. So the ENECO trial required patients that have measurable disease because we wanted to look at, to see if there's response from the drug.

And also we wanted to track the volume of the tumor before treatment and then afterwards to see if there's a change in tumor growth rate trajectory. But the FDA approval allowed patients to have a growth total resection. And we know that even after a gross total resection, patients have residual disease. And that residual disease is growing, even if it's at a slow rate. And so it makes sense to treat those patients with the drug.

In other cancers, for instance, CML, you don't wait till you see recurrence before you treat the patients. Treating the patient earlier is usually better. difference between the FDA approval and the INDICO trial is that it allows for patients to be treated immediately after surgery and not have to wait a year. And again,

You know, for most cancers, earlier treatment is generally better. The challenge here is that some patients with a growth to resection may look fairly stable with no recurrence for a number of years. And so whether you should put those patients on drug or watch them closely and put them on drug when there's a hint of recurrence is up for debate. And then, as I mentioned in the talk,

These patients are in their 30s and 40s, and especially for women, some of them would want to have children. And having this window after a gross total resection potentially allows them to have children. You know, we don't know what the effect of vorocytinib is on the fetus, but it's not allowed to try to bear children on vorocytinib. And then I think the other area of debate is whether to treat newly diagnosed grade 2 gliomas with contrast enhancement.

Because we know for recurrent tumors with contrast enhancement, they don't respond as well to the drug because the other pathways presumably are activated and they're more aggressive. But in newly diagnosed tumors, we think that it's probably not as important to have contrast enhancement. You know, even though they have contrast enhancement, you have the histology showing that it's a grade 2 tumor. And we think it's appropriate to...

to consider treating these patients also. I think the really controversial area is whether to treat grade 3 tumors or not. And I think the biology... of these tumors is much less than most people realize. I think for grade three tumors, the diagnosis of a grade two and grade three tumors is not as... definite as most people think. Most neuropathologists will tell you that it's a gray area and there's a gradation between grade two and three.

And something that someone would call a grade 2, another pathologist may call a grade 3. And so that's one area where there's a lot of debate about whether this drug should also be considered in grade 3 tumors.

Can you talk about some of the ongoing studies looking at voracinib, including the Alliance Phase III trial? Yeah. I think there's a lot of interest in seeing if this drug can add to standard radiation and chemotherapy because there will be patients that will need radiation and chemotherapy from the onset. radiation chemotherapy for astrocytomas is you treat with the radiation for six weeks at six to 60 gray, and then you follow the treatment with 12 cycles of temozolamide.

And so the Alliance trial will be adding voracitinib or placebo to adjuvant temozolamide and then continuing that treatment after completion of chemotherapy. And so this is a large study that will start later this year. The other major trial is the VIGO trial being done in EORTC. Here they're looking at the value of adding vorocyaninib. after completion of radio chemotherapy. The Alliance is looking at the addition of our sign in both during...

the chemotherapy and afterwards. The Vega trial just looks at the value of our Cytinib after completion of radio chemotherapy. And then the company is looking at the addition of racylinib to temozolomide for grade 4 tumors as well. These are very hard-to-treat tumors with a much worse prognosis. And because they are now split off from glioblastoma, there are actually very few clinical trials for these patients. What about combining this with...

Other agents, you referred to a trial combining with an IO pembrolizumab. What's the thinking there? So in these tumors, the very high 2-hydroxyglutarate, 2-HG levels in the tumor is very immunosuppressive. And if you can lower the 2-HG levels with boroside in it, then you augment the immune response. And this was shown in that surgical window of opportunity trial. And so you can potentially combine it with either.

a vaccine, or with checkpoint inhibitors. So there are trials that are ongoing doing both. There's a trial that combines an IDH1 vaccine with vorocytinib. And the trial we're involved with combines for a sidinib with pembrolizumab. These are for recurrent tumors. What kind of vaccine is it? It's a peptide vaccine against IDH1. So I know there's another IDH inhibitor that I think is approved in...

I can't pronounce it too well, but it looks like it's been studied in gliomas also. What do you see there? So, yeah, they did a phase one trial, and similar to vercetinib, there was a number of patients with prolonged stable disease, and a small number had partial. responses. So this is being studied in pediatric IDH-mutated tumors, and I think they're trying to decide how to develop the drug in adults as well.

It's a challenge now that 4-cidinib is approved to develop a somewhat similar drug in that space. I think one area that's pretty wide open is in the recurrent setting still.

But I think that they're trying to decide. So I thought maybe we could also take this opportunity, provide a little bit of an update to glioblastoma. which, of course, is the major primary tumor. Can you talk a little bit about current management, new innovations that are being looked at, and where you see things heading in the future? So glioblastomas make up more than 50% of malignant primary brain tumors, and the outcome really hasn't changed for the past 10, 15 years.

Standard treatment is maximum safe resection, followed by radiation therapy over six weeks to 60 gray, together with a low dose of temozolamide. followed by a month break, and then six cycles of adjuvant temozolamide. There's also a device called tumor treating fields that's FDA approved. to be combined with the adjuvant temozolamide and then to be used afterwards. So that is the standard treatment. Unfortunately, with standard treatment, at a median of only about seven months, patients recur.

And when patients recur, there really is no treatment that significantly prolongs survival. Patients can consider re-operation. But re-operation only has a survival benefit if you can do a gross total resection of the recurrent tumor. The other chemotherapies, retreatment with termazolamide or lomastine, have a minimal effect.

And then the other treatment that's currently available is bevacizumab. This is very helpful in reducing the peritumul edema. So it helps patients' symptoms, helps the patient's quality of life. and allows them to reduce or come off corticosteroids, but doesn't have a significant benefit in terms of survival. So unfortunately, those are the only approved treatments.

So people have been looking at many other treatments to see if they can improve outcome. There's been a lot of interest in targeted therapies. But glioblastomas... have significant heterogeneity and there's significant plasticity between the subtypes. And so with the rare exception, targeted therapies have not been very helpful. The two exceptions are in the 2% to 3% of glioblastoma that have BRAF V600E mutations. In the raw trial, we showed that Dibrafenib and Tremetinib

can produce a response that's durable in a subset of these patients. And it was part of the general approval for refractory or recurrent BRAF mutated tumors that occurred in 2020. two, I think. And then the very rare subgroup of patients with intrac fusions. They do have responses, but intrac fusions are incredibly rare in glioblastomas.

But for other targeted therapies, there's a lot of interest in DNA damage repair pathway. And so there's an ATM inhibitor, AZD1390, that's going into a phase 3 trial. There's also a lot of interest in theranostic agents. And then with antibody drug conjugates, which has been a major advance in cancer, there's also interest... Problem is that these are big molecules, and they're unlikely to get into the brain through the blood-brain barrier. And so there's thought of combining these with...

focus ultrasound and mycobubbles that opens up the blood-brain barrier for a few hours around the infusion. The other area that is not novel to brain tumors, but it's a major area in neuro-oncology, is that there's increasing evidence that neurons interact with glioma cells to promote the growth of glioma cells. So for instance, neurons form synapses with glioma cells. And so those receptors can be targeted.

And then the glioma cells form interconnecting tumor networks that mediate resistance to treatment. And so targeting those tumor networks is also an area of interest. And then the other area of interest is in immunotherapies. Unfortunately, the immune response in these tumors is very suppressed. They're code tumors with a paucity of T cells, and they... microenvironment and the macrophages are very immunosuppressive. And so checkpoint inhibitors on their own have not been helpful.

There's a lot of interest in vaccines, and we'll have to see whether they pan out. The one area where there's been a lot of interest is in CAR T cells. There have been a number of CAR T cells that have been developed that have shown responses in a small number of patients that appear quite durable. In most patients, it isn't effective.

And part of the problem is CAR T cells, if you administer them systemically, they don't get into the tumor very well. And so people are giving it into the ventricle or into the tumor cavity. And then when you give the Kati cells, this upregulation of many immunosuppressive pathways in the tumor. And so combining the Kati cells with mechanisms to suppress. the regulatory T-cells or the upregulation of PD-L1 will be important. That's incredible. What's the target for the CAR-T?

Different targets, one common one is EGFR, which is amplified in half of glioblastomas and mutated in about a quarter. interleukin-13 receptor alpha-2, but there are a number of others. You said EGFR is mutated. Do EGFR, TKIs, legosimertinib work? So osimertinib doesn't work. Most of the drugs developed for lung cancer target different mutations from glioblastoma.

But even those drugs that were developed to be brain penetrant and target the glioblastoma mutations, which are usually in the extracellular domain, haven't worked that well. And this is because of the heterogeneity and the plasticity of these tumors. The other treatment that I didn't mention, actually, that's of a lot of interest in the field right now, are viral therapies.

So these oncolytic viruses were originally developed either to grow through tumor cells, killing them, or to introduce genes that sensitize the tumor cells to chemotherapy or other agents. But it turns out that they also stimulate a very potent immune response. And so they're a mechanism to convert code tumors into heart tumors. The problem is that all these viral therapies...

although they can occasionally produce responses, the response rate is very low. And one thought is that maybe one injection of a virus is not enough. And so one area of interest right now is to give multiple viral injections. Fascinating. So just to pick up on a few of the things that you were talking about.

One, you were talking about antibody drug conjugals, which, of course, we hear every day no matter what tumor we're talking about. But I'm kind of curious because you said that, quote, I think you said they don't get into the brain very well. I'm curious.

Well, your thoughts are, you know, we were talking before about your colleague, Nancy Lynn, who we work with all the time. We just worked with her a couple weeks ago. And, of course, the ADC, Trastuzumab-Druxacan, in breast cancer seems to have a lot of CNS activity. So how do you explain that? So I think it's because of the difference in the blood-brain barrier in brain metastases. You know, most of the tumor in brain metastases is enhancing. And so the drug gets through enough.

that it has a therapeutic effect. There's relatively fewer cells that are infiltrating into normal brain. Whereas glioblastoma, even though the center is enhancing, There's a significant amount of tumor in the surrounding flare areas and even beyond a normal-looking brain. And those tumor cells are behind an intact blood-brain barrier.

And so an ADC might get into the contrast-enhancing center, but it doesn't get into the rest of the tumor. And so that, I think, is a major difference between glioblastomas and brain metastases. So another thing you mentioned was BRAF therapy. Just kind of curious whether or not, you know, I guess in melanoma and colon cancer, they've...

Actually, melanoma and lung cancer, for sure, they've moved away from DabTram, also in colon, to N-carafenib, binimetinib. Any thoughts about doing that with gliomas? Yeah, Clarissa Schreck at Hopkins actually had a trial of that combination, but the trial was discontinued because the companies stopped supporting it. These are rare tumors.

They're only about 2% of glioblastoma. So the trials are difficult to do. But it would make sense to look at other combinations that are perhaps slightly better tolerated. So you mentioned tumor treating fields. I had kind of a flashback because we were actually at the SNOW meeting, I forget how many years ago.

when tumor treating fields were just coming out and everybody was like, what are we talking about here? I'm curious right now in your own practice to what extent you use TTF and how do patients deal with it? So it's an FDA-approved treatment, so we tell all patients about it. I think for clinical trials...

Most trials exclude tumor-treating fields. So for patients who want to do clinical trials, that's usually not an option. But for other patients where it is an option, the uptake is still not as high. in our practice, maybe 10 to 15%. I think there's a quality of life component. I think they've been trying to make it easier for patients, but you still have to shave your head, replace the electrodes every few days.

and just deal with wearing the apparatus and being connected to a battery. And so a lot of patients choose not to do it. Again, there's been a lot of skepticism about this. People don't understand how it might work. What's your take? Do you think from a scientific point of view, there's really something there and maybe something that could be further studied or maybe not?

They did a phase 3 trial in glioblastoma, and the survival was 4.9 months, which is not trivial. It's actually longer than temozolomide. And there have been some other studies in lung cancer. and brain metastases where there appears to be some benefit. So even though it's difficult for us to understand this treatment, I think there probably is some activity there.

Do you think that maybe there's something there that could be explored further? And I don't know to what extent it is. I mean, it is a completely different strategy. Any thoughts about whether if it was maximized it might be more effective or you think it's kind of hit its limit with where it is right now? So the company is actually doing a trial. that uses it early in treatment. Right now it's approved for treatment with adjuvantemazolamide after radiation therapy.

They have a trial called the Trident trial where they're giving it during radiation therapy and afterwards. I think that trial's pretty much finished accrual. So we'll see if that's a benefit. I think there's potential rationale to combine it with other agents, but I don't know what the development plans are. There were some reports that tumor treating fields could affect the immune response.

at least preclinically and in a small phase two trial. And so there's some discussion about whether to combine it with checkpoint inhibitors or not. Yeah, lung, it looked like there was a signal in the patients who got PD-1 therapy. So I don't know. Maybe that's tied in with what you just said. Another thing you mentioned was the issue of ATM mutations, and I'm curious how often you see that and other...

HRD mutations, do PARP inhibitors work? And I'm really curious about an ATM inhibitor. I've never heard of that before. Actual mutations are relatively uncommon. You know, we don't have the same incidence of BRCA mutations. They're very uncommon.

There is an ongoing phase three trial of a PARP inhibitor, noreparib in glioblastomas. So that study is ongoing. With ATM, I think it's more that it helps the... DNA damage repair pathway in preclinical studies, this particular drug, the AZD1390, got into the brain very well and had significant activity in preclinical models.

And so we finished a phase one study, and it's going into a phase two, three trial called GBM Agile. You know, one of the challenges in glioblastoma is that drug development is very slow and expensive. And so GBM Agile is a platform trial using Bayesian adaptive randomization and a shared control arm to try to evaluate drugs more efficiently. with fewer patients and a faster timeline. And so this drug AZD1390 is being added as the newest arm on that platform trial.

So the last thing I want to ask you about is... This is a very specialized field, and particularly some of the things we were talking about today, oncologists in practice, you know, rarely see. I'm curious when, I'm sure you see a lot of patients for second opinions who've been primarily managed in the community.

both with all types of gliomas. I'm curious about any, I'm not going to say errors, but things you see people doing or not doing in the management of these patients that let's say you would do differently. I think one critical thing, because you're right, it's rare. It's not something that medical oncologists will encounter very often.

And it's difficult to keep up with all the nuances. So I think it's often helpful for the patient to get second opinions. You know, we can send the patient back to the oncologist for the actual treatment and follow up. But to try to find the best treatment approach for the patient at each stage of their disease course is important. And then because having a good resection is really critical.

Referring the patient to a brain tumor surgeon early on is important. It makes a difference for the patient whether they have a gross total resection or a subtotal resection. That makes a huge difference. to their long-term outcome. What about outcomes in the community with neurosurgery versus in tertiary centers? I think for low-grade gliomas, they often occur in eloquent areas, especially the insular and language areas and motor areas, because they tend to occur in the frontal cortex.

And so being able to do those surgeries, even tumor surgeons, not all of them can do it well. So I think for someone who does tumors as part of... a practice that includes mainly spine. Even in talented surgeons, it's difficult to get the extent of resection compared to a specialized tumor surgeon. So I think for the patient's benefit, it's worth referring them. So one final question. I was actually doing a video earlier today.

with a general medical oncologist. I sit down with them, and they present cases to me, and then I take that and present it to other people. And he presented a patient. I think the patient might have had colon cancer. who'd gone through all the approved therapies and wanted to be treated, but...

There were no clinical trials available. None of the available treatments really offered any kind of hope for a good risk-benefit decision. And he was saying that a lot of patients like that... when there's still a great performance status, start dealing with something I have never really actually even heard of, which is longevity clinics.

And I'm curious because you talked about some of these low-grade gliomas where these people live for 10 or 20 years. Whether you see your patients trying to access... alternative means to extend their life, so to speak. I mean, it's sort of like alternative therapy, but this seems to be more oriented, not just towards people who are ill, but healthy people who want to live longer.

you know, that kind of dynamic. And he was saying that they even at times recommend therapeutics. They have MDs there, et cetera, et cetera. So I'm just kind of curious, like what kind of advice you give to patients where you really don't need to treat? them, but they want to try to do something to help themselves live longer, anything that you recommend to them. Yeah, unfortunately, the actual proven treatment options in that situation, it is...

is very, very limited. So I think we try to advise them not to do things that are potentially harmful. But I think one area that's been lacking in our field is having survivorship clinics. to try to maximize their quality of life during this period where they don't need to be on treatment. That's something that's growing, but is not available at all tumor centers.

What do you think it is that they learn there that's useful to them? I think information about diet, exercise, how to deal with the stress. I think a lot of them... but unfortunately have cognitive issues and how to manage that and getting the help, the testing and the help to maximize their cognitive function. Because unlike a lot of cancer patients, brain tumor patients over time don't work very often. And that's also an important issue. And that has financial and social implications as well.

I mean, you know, cognitive, you know, issues are not confined to people with the CNS tumors. You know, a lot of, you know, chemo, brain, et cetera, et cetera. Are there specific, like... therapies or exercises or things that people can do that improve their cognitive function? I think cognitive therapy helps.

to some extent. A lot of the agents that are used, for instance, in Alzheimer's to improve memory, don't really work very well. Dinepezil can help a little bit in people who are severely affected. And there's been a study of memantine for patients with whole brain radiation that has a modest effect in reducing neurocognitive problems. We don't know if memantine has a protective effect for glioma patients who get radiation, but that's sometimes used.

I think it's a huge area that needs to be studied better because hopefully, as with other areas of cancer, the treatments will get better, patients will live longer, and then more and more of them will live longer. long enough from their radiation therapy to get problems. And right now, we don't have a lot of studies in that area. What kind of specialists focus on that? Is it like a psychology background or who is it that knows the most about this?

I think that's part of the problem. I think neuro-oncologists focus on the treatment. Psychologists and behavioral neurologists, their main interest is usually not cancer and especially brain tumors. their focus on Alzheimer's. And so this leads to a paucity of people who are studying this area. And I think probably the neuro-oncologist needs to... try to galvanize other specialties to work together to start thinking about what treatment options might be available to mitigate these problems.

This concludes our program. Special thanks to Dr. Nguyen, and thank you for listening. This is Dr. Neil Love for Oncology Today.