Podcast: Targeted Therapies for Relapsing/Remitting Pediatric Low-Grade Glioma (R/R pLGG)

Eugene Hwang, MD: Hi, my name is Eugene Hwang. I'm a pediatric neuro-oncologist at Children's National Hospital in Washington DC, and I'm excited to talk a little bit more about pediatric low-grade gliomas, our most common kind of pediatric brain tumor, and specifically about some of the targeted therapies that have really been developed for those tumors when they recur.

We'll talk about a few of the molecularly targeted therapies that have really started to gain traction, especially in the recurrent and relapse setting. The first of course, is the MEK inhibitors, which impedes signaling at the MEK level, which is part of the Ras-Raf-MEK-ERK kinase pathway, of course. It's downstream of the Ras-Raf moieties and of course downstream of the surface receptors, the tyrosine kinase receptors, and so we really hope and think that this is a pretty pinpoint place to inhibit a lot of different pro-proliferative signaling through different MAP kinase pathways down to a point where we can attain pretty widespread targeting of these tumors. When we think about MEK inhibitors, the one that is I think used—has been used the most, or has been used historically for the longest—is selumetinib. That was an oral medicine, and I should take a second to mention that unlike the upfront chemo regimens, which typically tend to be IV weekly-based, which requires line placement and of course fever management and many other chemo-based toxicity managements, the MEK inhibitors have been predominantly oral and are taken once or twice a day in typically pill form, although some liquid solutions for some of the agents exists.

Moderator: What are the average response rates for MEK inhibitors?

Eugene Hwang, MD: Again, selumetinib, which tested in the Pediatric Brain Tumor Consortium Trial 29 had pretty remarkable response rates of about 30 or 40% in patients with recurrent low-grade gliomas. So, these are not patients that have had just a new diagnosis of low-grade glioma, they're patients that have failed some other treatment, typically chemotherapy. The tumor has come back, so we're already selecting a group of patients that we think are probably more resistant to at least the upfront treatment modalities that we had. PBTC 29 included a bunch of different tumors including those low-grade gliomas that we didn't really know what their molecular alteration was and patients with neurofibromatosis type 1, which of course, through a different mechanism signals similarly and activates this pathway, which is why children with NF type 1 have an increased predilection for development of low-grade gliomas. Trametinib was a second kind of MEK inhibitor that had a slightly worse objective response rate of about 15%, but it's really important to know that when we talk about these low-grade gliomas, they're not all the same tumors.

It's a basket of tumors, and if we pull out those tumors that were ^V600E-positive, then a recent publication really demonstrated that when combined with vemurafenib, which is a BRAF inhibitor, that ^V600E-positive pediatric low-grade gliomas had a tremendous response. We'll talk a little bit later about what that means for children with ^V600E-positive pediatric low-grade gliomas in the upfront or the newly diagnosed context, but as a single agent, trametinib had a very similar sort of objective response rate, a toxicity profile, which we'll talk about later as well, to the other MEK inhibitors. Binimetinib had a little bit better response rate of greater than 50% in fusion-positive tumors, but a lot of those patients, almost a quarter of the patients on that trial, discontinued due to toxicity, primarily dermatologic, which one could argue in pediatric brain tumors or brain cancers, is a lower level toxicity, but as we'll talk about, significant acne and rashes that were actually sometimes advanced to pretty intense medical complications were a major cause of a discontinuation for binimetinib. Mirdametinib is perhaps one of the newer MEK inhibitors has an even better objective response rate of around 64%. Cobimetinib and other agents have similar sort of signals of stabilization of disease progression, which we think of in brain tumors as a positive signal and even regression of brain tumors down to PRs or CRs as well.

Moderator: How does a clinician decide which MEK inhibitor to use first and when to switch to a different one?

Eugene Hwang, MD: Switching between agents is something that hasn't really received consensus. It certainly appears that when you use a MEK inhibitor and you attain a positive response, it be the regression or stabilization, that when that treatment duration is eventually completed, that reinduction with that exact same agent can be quite effective—sometimes even achieving greater responses than the first time through. So, it's still unclear whether, if somebody has either progressed on a particular MEK inhibitor or the tumor has come back, whether switching to another MEK inhibitor—one of the class—will actually attain a better treatment response than just restarting the same one.

Moderator: What are some common side effects of MEK inhibitors?

Eugene Hwang, MD: Now, the toxicities of MEK inhibitors are existent as well, so side effects of course are going to be in play for anything. However, toxicity side effects for MEK inhibitors, they're oral agents. You get away from a lot of the chemotherapy-related administrative components, like having a port, and coming in very frequently, and worrying about fevers, but there are toxicities, they're mostly grade 1 or grade 2. Rash is I think the first thing that's going to jump into anybody's mind and that rash can display from just a generic maculopapular rash, but typically is more acneiform and certainly in the patient population that we know will often be taking MEK inhibitors, those adolescent children who already have acne to start with can really escalate to full involvement of their entire body, or large swaths of their body, with not only painful, but also, I think cosmetically disfiguring acne.

And so, that's been a pretty common side effect for MEK inhibitors so far that dermatology has really engaged with this patient population and just as regular acne I think has achieved really remarkable treatment paradigms and treatment options today, so too have children who have worsened acne because of MEK inhibitors really attained pretty good control with a dermatologically directed management therapy, which sometimes includes oral treatment for the acne as well. Otherwise, I think there's—in the world or brain tumors even relatively low-grade ones—fatigue is always a problem and that can be a problem with MEK inhibitors. Sometimes GI issues, a little bit of nausea, diarrhea—especially for some of the older MEK inhibitors—is something that is controllable with things like Imodium, but is something that we've seen. One of the cosmetic changes that some kids actually really enjoy is that there can be a bleaching or a lightening of the hair, and so during the duration of treatment with MEK inhibitors, some kids with fairly dark hair will be really bleach blonde, and then after their couple years of treatment is over will be a little sad that they're going to go back to their normal hair color off of the MEK inhibitor.

But there are some very rare but potential toxicities of MEK inhibitor that are pretty significant. One is cardiac toxicity. So, children on MEK inhibitors get periodic EKGs and echocardiograms because there is a signal for ejection fracture or functional deterioration as well as QTC prolongation. So, it's important to note that when you're on these kinds of targeted therapies that there aren't additional instigators of things like QTC prolongation, so we look very carefully at other medications that a child might be on and are careful about making sure that they're not on something that would combine with a MEK inhibitor to cause any electrical disturbance in their cardiac components. The retinal layer can become edematous and those layers can sometimes separate. That's been a toxicity that has not seemed to lead directly to visual impairment, but it is an important one because clearly, especially since so many of these children have optic pathway gliomas and vision is probably the biggest thing that we're trying to save in that child, having some kind of toxicity related to the vision is particularly discomfiting.

Moderator: How do you monitor for those side effects?

Eugene Hwang, MD: We really do a lot of neuro-ophthalmological exams. We'll do measurements like optical coherence tomography, or OCT, to measure the thickness of the retinal layer, but really rely on our colleagues to tell us when there's been an issue in the retinal layer, which is important. RVOs are something that you can see, although extraordinarily rare, essentially. In general, again, the toxicities of MEK inhibitors that the patient will feel seem to be relatively well tolerated. And of course you'll always have lab surveillance of these patients and you'll probably see, occasionally, some hepatitis—mild transaminitis really—and potentially a few other alterations, like in the CPK measures, which we note can be pretty high on targeted MEK or BRAF inhibitor therapy, but which don't tend to cause a lot of direct muscular issues that we've seen and also tend to disappear once you stop or reduce the therapy dose.

Moderator: How do BRAF inhibitors work?

Eugene Hwang ,MD: Now, BRAF inhibitors are very similar to the MEK inhibitors. Clearly, they're just a little upstream of the MEK on the pathway, so in some ways they probably miss out on impairment of some of the pro-proliferative single drivers if they're not in the BRAF gene. But on the other hand, do a pretty complete job of attacking those that are, which again, are the majority of patients. The first generation of the BRAF inhibitors were vemurafenib was used against V600E in multiple studies. Typically, the first foray was in skin cancer, with a dramatic objective response rate of about 44%. It should be mentioned here that in newly diagnosed V600E pediatric low-grade gliomas—so those low-grade gliomas that look pretty benign but have a ^V600E mutation—that vemurafenib has had a signal of efficacy, but there have been recent publications after clinical trials that have, sort of mimicking the melanoma world, combined dabrafenib, which is another BRAF inhibitor, with trametinib a MEK inhibitor. They actually did a trial that compared that against that standard of care chemotherapy we were talking about, carbo-vincristine, and saw such a difference in objective response rate. I said 44% for the dabrafenib and trametinib and only 11% for the carbo-vincristine and with a very different median progression-free survival. The dabrafenib-trametinib combination had a median progression-free survival of almost 2 years, whereas the carbo-vincristine was less than a year. And so, the FDA has approved the combination for ^V600E-positive low-grade gliomas as frontline therapies.

Moderator: What is the current standard of care for pediatric low-grade gliomas?

Eugene Hwang, MD: While we just talked about the fact that, in general, we use standard—what we think of as standard of care—as remaining chemotherapy-based—with the caveat that there are at least three large randomized trials going on now to see if that should still be the case—that in this instance, a combination of MEK inhibition and BRAF inhibition has already been approved because they were so dramatically effective. We don't know how good in the newly diagnosed setting a ^V600E-positive low-grade glioma will respond to just one agent. There have been case reports that they have been pretty effective and certainly you could think about one medicine vs two and perhaps combinatorial toxicities, but at the moment, this moment in time, I think that probably standard is to think about dabrafenib-trametinib in that context of newly diagnosed of tumors. And there has been some literature talking about some older BRAF inhibitors and the problem that it had, when they were in the context of fusion-positive tumors, in those contexts, because of receptor dimerization, or at least that was a hypothesis, they actually thought that they saw acceleration of growth. Meaning, by using a BRAF inhibitor and a fusion-positive tumor, so not a ^V600E tumor, that you might actually see some growth acceleration.

And again, this was in the context of really pre-first-generation or perhaps you could consider them first-generation BRAF inhibitors. So, something to think about when you're thinking about what treatments to use, especially what treatments to use if you don't yet really know what the molecular phenotype of that tumor is. Now, second-generation type II RAF inhibitors target both the mutant and the wild type, and they actually inhibit that RAF dimerization that we were talking about. So, the two agents really that were in this context were tovorafenib and vemurafenib, and really the, I think that the more well known second-generation RAF inhibitor is tovorafenib. So, in the Firefly 1, phase 2 trial, which was a trial in recurrent low-grade gliomas, there was over 50%, a 51% objective response rate by RAPNO, by the Pediatric Neuro-Oncology Radiology Initiative, despite most of those patients having previously been treated with MEK inhibitors.

So, you get all these kids with low-grade gliomas, they've recurred, and then many of those actually received MEK inhibitor therapy and recurred again and yet saw a tremendous objective response with the second-generation type II RAF inhibitor, which was really, really exciting for the community. Important to also note that for that medication in particular, that it was also delivered orally but delivered in a weekly format, so a little bit different from the once to twice a day treatment that the other oral MEK inhibitors really are taken, so not too hard to do, but less is sometimes much easier, and so that was a positive also, I think.

Moderator: What are some common side effects of BRAF inhibitors?

Eugene Hwang, MD: The toxicities of the BRAF inhibitors are not too dissimilar as one might imagine from the MEK inhibitors. They're, again, they're targeted therapies, so rash is certainly something that pops up for these and fatigue and photosensitivity and transaminitis and CPK elevation. You still have to worry about the cardiac issues and so that left ventricular dysfunction in the QT prolongation, you still need to monitor with EKGs and echocardiograms, you don't see it often, but when you do, it's obviously a big-ticket item. Secondary malignancies with something different between the MEK inhibitors and the BRAF inhibitors, those secondary malignancies are really centered around secondary skin cancers. And although they were not melanomas and eventually were thought to be really unmasking of preexisting disease rather than causing secondary disease, it's still important to make sure that these children are getting dermatologic exams so that we know that their skin is clean on either of these targeted therapies.

The tovorafenib has also had a relatively unique side effect that we've seen. It's still, I think, being litigated and understood, but it seems to impair growth velocity, vertical growth velocity, in a lot of patients. Now, the current thought is that that growth velocity is reattained. So, you may slow down your height while you're on the tovorafenib, but when you stop it, you tend to accelerate pretty quickly and recapture the height potential that you had initially. But there's a lot more work that needs to be done to really understand that. The one other point that I'll make about toxicities is, I did mention that when we were talking about the dabrafenib and trametinib combinatorial therapy, that it’s reasonable to then assume that you have twice as many, or at least a few more side effects, but it's actually seemed like using that combination decreased the adverse event profile for the children taking that combination.

So, I think that that still probably requires a little bit more longitudinal assessment, but it's not a slam dunk that using the combination is going to be worse from a toxicity standpoint than the first one. So really, in general, I think that toxicities for this entire class are fairly mild, although there are children on all of these trials or non-trial treatment that are forced to stop the drug because of some toxicity. In some children before the dermatologic interventions, I think acne in an adolescent is something that's quite discomfiting and cosmetically unfavorable. And so, some children said, ‘I don't care if my tumor keeps growing because I just can't have this much acne. It's hurting me from the perspective of my quality of life.’ Certainly, other issues like transaminitis or other rashes or other issues that are relevant from a toxicity standpoint have led to a stoppage of these medications. Although virtually every one of these toxicities seems to be relatively easily reversible if you stop the medication, but even if you stop it and then alter the dosing regimen.

Moderator: Can you clarify what that means?

Eugene Hwang, MD: What do I mean by altering the dosing regimen? We talk about this fact that these are oral medications. They're either given daily or twice daily typically, or once a week, and either tweaking the dose or doing more intermittent dosing seems to anecdotally have had some positive effect in the cost-benefit of these targeted therapies, although that has not really been rigorously investigated. And, so, there's actually a study that's being developed now to investigate different kinds of targeted therapy dosing. From an efficacy standpoint, I think both of the targeted therapies, or really all the targeted therapies from a second-line perspective, has really been thought to, in general, have pretty good activity to at least stabilize a pediatric recurrent low-grade glioma. And although we know that once that low-grade glioma has recurred, they're almost certainly going to recur again at some point after you stop treatment. And again, this idea of the recurrent low-grade glioma as being more of a chronic disease, that these targeted therapies have done a good job in sort of maximizing the quality of life and minimizing the hit to families in terms of frequent IV chemotherapy. We'll talk a little bit later about resistance to these targeted therapies and how we can mitigate or circumvent that resistance and continue to think about ways that these targeted therapies can be used.

Moderator: What about immunotherapy?

Eugene Hwang, MD: Immunotherapy is another area that we have thought about for all pediatric brain tumors and brain cancers. In general, because low-grade gliomas really have such a high rate of survival and are so responsive to now many of the medical management strategies that exist, they have mostly been exempted from a lot of the trials with immunotherapy, recognizing that they're all unproven and potentially very dangerous, such as immune checkpoint blockade and adopted cellular therapy. But there are some really intriguing signals for immunotherapy. There was a vaccine trial led by Ian Pollack out of Pittsburgh that targeted the EphA2, IL13Rα2 survivin in low-grade gliomas and had a good number of those children with prolonged partial responses. There's another study that looked molecularly at these tumors and said, okay, some kids actually don't respond to MAP kinase inhibition. If we divide those, what are the differences?

They went sort of objectively without any biases and found that those tumors that tended to respond to MAP kinase inhibition tended to have an increased sort of inflammatory signal with more immune cell infiltration and microenvironment, which suggested that pediatric low-grade gliomas might be actually more amenable to immunotherapy than some of our more intense and aggressive cancers. And, of course, in the IDH mutant low-grade gliomas, which again tend to be more in the adult-adult population, they're investigating strategies like immune checkpoint blockade and dig cell vaccines and poly-