Leading Scientifically Rigorous Research in Novel Brain Cancer Therapies

Shwetal Mehta, PhD

Ivy Brain Tumor Center

Barrow Neurological Institute

Phoenix, Arizona

By adopting a scientifically rigorous, patient-focused philosophy, researchers at the Ivy Brain Tumor Center aim to deliver timely answers to those with brain cancer while moving novel therapeutic strategies down the development pipeline, according to Shwetal Mehta, PhD.

CancerNetwork^® spoke with Mehta, the deputy director and pre-clinical core leader at the Ivy Brain Tumor Center of Barrow Neurological Institute in Phoenix, Arizona, about her translational science work related to brain tumors at her institution. She highlighted her team’s focus areas within a clinical lab and a pre-clinical arm to identify potential drug candidates that demonstrate activity in diseases such as glioblastoma.

Focusing on specific efforts within her research team, Mehta described a phase 0/1 clinical trial (NCT06072586) assessing treatment with a brain-penetrant fourth-generation EGFR inhibitor, BDTX-1535, for patients with recurrent high-grade glioma harboring oncogenic EGFR alterations or fusions.¹ Investigators announced that the first patient had received study treatment in November 2023.²

Mehta also detailed the use of gene sequencing and immunohistochemistry to efficiently assess biomarkers such as MGMT status and IDH mutations, which can help identify patients who may benefit from specific targeted therapies. Regarding the potential next steps for research, she highlighted treatment classes such as proteolysis targeting chimeras (PROTACs) and antibody-drug conjugates (ADCs) that might demonstrate benefits in brain cancer therapy.

"Neuro-oncology is only now trying to test these things out, and we are uniquely situated to ask some of the important questions for these types of molecules,” Mehta said about these types of treatments. “That’s where our focus is going to be in the coming years, and we’re very excited about that.”

CancerNetwork^®: What philosophy do you live by as you aim to develop novel therapies for patients with brain cancer?

Mehta: At the Ivy Brain Tumor Center, even within the research arm, our philosophy remains the same: to be patient-focused. We want to ensure that we are scientifically rigorous when we are asking questions. We’ll also be mindful of the time constraints and provide quick answers back to the patients, whether they’re going to be eligible for the drug that we are testing and whether the drug is showing any activity in their tumor.

Within the research team, we have 2 broad focus areas. We have the clinical lab that performs tissue screening for trial eligibility. They would also then test the tissue once the patients have taken the drug for a few days to see whether the drug is reaching the regions of the tumor where the blood-brain barrier is intact and modulating the target. If we do see activity within the brain, then that patient is eligible to start taking the drug therapeutically long-term. But if the answer is no, then they can decide to stop and enroll into something else that’s going to benefit them. We also have a pre-clinical arm where we move, identify, and screen novel drug therapies for brain cancer; some of the ones that have been promising in other cancers but haven’t been tested in glioblastoma. Again, we employ the same philosophy here. Is this drug reaching the brain? Does it have activity? Do we think this is going to be promising for patients? Only once we’ve screened them here in this stage [do] we put those forward into a clinical trial.

What are some ongoing trials at the Ivy Brain Tumor Center?

There are several other novel clinical trials that we are part of. One of them is with an EGFR inhibitor. In neuro-oncology, people have been trying to target EGFR, which has been quite commonly mutated in glioblastoma, for a while. It’s not a new target. Normally, people don’t want to get into the space, but this drug that we are testing is a fourth-generation EGFR inhibitor. It’s brain-penetrant. In the past, people have tested drugs that were not brain-penetrant. We’re excited to ask more questions.

We know the drug gets in, [but] are there specific patient populations that are going to benefit from this drug? Is that what we need to identify? Are there going to be resistance mechanisms that we need to figure out and address? We have a whole new program of liquid biopsy where we sample cerebrospinal fluid from patients while they’re on treatment to see if the tumor is evolving [or] changing. If that can immediately give us an answer even before we start seeing symptoms of progression, [we might see] if there is a way to pivot, add a new therapy, and help these patients.

Is there anything else that should be highlighted about the EGFR inhibitor trial?

Our EGFR inhibitor clinical trial is for patients who have either EGFR amplifications, mutations, or fusions. Our panel detects all 3 of them, so we look for mutations in the DNA as well as any fusions using RNA from the tumor sample. That helps us in the enrollment of these patients into the trial. But once patients have taken the drug, we are now asking a question of whether the drug is being active within the tumor. We compare their pre-treatment biopsy—if available—or archival tissue to the tissue that comes after the patients have [received] the drug for several days. Here, we use a panel of an additional 6 to 7 biomarkers, which are downstream markers. If [a patient has] blocked EGFR signaling, are we seeing a [complete] shutdown of the pathway? Maybe the immediate downstream molecule is shut down, or maybe it's not shut down all the way.

Those are the questions we are now trying to ask. Some of those things were done in the past, but those drugs were sometimes not great in terms of brain penetration. We want to be comprehensive to assess if we have all the checkboxes checked. If the drug was getting in, and we saw EGFR inhibition, then what else was going on if the drug was not being effective?

What are the current strategies and protocols related to biomarker testing in brain cancer?

In glioblastoma, we don't have [a lot of] great biomarkers that identify patient populations that are going to benefit [from treatment]. We have 2: MGMT—which identifies patients who are going to be more responsive to DNA-damaging agents—and then IDH mutations. Recently, there was a drug [vorasidenib; Voranigo] that got approved for those patients [with IDH mutations], which is great.³

But for all the drugs and the small molecule inhibitors that we're testing at the Ivy Brain Tumor Center, we always try to identify—based on literature, past studies, data from other trials, and some of the preclinical studies—whether other specific mutations, aberrations, or protein expressions can identify a patient population that will most likely benefit with that drug. We develop assays, and we are agnostic of what assay we use. We always keep time in mind; we want to make sure we can give a fast turnaround, so we deploy multiple different ways of assessing those biomarkers.

[Biomarker analysis] could involve sequencing. We have a panel of 298 actionable genes...that, if we know there's a mutation or an aberration, will probably tell us whether a patient is eligible for one of our trials. We use sequencing and immunohistochemistry; those [are the] 2 quick assays that we could do in that period to give answers whether the patient's going to be eligible.

What additional work is the Ivy Brain Tumor Center doing? What is your outlook on the current state of brain cancer treatment?

When we started at the Ivy Brain Tumor Center 7 years ago, we [had] the largest early phase clinical trials program. Our goal was to move drugs through this pipeline using pharmacokinetics- and pharmacodynamics-based approaches to identify drugs that have activity in the brain, move those good drugs forward, and then also weed out the ones that are not good; those are the ones where we are not seeing any activity. [We do this so] that we in the community don’t spend too much time, patience, and resources on these drugs.

We’ve done that. Now, over the last year, we’ve seen that we were capable of not just doing these early phase clinical trials [but entering] this phase of moving drugs into phase 3 [studies]. That’s exciting. For us, right now, we are excited about these new classes of agents that are within the space, like the PROTACs, protein degraders, and ADCs, which have shown amazing promise in the rest of the oncology space. Neuro-oncology is only now trying to test these things out, and we are uniquely situated to ask some of the important questions for these types of molecules. That’s where our focus is going to be in the coming years, and we’re very excited about that.

References

1. Study of BDTX-1535 in recurrent high-grade glioma (HGG) participants with EGFR alterations or fusions. ClinicalTrials.gov. Updated January 15, 2025. Accessed January 15, 2025. https://tinyurl.com/m6kwr2b3
2. Ivy Center announces first patient treated in targeted phase 0/1 clinical trial for high-grade glioma study tests targeted agent, BDTX-1535, an EGFR inhibitor with brain-penetrant properties. News release. Ivy Brain Tumor Center. November 6, 2023. Accessed January 13, 2025. https://tinyurl.com/mw8dcxzk
3. FDA approves vorasidenib for grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation. News release. FDA. August 6, 2024. Accessed January 15, 2025. https://tinyurl.com/25r9fkvy