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Clinical

In season 4, episode 10 of Targeted Talks, Craig Horbinski, MD, PhD, director of neuropathology in the Department of Pathology, and professor of pathology, neurological surgery, and neuropathology, Feinberg School of Medicine at Northwestern University, reviews the clinical guidelines for central nervous system (CNS) cancers. This tumor type includes glioma, intracranial and spinal ependymomas, medulloblastoma, limited and extensive brain metastases, leptomeningeal metastases, non-AIDS-related primary CNS lymphomas, metastatic spine tumors, meningiomas, and primary spinal cord tumors.

In 2022, the National Comprehensive Cancer Network (NCCN) published an update to its Clinical Practice Guidelines for Central Nervous System Cancers (NCCN Guidelines). Horbinski explains that in the guidelines, there are important recommendations for screening of patients with gliomas and identifying key disease features.

“The first step is diagnosing them. For the community pathologist or community oncologists, the threshold for having a case sent to a tertiary academic center that has this kind of molecular armamentarium available should be kind of low, because we're finding that the more screening we perform, the more interesting things we catch, some of which are targetable. Something that might radically change the prognosis substantially, like glioblastoma or something that was thought to be glioblastoma by methylation profiling might be a pleomorphic xanthoastrocytoma. That radically changes the patient's prognosis and management. That's the first thing, said Horbinski. Then, once the testing is done, integrate it with the histopathology, producing a unifying diagnosis. Based on that, there is a lot of information in the NCCN Guidelines as it concerns specific recommendations, according to what type of tumor [a patient has].

Looking forward in molecular profiling of CNS cancers, Horbinski explains that there is much work to be done. Horbinski foresees advances in the way these tumors are diagnosed and prognosticated. A bigger undertaking, however, will be developing therapeutics that target newly-discovered biomarkers. But Horbinski notes, that there is research ongoing in this area.

“Right now, we're studying DNA modifications. DNA methylation by histone methylation and acetylation might yield even more data on tumor types. But we're talking years and years of research before we can tell what's going to pan out,” says Horbinski.

In season 4, episode 10 of Targeted Talks, Craig Horbinski, MD, PhD, reviews the clinical practice guidelines for central nervous system cancers.

Recommendations for Treating Central Nervous System Cancers

Data from the phase 2 FIREFLY-1 trial support the new drug application for tovorafenib in relapsed or progressive pediatric low-grade glioma. The regulatory agency anticipates filing the application by mid-November 2023

FDA Receives Rolling NDA of Tovorafenib for Pediatric Low-Grade Glioma

Experts believe VAL-083 has the potential to change the way oncologists treat glioblastoma in the future.

Could VAL-083 Address Modest Treatment Efficacy in Glioblastoma?

Patients treated with VT1021 for recurrent glioblastoma were found to have immune markers associated with response to treatment in a phase 1/2 study. 

Favorable Immune Profile Linked to VT1021 Treatment Response in rGBM

Identifying alterations to tailor treatment is important for patients with pediatric low-grade glioma as it accounts for one-third of all pediatric central nervous system tumors.

Crafting Targeted Treatments in Pediatric Low-Grade Glioma Improves Results

ABM-1310 is a novel small molecule BRAF inhibitor that has shown promising anti-cancer activity and a good safety profile across a variety of advanced BRAF V600-mutant solid tumors. 

FDA Grants Orphan Drug Designation to ABM-1310 for Glioblastoma

Craig Horbinski, MD, PhD, director of neuropathology in the Department of Pathology, professor of pathology, neurological surgery, and neuropathology, Feinberg School of Medicine at Northwestern University, discusses the classification of gliomas based on histology and molecular features.

The importance of molecular and genetic testing is highlighted in the updated guidelines from the National Comprehensive Cancer Network (NCCN) for patients with central nervous system (CNS) cancers, including glioma, intracranial and spinal ependymomas, medulloblastoma, limited and extensive brain metastases, leptomeningeal metastases, non-AIDS-related primary CNS lymphomas, metastatic spine tumors, meningiomas, and primary spinal cord tumors.

According to Horbinski, molecular and genetic testing provides diagnostic and prognostic information which helps determine individualized treatments for patients with these cancers.

In the video, Horbinski also discusses how these molecular features are already being incorporated into practice, including with next-generation sequencing, whole genome copy number profiling, methylation profiling, genomic DNA methylation profiling, and more.

The molecular revolution in pathology and neural pathology, as it concerns brain tumors, has been going on for now, better part of 2 decades. It culminated more recently with the fifth edition of the World Health Organization that was published in 2021. To the greatest extent, we are incorporating molecular features specific molecular features as part of the diagnostic criteria for a lot of tumors, a lot of tumor subtypes. It's gotten to the point where pretty detailed molecular workup is essential, and it's indispensable for routine neurosurgical practice and neuropathology practice.

We do it on a routine basis, specifically for all our gliomas or anything we suspect to be a glioma. We run next-generation sequencing, whole genome copy number profiling, methylation profiling, genomic DNA methylation profiling, and integrate those results in with histopathology. If the histopathology says 1 thing or is a little broad in terms of what the differential could ultimately be, we add in the molecular data and then produce an integrated diagnosis.

Videos

Craig Horbinski, MD, PhD, discusses the classification of gliomas based on histology and molecular features.


News

Incorporating Molecular Testing for Gliomas Into Clinical Practice

Katherine B. Peters, MD, PhD, neuro-oncologist at Duke Cancer Center, discusses the findings from the phase 3 INDIGO trial (NCT04164901) which were presented at the 2023 ASCO annual meeting.

The study evaluated treatment with vorasidenib (AG-881), an IDH1/2 inhibitor, in patients with low-grade glioma.

presentation of the study during the 2023 ASCO Annual Meeting

, the median independently assessed imaging-based progression-free survival was 27.7 months among patients treated with vorasidenib (95% CI, 17.0-not estimated) vs 11.1 months (95% CI, 11.0-13.7) for those given placebo (HR, 0.39; 95% CI, 0.27-0.56; 

These findings provide potential to change the treatment paradigm for patients with this type of glioma by allowing vorasidenib to become the first targeted therapy for low-grade glioma.

What's exciting is this is a development that we haven't seen in over 20 years, and what we found is that when we looked at our patients that received vorasidenib in comparison with the placebo, those patients had a much improved prognosis, such that their progression-free survival was extended to 27.7 months compared with 11 months, which is a very large, statistically significant difference. For our patients with low-grade glioma, the approach we use is usually a watch and wait, and then if the tumor starts to grow or progresses, we have to go to more aggressive treatments such as surgery, radiation, and chemotherapy. This is challenging because those patients are in the young adult years, and those can cause a lot of significant toxicities.

One of the key secondary end points was time to the next intervention. What we found is that patients that received the vorasidenib had a significant extended time to delay the next intervention, whereas patients that received just the placebo, they had to have an extra intervention by 17.8 months. What our data shows is we haven't even reached that median value for those patients. So this can be a durable therapy that can slow progression and slow the chance of your patients having to go to those more aggressive therapies which are more surgery, radiation, and chemotherapy.

Katherine B. Peters, MD, PhD, discusses the findings from the phase 3 INDIGO trial which were presented at the 2023 ASCO annual meeting. 


Conference News

INDIGO Trial Shows Potential of Vorasidenib in Low-Grade Glioma

Manmeet Ahluwalia, MD, the chief of Medical Oncology, chief scientific officer & deputy director at Miami Cancer Institute of Baptist Health South Florida, discusses results from the CRUX trial (NCT03514069) which were presented during the 2023 American Society of Clinical Oncology Annual Meeting.

According to findings from the study, ruxolitinib (Jakafi) with 75 mg/m

 of temozolomide with radiation of 60 Gy over 6 weeks is safe, feasible, and demonstrated positive efficacy among patients with WHO Grade 3-4 newly-diagnosed high-grade gliomas.

At ASCO 2023, we were very excited to present a final report of CRUX study, which was looking at the JAK/STAT inhibitor ruxolitinib in patients with newly diagnosed high-grade gliomas. The outcomes for patients with high-grade gliomas is fairly dismal, despite the advances in surgery, radiation, and chemotherapy. Hence, novel agents like ruxolitinib are urgently needed. Ruxolitinib targets the JAK/STAT pathway that has been associated with tumor progression and worse outcomes in patients with glioblastoma. Hence, we combined this agent with radiation alone in the MGMT unmethylated patients, and we combined it along with temozolomide and radiation in the MGMT methylated patients because temozolomide only confers a 21 day benefit in patients with unmethylated MGMT glioblastoma.

What we found out was that the agent ruxolitinib was extremely well-tolerated, both in combination with either radiation or with temozolomide and radiation. The highest dose of ruxolitinib that was given on this trial without any dose-limiting toxicity was 20 milligrams BID dosing. We also found that the outcomes of the patients treated with ruxolitinib along with radiation in arm 1 unmethylated patients and ruxolitinib and temozolomide with radiation appear promising compared with the historical controls with these patients. Hence, currently, we are planning a phase 2 trial looking at ruxolitinib along with radiation and temozolomide in patients with glioblastoma.

Manmeet Ahluwalia, MD, discusses results from the CRUX trial which were presented during the 2023 American Society of Clinical Oncology Annual Meeting.


Toxicity Data From the CRUX Trial of Ruxolitinib in High-Grade Gliomas  

Rupesh Kotecha, MD, chief of Radiosurgery and director of Central Nervous System Metastasis with Baptist Health Miami Cancer Institute, discusses the key findings from an analysis centered around the use of pulse reduced dose rate intensity-modulated radiotherapy in patients with central nervous system (CNS) malignancies.

 were treated with 45 Gy of pulse reduced dose rate intensity-modulated radiation, leading to a median progression-free survival of 6.3 months (95% Cl, 0.9-11.6 months), and a median overall survival of 8.6 months (95% Cl, 4.9-12.3 months).

These data show that pulse reduced dose rate intensity-modulated radiotherapy can now derive benefit. This method provides disease control for a number of months among patients with CNS cancers and according to Kotecha, this technique can be used in clinical practice. Further research in this space will continue to work on improving control rates for patients, reducing toxicity, and more.

The first key takeaway is that pulse reduced dose rate intensity-modulated radiotherapy is a technique that can be utilized in clinical practice now. Out of the institutions that have been using it, for example, those 5 that have published outcomes, this should be available across the country at other institutions. In our experience, it was relatively safe and is a feasible treatment for patients who have recurrent tumors. This technique can provide disease control for a number of months.

The second takeaway is that this provides us with baseline estimates of what are the toxicity rates at certain thresholds of dose to the key organs at risk in the brain. Using these, we can now build and develop newer techniques to help reduce the toxicity more and potentially improve our control rates further. This is where our research is going.

Rupesh Kotecha, MD, discusses the key findings from an analysis centered around the use of pulse reduced dose rate intensity-modulated radiotherapy in patients with central nervous system malignancies.

Key Takeaways Regarding Use of 45 Gy Novel Radiotherapy in CNS Cancers

Rupesh Kotecha, MD, chief of Radiosurgery and director of Central Nervous System Metastasis with Baptist Health Miami Cancer Institute, discusses results of an analysis which centered around the use of pulse reduced dose rate intensity-modulated radiotherapy in patients with central nervous system malignancies.

study assessed 18 patients with CNS malignancies

 who were treated with 45 Gy of pulse reduced dose rate intensity-modulated radiation. Findings showed that the median progression-free survival with the novel radiation modality was 6.3 months (95% Cl, 0.9-11.6 months), and the median overall survival was 8.6 months (95% Cl, 4.9-12.3 months).

Kotecha notes that these overall findings were in line with what has been published in prior research.

 Our study looked at 18 patients with recurrent primary CNS tumors that were treated at our institution over a 4-year period, and the median dose of radiation therapy in our series was 45 Gy…But then that cumulative dose of radiation when we incorporate the prioritization that those patients have had is over 100 Gy in this series, it's a very high dose of radiation. Even with that our toxicity rates are very modest in this patient population.

We saw that the median progression-free survival was 6.3 months. Now going back to that systematic review of the literature that we performed, we also looked at the outcomes across the 5 studies that have been published in the literature to date on this same topic. It was a limited series, but at least in pooled analyses. The median progression-free survival across the literature across these studies was 5.7 months. Overall, our results are basically in line with those that have been published. This gives us some idea of what are our baseline statistics or safety thresholds that we can determine as we think about newer techniques to build upon this.

Rupesh Kotecha, MD, discusses results of an analysis which centered around the use of pulse reduced dose rate intensity-modulated radiotherapy in patients with central nervous system malignancies.

Kotecha Analyzes Use of 45 Gy Novel Radiotherapy in CNS Cancers

Patrick Wen, MD, professor of Neurology at Harvard Medical School and director of the Center for Neuro-Oncology at Dana-Farber Cancer Institute, discusses the evolution of treating patients with brain cancer with immunotherapies and targeted therapies.

Immunotherapies and targeted therapies have improved survival outcomes and shown that they are active for patients with glioma. Previously, it was thought these kinds of targeted therapies wouldn’t work for patients with a glioblastoma, but according to Wen, a small subset of patients with glioblastoma have shown 

 V600E mutations have responses to treatments like dabrafenib (Tafinlar) and trametinib (Mekinist) that are approved for different subtypes.

The evidence for these inhibitor combinations has allowed clinicians to think differently about what mutations are active in glioblastoma and how to target them appropriately. For instance, looking for 

 fusions in glioblastoma has led to emerging evidence that entrectinib (Rozlytrek) is active for these patients and that it is worth pursuing evidence for other inhibitors, like erdafitinib (Balversa). Wen explains how the evidence has led to more studies and the hope that over time they will be fruitful.

 I think for a long time, because of the issues of the blood brain barrier, heterogeneity, and redundancy of signaling pathways, there was thought that targeted therapies would never work for glioblastoma. But we have found that these small subsets of patients that do respond. Two percent of patients with glioblastoma that have 

 V600E mutations have shown responses to the dabrafenib and trametinib, a BRAF and MEK inhibitor combination that's approved for melanoma.

 The response rate in glioblastoma is about 32%. In low-grade gliomas, it's 69%. Responses in both populations are durable, and it was part of a study with multiple tumors that led to the FDA approval for that combination for all solid tumors in 2022. There's also evidence that targeted therapies may be helpful for tumors with the very rare 

 fusions. Entrectinib seems to be active for gliomas with 

 fusion. There's also emerging evidence that erdafitinib, an FGFR inhibitor, has activity in gliomas.

Patrick Wen, MD, looks at how emerging evidence has shown promise for targeting mutations in patients with glioblastomas when it was once believed these therapies may not work for these patients. 

Discussing Immunotherapies and Targeted Therapies in Brain Cancer

Rupesh R. Kotecha, MD, chief of Radiosurgery and director of Central Nervous System Metastasis at Baptist Health Miami Cancer Institute, discusses a newer radiation modality known as pulse reduced dose rate radiation therapy.

Kotecha co-authored a study that used pulse reduced dose rate radiation therapy and presented the research at the American Society for Radiation Oncology (ASTRO) Annual Meeting.

 Pulse reduced dose rate radiation therapy is a very specific reirradiation approach, which has been used primarily in the central nervous system space for recurrent primary brain tumors. But it's also been explored in a couple of circumstances outside of the brain itself. Now, this research was previously limited to very few institutions who had experience with using this technique, and also who see this patient volume. Typically, patients with recurrent primary brain tumors traveled to specific centers of excellence or those who have clinical trials. And then sometimes those centers may not have clinical trials that the patient will be eligible for. But then we have a larger experience or volume of patients with that particular need.

 So, this was developed at a number of institutions, as one of those re-irradiation approaches to try and control the disease after somebody has progressed on multiple lines of systemic therapy. We had previously known at least in the limited series that had been done, that there was some aspect of disease control that looked very favorable, and the order of maybe six months or so longer in some series, shorter and other series.

 The purpose of our study was to do two things. Number one is to actually incorporate the prior radiation therapy plans, and then add the new reirradiation plans together to come up with those constraints, safety threat thresholds that could be used in the future when patients are undergoing radiation. The second goal was to basically pull the analyses from these different institutions so that we would know what [the] composite outcomes are, not just what does institution A or B, or C actually present or publish. But what happens when you pull all the outcomes together statistically, to look at what those outcomes could be across all of the institutions

Rupesh R. Kotecha, MD, discusses a newer radiation modality known as pulse reduced dose rate radiation therapy.



Understanding Pulse Reduced Dose Rate Radiotherapy 

The final patient with glioblastoma multiforme (GBM) has been enrolled in the ongoing phase 2 clinical trial of VAL-083, which is evaluating the efficacy, safety, and pharmacokinetics of the agent in patients who have been pre-treated with temozolomide (Temodar) prior to disease recurrence, according to a press release from Kintara Therapeutics, Inc.

VAL-083 is a first-in-class small molecule bifunctional alkylating agent that has the ability to cross the blood-brain barrier. VAL-083 was previously granted Orphan Drug Designation for GBM by the FDA as well as a Fast Track designation for the treatment of patients with recurrent GBM.

The study, which is being conducted at the MD Anderson Cancer Center in Houston, Texas, enrolled 83 patients into the recurrent arm to determine whether the drug will improve overall GBM survival. Of the 83 patients, 35 patients will receive 40 mg/m2/day of VAL-083 and 48 patients will receive 30mg/m2/day. Efficacy is determined by overall survival (OS) as well as progression-free survival (PFS). 

The final patient with glioblastoma multiforme has been enrolled in the ongoing phase 2 clinical trial of VAL-083, which is evaluating the efficacy, safety, and pharmacokinetics of the agent in patients who have been pre-treated with temozolomide prior to disease recurrence.

BRAIN CANCER

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