‘Very Promising’: New Cancer Drug, Plixorafenib, Shows Promise for Hard‑to‑Treat Brain Tumors as FDA Speeds Its Development

A Breakthrough Therapy Designation isn’t FDA approval, but it signals the agency’s commitment to speed the drug’s development for patients with serious, unmet medical needs.

WATCH: What Is Glioma & How Is It Analyzed?

Plixorafenib is an oral therapy designed to shut down cancers driven by abnormal BRAF proteins. It works by blocking mutated BRAF proteins while sparing normal BRAF function, helping slow or stop tumor growth in cancers that rely on these mutations to thrive.

“This designation is a big step for targeted therapies in high‑grade glioma patients with actionable molecular markers,” adds Dr. Jacob Young, a neurosurgeon at UCSF Health.

High‑grade gliomas are among the most aggressive brain tumors and typically require a combination of surgery, radiation, and chemotherapy.

“Grade 1 is the least aggressive; grade 4 is the most aggressive,” explains Dr. Ashley Ghiaseddin, a neuro‑oncologist at University of Florida Health.

“The grading tells us how the tumor behaves under the microscope and guides the treatment we offer,” Dr. Ghiaseddin added.

Grade 3 gliomas are considered high-grade and are malignant and fast‑growing. They often require intensive multimodal therapy, including surgery, radiation, and chemotherapy, among others.

Grade 4 gliomas, such as glioblastoma, are the most aggressive and tend to invade the surrounding brain tissue. These tumors are locally aggressive and require intensive treatment.

For patients whose high‑grade gliomas also carry the BRAF V600E mutation, the disease can be even more challenging. This mutation drives uncontrolled cell growth, but it also creates a potential therapeutic target for cancer drugs designed to stop its proliferation.

Several drugs are designed to inhibit the mutant BRAF protein and disrupt tumor growth.

WATCH: Personalized Medicine and the Tremendous Value of Molecular Testing for Gliomas

To determine whether a glioma carries mutations like BRAF V600E, molecular testing is essential. This testing analyzes the tumor’s DNA to identify specific genetic changes that influence how the tumor behaves and how it can be treated.

“In the past, we treated all gliomas the same way, but molecular testing has changed that,” says Dr. Reid Thompson, Chair of Neurosurgery at Vanderbilt University Medical Center.

“Now we can identify specific mutations and tailor treatment to the individual patient,” Dr. Thompson added.

What Led to the Breakthrough Therapy Designation?

Plixorafenib was a key focus during the Phase 1/2a clinical trial and the ongoing Phase 2 FORTE clinical trial.

Data presented at the 2023 Society for Neuro-Oncology (SNO) conference showed that patients with BRAF V600-mutated tumors had a “67% overall response rate” after taking plixorafenib.

“The promising overall response rate reported in the Phase 1/2 trial for patients with BRAF V600E-mutated high-grade glioma treated with plixorafenib data is very encouraging,” Dr. Young tells SurvivorNet.

Some of the side effects experienced by patients using plixorafenib included fatigue, nausea, diarrhea, vomiting, and liver disruptions such as inflammation.

“Overall, the results from the phase 1/2 clinical trial of plixorafenib in patients with primary brain tumors with a BRAF mutation are very promising. The study demonstrated an improved side effect profile compared with prior alternatives and promising response rates,” says Dr. Juan Pablo Ospina, a board-certified neurologist at the University of Pennsylvania Health System.

“Although these findings will require validation in larger clinical trials, the early signals are notable and support the FDA’s designation of plixorafenib as a breakthrough therapy,” Dr. Ospina tells SurvivorNet.

Dr. Ospina adds that these ongoing studies underscore the importance of continued molecular profiling, including next-generation sequencing, which allows scientists and doctors to examine the genetic material (DNA and RNA) in tumor cells “beyond the initial diagnosis.”

Molecular Testing of Gliomas

“I recommend next-generation sequencing and molecular profiling for all of my patients. I believe this is a must-have. This is the next frontier of treatment that we’re looking at now,” Dr.Ghiaseddin explains.

Next-generation sequencing enables the rapid sequencing of genetic material. Simply put, it’s like reading the instruction manual of the tumor at an incredibly detailed level. Every cell in our body has DNA, which contains genes that serve as instructions for how cells grow and function. In cancer, including gliomas, some of these instructions become faulty due to mutations or other changes in the DNA. These changes can drive tumor growth and affect how a tumor behaves.

How NGS Is Used in Glioma Treatment

More Accurate Diagnoses

Gliomas can look similar under a microscope, but their molecular features are what truly define them. NGS identifies key mutations—such as IDH1/IDH2—that help classify the tumor more precisely and predict how aggressive it may be.

• Personalized Treatment Planning
  • NGS reveals the genetic changes driving a patient’s tumor, allowing clinicians to tailor therapy. For example, MGMT promoter methylation detected through molecular testing can signal a better response to temozolomide.
• Access to Clinical Trials
  • Many trials require specific molecular markers. NGS can uncover rare mutations or fusions that make a patient eligible for targeted or experimental therapies they otherwise wouldn’t have access to.
• Monitoring How the Tumor Evolves
  • Tumors change over time, especially under treatment pressure. Repeat NGS can detect new mutations or resistance mechanisms, helping clinicians adjust therapy as the disease progresses.

Key Results Doctors Look For in NGS Reports

• Gene Mutations
  • NGS identifies DNA changes that drive tumor growth. In gliomas, mutations in IDH1, IDH2, TP53, and EGFR are especially important for diagnosis and prognosis.
• Chromosomal Changes
  • Some gliomas show characteristic chromosome patterns—like the 1p/19q co‑deletion—which can signal better treatment response and outcomes.
• Gene Expression (RNA) Patterns
  • By looking at RNA, NGS shows which genes the tumor is actively using. This helps reveal how the tumor behaves and where it may be vulnerable.
• Tumor Mutational Burden (TMB)
  • TMB measures how many mutations the tumor carries overall. Higher TMB can sometimes predict better responses to immunotherapy.
• Actionable Targets
  • One of the main goals of NGS is to find genetic changes that can be treated with targeted drugs—such as BRAF mutations that may respond to BRAF‑directed therapies.

10zzgIYd

How Next-Generation Testing Benefits Patients

For glioma patients, NGS helps personalize care by revealing the specific genetic features of their tumor. This allows doctors to choose treatments more likely to work and gives patients clearer guidance when considering options, including whether a clinical trial might be a good fit. The added genetic detail helps patients and care teams make more confident, informed decisions.

Better Understanding Brain Tumors

Brain tumors can impact a person’s cognitive function and overall well-being, depending largely on the tumor’s size, type, and specific location within the brain. When large enough, tumors may interfere with the central nervous system, pressing on nearby nerves, blood vessels, or tissues. This disruption may result in difficulties with coordination, balance, or mobility.

WATCH: Hope for Glioblastoma Research

While some brain tumors cause noticeable symptoms, others can go unnoticed for long periods. When symptoms do occur, they might include:

• Persistent headaches
• Difficulty speaking or processing thoughts
• Muscle weakness
• Behavioral or personality changes
• Vision disturbances
• Seizures
• Hearing loss
• Confusion
• Memory issues

Types of Brain Tumors: Cancerous and Non-Cancerous

According to the National Cancer Institute, brain tumors can vary greatly in behavior. Some common non-cancerous (benign) types include:

• Chordomas: Slow-growing, often found near the spine’s base or where it meets the skull
• Craniopharyngiomas: Develop near the pituitary gland; rare and slow-growing
• Gangliocytomas: Form in the temporal lobe and affect the central nervous system
• Glomus jugulare: Rare and slow-growing
• Meningiomas: Typically grow on the brain’s outer protective layer (dura mater)
• Pineocytomas: Arise from the pineal gland near the brain’s center
• Pituitary adenomas: Located in the pituitary gland; generally slow-growing
• Schwannomas: Originate in Schwann cells, which insulate nerve fibers
• Acoustic neuromas (vestibular schwannomas): Impact on hearing and balance nerves

Common malignant (cancerous) brain tumors include:

• Gliomas: The most frequent and aggressive form of primary brain cancer
• Astrocytomas: Derived from star-shaped brain cells, with four growth grades
• Ependymomas: Graded based on aggressiveness
• Oligodendrogliomas: Can grow slowly (Grade 2) or aggressively (Grade 3)
• Medulloblastomas: Fast-growing and often found in children
• Glioblastomas: The most common and aggressive brain tumor in adults

Questions to Ask Your Doctor

If you or someone you love has been diagnosed with a glioma, it’s important to talk with your care team about molecular testing. SurvivorNet’s AI‑powered tool, “My Health Questions“, can also help you better understand your diagnosis, explore treatment options, and prepare meaningful questions for upcoming appointments. Here are a few to consider:

• Do you need both the tissue sample and blood samples for molecular testing?
• What specific mutations will you be testing for in my tumor?
• Do I have any genetic mutation that would change the course of my treatment?
• Am I eligible to receive targeted therapy? What about immunotherapy?
• Is there a clinical trial that would be relevant for me?

Learn more about SurvivorNet's rigorous medical review process.

---