In late June 2022, the U.S. Food and Drug Administration (FDA) granted accelerated approval to a new treatment combination that will now be available as an option for certain brain tumor patients. The approved combination of two oral drugs, called dabrafenib (brand name: Tafinlar) and trametinib (brand name: Mekinist), is for the treatment of advanced tumors that have a mutation called “BRAF V600E,” including in both adult and pediatric (older than 6 years of age) high- and low-grade glioma patients with this mutation whose tumors progressed after prior treatment.
Q: For patients impacted by a brain tumor diagnosis, who is this drug treatment approved for?
A: These two drugs are approved for all cancers that have the BRAF V600E mutations. Specifically, for brain tumors, these mutations are mostly seen in gliomas. BRAF V600E mutations are estimated to be present in approximately 2% of glioblastoma (GBM) – though a little more common in a subtype of GBM called epithelioid glioblastoma – and 60% of some lower-grade gliomas like gangliogliomas and pleomorphic xanthoastrocytoma (PXA). However, they are very rare in other gliomas like ependymomas.
Q: Can this treatment be given without a patient showing evidence of recurrence? If a patient’s initial biomarker testing at diagnosis shows the BRAF V600E mutation, can this drug combination be given as a part of standard of treatment?
A: Right now, the approval is for recurrent tumors. But a recent presentation at the American Society for Clinical Oncology meeting showed that, specifically for pediatric low-grade glioma patients with the mutation, they did better with this combination at first diagnosis, too, compared to current treatments. So as more evidence becomes available, this combination might ultimately be able to be given at initial diagnosis, but for right now, again, it’s only recurrent tumors.
Q: How do I know if my tumor has the BRAF V600E mutation?
A: Biomarker testing needs to be performed on your tumor tissue to look specifically for this mutation. Fortunately, neuropathology labs at cancer centers are already performing these tests, as the field realizes that additional treatment options might exist for patients with this and other specific mutations. But not every hospital and cancer center is, so it’s important that you ask in case they are not. Additionally, while biomarker testing for BRAF V600E is very likely to be part of the standard testing panels neuropathology labs perform, it’s still a good idea to check with your doctor to make sure it’s being tested for. Most of these panels will look for other potentially treatable targets, including the NTRK-fusion, for which there are drugs that are also FDA approved. It’s generally useful for doctors to test for a wide range of targets in your tumor for anything that could potentially be treatable.
Q: Can biomarker testing be done on a brain tumor now if it wasn’t after initial surgery?
A: If there is enough tissue properly stored and remaining from your initial surgery, yes, biomarker tests can be performed later on. However, a limiting factor may be for patients who had only a biopsy performed. While tissue taken during a full tumor resection is typically enough for testing, sometimes with biopsies only there is not enough.
Q: Does the patient require a second surgery at recurrence to identify if the markers have changed before prescribing this treatment?
A: There are some mutations that are “lost” at recurrence. But most of the time, the BRAF 600E mutation is not a mutation that is usually lost. Most of the time, it will still be there at recurrence. You may need to test again to be 100% sure, but most likely, it is a mutation that doesn’t get “lost.
Q: How are these drugs administered? Do I have to be in the hospital, or can I take them at home?
A: Orally. Patients can just take the drugs at home. You don’t have to go into the hospital for the treatment.
Q: For this treatment to be effective for brain tumor patients with the BRAF V600E mutation, would dabrafenib and trametinib always be given in combination, or would there ever be a reason to give only one of the drugs to a patient?
A: It is best to give the combination together. That is what the approval was for. Additionally, prior research with melanoma patients (the drugs were first approved for melanoma) found that it is better if you give the drugs together, both in terms of anti-tumor activity and fewer side effects. By using both drugs, you actually see a reduction in some of the side effects of either alone.
Q: What are some of the most common potential side effects that have been observed specifically in glioma patients in these trials?
A: Fatigue (usually not terrible), sometimes decreased appetite, occasional bowel problems. But the main side effect we’ve seen is a rash. That rash is less severe if you use both drugs instead of just one.
Q: Would taking the combination of dabrafenib and trametinib exclude me from participating in clinical trials?
A: There are other trials using different combinations of BRAF and MEK inhibitors, which is what these two drugs are. Some of these are in adult, BRAF V600E mutated gliomas – both high-grade like GBM or low-grade gliomas – and there are a lot of ongoing trials for pediatric low-grade gliomas. Taking these two drugs would probably exclude you from those specific trials. Also, some trials will exclude you if you’ve already tried too many other treatments. It may make more sense to do a trial first if you have one you’re interested in and then go back to these treatments if the trial is not helpful.
Q: How can patients learn more about this treatment and if it is right for them?
A: It is important to talk to your neuro-oncologists. They will be able to send your tumor for testing and tell you if this mutation is in your tumor. They should also be equipped to talk with you about the pros and cons of trying this treatment compared to other options that might be available**.
Q: Because this drug is approved by the FDA, will it be covered by patients’ insurance plans
A: Because the evidence of these drugs for certain brain tumors had been emerging, we had seen some insurance plans paying for these treatments even before this approval. This recent approval will only make that easier. There sometimes can be a lag, though, between FDA approval and insurance coverage. But most patients should be able to work with their providers to get insurance to cover it ultimately. Eventually, the NCCN guidelines will likely be adjusted to reflect this approval, possibly for next year. Having this treatment combination as part of the NCCN guidelines will also make it easier to ensure insurance coverage, too.
Q: How will this approval by the FDA impact the field of neuro-oncology research?
A: This is really the first time, particularly for GBM, that a targeted therapy has shown real effectiveness. This fact suggests that targeted therapies – also known as “precision medicine” approaches – are feasible in tough-to-treat tumors like GBM. Previously, there had been some doubt there could be an effective targeted therapy for these tumors because they are so heterogeneous (have lots of different types of mutations within the same tumor and from patient to patient.) This shows it’s possible, at least in some subsets of patients, and certainly when targeted treatments are used in rational combinations. There is additional hope that this approval could also prove to companies that they can develop treatments in this space.
*Details on brain tumor clinical trials can be accessed by using the NBTS Clinical Trial Finder at trials.braintumor.org
**NBTS offers a Personalized Support and Navigation service staffed by a team with deep experience navigating brain tumor treatment options and questions. Patients and families who have questions about this or other options can contact the NBTS team at firstname.lastname@example.org.