The results from three small studies of targeted therapy for rare brain tumors were “remarkable,” according to, MD, a neurology professor at Johns Hopkins Medicine, Baltimore, who discussed the studies after they were presented at the American Society of Clinical Oncology meeting.
Although most patients don’t have targetable mutations, molecular testing “is well worth the effort,” for those that do. “I think it’s fair to say that precision medicine” – well established in other tumor types – “is finally here in full force for neuro-oncology,” Dr. Blakeley said.
A promising start
Fifteen of 16 patients (94%) inhad newly diagnosed and untreated papillary craniopharyngiomas (PCPs) that harbored BRAF V600E mutations, a common finding in PCPs, which have no effective medical treatment.
Tumors shrunk 68%-99% in 14 patients (93%) after treatment with the BRAF inhibitorplus the MEK inhibitor cobimetinib, which was included to stave off resistance to vemurafenib. The 24-month progression free survival was 93%.
The combination resulted in significant response in all patients who received at least one cycle of therapy, with a median 91% volume reduction. “Our study indicates that BRAF/MEK inhibitors could be a powerful tool in the treatment of previously untreated PCP, with the potential to avoid the morbidity associated with radiation and surgery,” concluded lead investigator and presenter, MD, associate professor of medicine at Mass General Cancer Center, Boston.
Thirty-three people in thehad a mix of high and low grade gliomas or other CNS tumors positive for TRK gene fusions, a known oncogenic driver; the majority were children. They were treated with the TRK inhibitor after progressing on other systemic therapies.
The objective response rate was 30%, and the disease control rate was 73% at 24 weeks, with a median time to best response of 1.9 months. Tumors shrank in 82% of evaluable patients. Median progression-free survival was 18.3 months, and overall survival was not reached.
“These results support testing for TRK gene fusions for all patients with CNS tumors, especially if there is no known driver and especially in infants,” concluded lead investigator and presenter, MD, a clinical assistant neurosciences professor at the University of Montreal.
The third studysuch as in seven patients with adult-onset neuroblastoma, a rare and almost invariably fatal tumor known to be enriched for ALK mutations; the subjects were positive for them.
Their disease remained stable anywhere from 3.4 to 37.4 months. Median time to progression was 15.5 months, and median overall survival was 46.5 months.
ALK inhibitors “can be a well-tolerated options for treatment, improving time to progression. Development of resistance to one agent does not preclude use of other agents in the same drug class. ALK inhibitors should be considered when treating patients with this diagnosis,” said lead investigator and presenter
A ‘strong’ recommendation
The data “are great news” across the board. Targeted therapy applied to the right CNS tumor can have “dramatic” benefit for tumor control, Dr. Blakeley said.
But organizing molecular testing is not straightforward and requires strategies to balance “the use of precious resources, such as time money, and tissue,” with the potential benefit. Interpretation of testing results isn’t straightforward either, and is best handled by a molecular tumor board. Clinical pharmacists are also key to accessing expensive medications off label for CNS tumors.
Adverse events are also a consideration. Most of the subjects in the PCP study had grade 3/4 toxicity. Three patients in the ALK inhibitor study had to stop because of adverse events. Almost 40% on larotrectinib had grade 3 or 4 toxicity; nobody came off treatment, but a third had to skip doses.
Once an actionable mutation is identified, Dr. Blakeley’s “strong recommendation” is to enroll patients in a clinical trial that targets it, to take advantage the structure already in place to secure treatment, managed patients, and assess outcomes.
The National Cancer Institute’sis one of several options.
The BRAF/MEK inhibitor study was funded by Genentech and the National Institutes of Health. Dr. Brastianos had ties to numerous companies, including Pfizer, Lilly, and Merck. The TRK inhibitor study was funded by Bayer/Lilly. Dr. Perreault is a speaker and researcher for the company and has other ties. Dr. Blakeley is an adviser and/or researcher for a number of companies, including AbbVie, Astellas, BMS, and Exelixis. Dr. Stiefel didn’t have any disclosures, and didn’t report outside funding.