Impressive Results with Targeted Therapy in a Rare Brain Tumor

According to Dr. Jaishri Blakeley, professor of neurology at Johns Hopkins University, results from three small studies of targeted therapy for rare brain tumors are highly meaningful.

Although most patients do not have targetable mutations, “molecular genetic testing is worth doing” Blakeley said, adding: “I think it is fair to say that precision medicine is finally here in full force for neuro-oncology.”

A promising start

In one study, 15 of 16 patients (94%) were newly diagnosed and had untreated BRAF V600E-mutant papillary craniopharyngiomas (PCPs).

What is craniopharyngioma?

Craniopharyngioma is a slow-growing tumor arising from remnants of Rathke’s pouch. It accounts for 3% of all brain tumors. It is the most common suprasellar tumor in children (54%) and in adults

it is the second most common. It has a bimodal age distribution, peaking twice, at ages 5-10 and in the 60s.

Two types of craniopharyngioma are described in the literature. In the childhood type, cystic changes and calcifications are common, and an adamantinomatous microscopic pattern is seen. The adult type generally has a favorable disease course, without calcification or cyst formation, and papillary squamous epithelium is seen microscopically.

Compression of the anterior visual pathways by the tumor causes various eye findings. The most common findings are bitemporal hemianopsia or inferior quadrantanopia and optic atrophy due to chiasmal compression.

Treatment of craniopharyngioma according to genetic testing

In the first study 15 of 16 patients (94%) with papillary craniopharyngioma, for which there was no effective treatment, had a BRAF V600 mutation.

• The BRAF inhibitor vemurafenib plus the MEK inhibitor added to reduce vemurafenib resistance, cobimetinib, produced tumor shrinkage of 68 – 99% in 14 patients (93%) after treatment.
• Progression-free survival at 24 months was 93%.

This combination produced meaningful responses in all patients who received at least one treatment cycle.

Study investigator and presenter Prof. Priscilla K said, “Our study suggests that BRAF/MEK inhibitors may be a powerful tool for treating previously untreated papillary craniopharyngioma, with the potential to avoid the morbidity associated with radiation and surgery.”

In a second study 33 people, positive for TRK gene fusions, a known oncogenic driver, had a mixture of high- and low-grade gliomas or other central nervous system (CNS) tumors; the vast majority were children. They were treated after progression on other systemic therapies with the TRK inhibitor larotrectinib.

• At 24 weeks, the objective response rate was 30% and the disease control rate was 73%, 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; overall survival was not reached.

Study investigator and presenter Sebastian Perreault, professor of clinical neuroscience at Monteral University, said, “These results support testing for TRK gene fusions in all patients with CNS tumors, particularly when there is no known driver and especially in infants.”

A third study tested ALK inhibitors such as crizotinib for treatment of the rare, almost always fatal tumor known to be rich in ALK mutations, neuroblastoma, in 7 patients. Their disease remained stable for 3.4 to 37.4 months. Median time to progression was 15.5 months and median overall survival was 46.5 months.

Study investigator and presenter Jessica Stiefel, a pediatric hematology-oncology specialist at Memorial Sloan Kettering Cancer Center in New York, said, “ALK inhibitors may be well-tolerated treatment options that extend the time to progression. The development of resistance to one agent does not preclude the use of other agents in the same drug class. ALK inhibitors should be considered when treating patients with this diagnosis.”

A strong recommendation

Across the board, the data are “great news.” Blakeley said that targeted therapy applied to the right CNS tumor can provide substantial benefits for tumor control.

However, organizing cancer genetic testing is not easy and requires strategies to balance the use of “valuable resources such as time, money and tissue” against potential benefits. Test results are also not easy to interpret.

Adverse events must also be considered. Most subjects in the PCP study had grade 3.-4. side effects. Three patients in the ALK inhibitor study had to discontinue treatment because of adverse events. About 40% of those in the larotrectinib study had grade 3. or 4. side effects; no one discontinued treatment, but they had to skip doses.

Targeted cancer drugs are an option when a suitable mutation is identified. Blakeley’s “strong recommendation” is to enroll patients in a clinical trial and take advantage of the existing structure to secure treatment, manage patients and evaluate outcomes.