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Targeted BRAF-MEK inhibition resulted in a response in nearly all patients with untreated BRAF V600E–mutated papillary craniopharyngioma, according to results from a small .

Of 16 evaluable patients treated with the BRAF inhibitor vemurafenib (Zelboraf) and the MEK inhibitor cobimetinib (Cotellic) over several monthly cycles, 15 had a durable, objective partial response or better to therapy, with a median reduction in tumor volume of 91%, reported Priscilla Brastianos, MD, of the Massachusetts General Hospital Cancer Center in Boston, and colleagues.

The one patient who did not respond received treatment for 8 days before stopping therapy due to anaphylaxis and acute kidney injury.

"Thus, all the patients who completed at least one cycle of therapy had a response to BRAF–MEK inhibition within 4 months after starting the combination regimen," Brastianos and colleagues reported in the .

In addition, estimated progression-free survival was 87% at 12 months and 58% at 24 months. Overall survival was 100% at both time points.

With a median follow-up of 22 months, an estimated 93% of patients continued to have a volumetric response at 12 months. In three patients who had had a response, progressive disease developed during the follow-up period after therapy had been discontinued.

"The near-universal radiographic response with subsequent long-term stability that was seen in this study supports a shift in clinical guidelines toward biopsy and molecular analysis followed by upfront drug therapy for newly diagnosed BRAF V600E papillary craniopharyngiomas," wrote Jaishri Blakeley, MD, of the Johns Hopkins School of Medicine in Baltimore, and Kevin Shannon, MD, of the University of California, San Francisco, in an .

"The marked reduction in gross target volumes for radiation therapy after the use of vemurafenib–cobimetinib further suggests that initial drug therapy may improve clinical outcomes by reducing the radiation field or making complete surgical excision feasible," they continued.

Craniopharyngioma is a rare and difficult-to-treat histologically benign, but locally aggressive, epithelial tumor. The location of the tumor -- at the base of the brain near the optic nerve and pituitary gland -- means complete resection of the tumor is usually not feasible. Treatment with radiation therapy is frequently used as an adjunct therapy to improve local control after surgery.

"No effective medical treatment for craniopharyngioma is known," however, as treatment with surgery, radiation, or both "is often associated with substantial morbidity related to vision loss, neuroendocrine dysfunction, and memory loss," Brastianos and colleagues pointed out. "These cumulative and debilitating long-term neurologic complications can have a substantial psychosocial effect on patients, rendering many unable to work or to live independent lives."

They noted that genotyping shows that more than 90% of papillary craniopharyngiomas carry a BRAF V600E mutation, and that therapies that inhibit BRAF and MEK have been approved by the FDA for treating melanoma and other cancers. Thus, they hypothesized that a BRAF-MEK inhibitor (vemurafenib/cobimetinib) might also be effective for treating papillary craniopharyngioma.

In this study, eligible patients had histologically proven BRAF V600E–mutant papillary craniopharyngiomas, had not undergone previous radiation or systemic therapy for craniopharyngioma, and had measurable disease. Their median age was 49.5 years, median baseline tumor volume was 2.75 cm, and 15 of the 16 had an ECOG performance status of 0 or 1.

Patients received vemurafenib at a dose of 960 mg orally twice daily for 28 days in combination with cobimetinib at a dose of 60 mg orally once daily for 21 days. Protocol dictated that patients undergo radiation or surgery after treatment with vemurafenib-cobimetinib for four cycles, but many were permitted to continue BRAF-MEK inhibition until the occurrence of documented progression, unacceptable adverse events, or withholding of drug therapy for longer than 28 days.

Regarding safety, three patients discontinued therapy due to adverse events (median treatment duration of 31 days).

Twelve patients had a grade 3 adverse event, with rash, dehydration, increase in alkaline phosphatase levels, and prolongation of the corrected QT interval observed in two or more patients.

Two patients had grade 4 adverse events considered to be "at least possibly related" to treatment, including an increase in the creatine kinase level, and a case of hyperglycemia.

In their editorial, Shannon and Blakeley suggested that while the range of toxic effects reported here were similar to those seen in other studies of BRAF-MEK inhibitors, "the incidence of adverse events in this study is problematic for long-term daily therapy for an indolent, histologically benign tumor."

Therefore, they added, an important question is whether dual inhibition is necessary to induce papillary craniopharyngioma regression.

Brastianos and colleagues acknowledged that it remains "an open question" whether BRAF-MEK inhibition is indicated for a therapeutic response or whether BRAF inhibition alone is sufficient.

"We chose the combination, given the improved progression-free and overall survival observed with the use of combination BRAF-MEK inhibitors in other tumor types, as well as the concerning rate of specific toxic side effects, such as proliferative skin lesions, that have been seen with BRAF monotherapy," they explained.

The authors cautioned that their study lacked a control group and had a small sample due to the rarity of the disease. Uncertainties also remain regarding the ideal duration of BRAF-MEK inhibition and its effectiveness in patients with recurrent craniopharyngioma after radiation.