BRAF-MEK Inhibition in Newly Diagnosed Papillary Craniopharyngiomas

Abstract

Background: Craniopharyngiomas, primary brain tumors of the pituitary-hypothalamic axis, can cause clinically significant sequelae. Treatment with the use of surgery, radiation, or both is often associated with substantial morbidity related to vision loss, neuroendocrine dysfunction, and memory loss. Genotyping has shown that more than 90% of papillary craniopharyngiomas carry BRAF V600E mutations, but data are lacking with regard to the safety and efficacy of BRAF-MEK inhibition in patients with papillary craniopharyngiomas who have not undergone previous radiation therapy.

Methods: Eligible patients who had papillary craniopharyngiomas that tested positive for BRAF mutations, had not undergone radiation therapy previously, and had measurable disease received the BRAF-MEK inhibitor combination vemurafenib-cobimetinib in 28-day cycles. The primary end point of this single-group, phase 2 study was objective response at 4 months as determined with the use of centrally determined volumetric data.

Results: Of the 16 patients in the study, 15 (94%; 95% confidence interval [CI], 70 to 100) had a durable objective partial response or better to therapy. The median reduction in the volume of the tumor was 91% (range, 68 to 99). The median follow-up was 22 months (95% CI, 19 to 30) and the median number of treatment cycles was 8. Progression-free survival was 87% (95% CI, 57 to 98) at 12 months and 58% (95% CI, 10 to 89) at 24 months. Three patients had disease progression during follow-up after therapy had been discontinued; none have died. The sole patient who did not have a response stopped treatment after 8 days owing to toxic effects. Grade 3 adverse events that were at least possibly related to treatment occurred in 12 patients, including rash in 6 patients. In 2 patients, grade 4 adverse events (hyperglycemia in 1 patient and increased creatine kinase levels in 1 patient) were reported; 3 patients discontinued treatment owing to adverse events.

Conclusions: In this small, single-group study involving patients with papillary craniopharyngiomas, 15 of 16 patients had a partial response or better to the BRAF-MEK inhibitor combination vemurafenib-cobimetinib. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT03224767.).

Figure 1.. Change in Tumor Volume from Baseline.

The blue bars indicate the 15 patients with papillary craniopharyngiomas who had a partial response to vemurafenib–cobimetinib therapy. The yellow bar indicates 1 patient who received only 8 days of therapy before withdrawing because of toxic effects. The horizontal dashed lines indicate the corresponding measures for each type of response.

Figure 2.. Estimates of Progression-free and Overall Survival.

Panel A shows the Kaplan–Meier estimates of progression-free survival as assessed by central review. Progression-free survival was estimated to be 87% (95% CI, 57 to 98) at 12 months and 58% (95% CI, 10 to 89) at 24 months. Hatch marks indicate data censoring. Panel B shows the Kaplan–Meier estimates of overall survival. The estimated percentage of overall survival was 100% at 12 months (95% CI, 69 to 100) and 24 months (95% CI, 16 to 100).