BRAF–MEK Inhibition Is Effective in BRAF^V600E-Mutant Papillary Craniopharyngioma

Craniopharyngiomas are rare brain tumors of the pituitary–hypothalamic axis, and although these tumors are histologically benign, their growth can impinge on critical brain structures, such as the pituitary gland, hypothalamus, and optic chiasm, and lead to lifelong neurologic sequelae despite surgery and radiation. Given that approximately 95% of papillary craniopharyngiomas harbor BRAF^V600E mutations, Brastianos and colleagues tested the efficacy of BRAF and MEK inhibition in papillary craniopharyngioma in a multi-institutional, phase II trial in which 16 patients with newly diagnosed BRAF^V600E-mutant papillary craniopharyngioma, not previously treated with radiation, were treated with the RAF inhibitor vemurafenib and the MEK inhibitor cobimetinib for four 28-day cycles, followed by definitive therapy with radiation or surgery. The primary endpoint of the study was objective response, while secondary endpoints included progression-free survival (PFS), overall survival (OS), response as defined by volume, response duration, and adverse events. Fifteen of 16 evaluable patients (94%) achieved a complete or partial response, as evaluated by volumetric measurement at 4 months. A response was achieved in every patient who completed at least one cycle of therapy, as the one patient who did not have a response stopped treatment after 8 days following toxicity. PFS was estimated to be 87% at 12 months and 58% at 24 months, and OS was 100% at both 12 and 24 months. The median reduction in tumor volume was 91%, and 93% of patients maintained a volumetric response at 12 months. Grade 3 or 4 adverse events determined by the treating physician to be at least possibly related to treatment were observed in 12 and two patients, respectively. Notably, tumor progression was not observed at a median follow-up of 23 months in six of seven patients who received no treatment after discontinuing vemurafenib–cobimetinib, and exploratory analysis suggested that vemurafenib–cobimetinib decreased tumor radiation volumes. In summary, this Alliance for Clinical Trials in Oncology study indicates the efficacy of BRAF–MEK inhibition in newly diagnosed BRAF^V600E-mutant papillary craniopharyngioma and supports further clinical investigation of this combination as well as incorporation of this regimen in the up-front management of patients with biopsy-proven papillary craniopharyngioma.

Brastianos PK, Twohy E, Geyer S, Gerstner ER, Kaufmann TJ, Tabrizi S, et al. BRAF–MEK inhibition in newly diagnosed papillary craniopharyngiomas. N Engl J Med 2023;389:118–26.

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