Neoadjuvant B-RAF and MEK inhibitor targeted therapy for Adult Papillary Craniopharyngiomas: A new treatment paradigm

F. Calvanese*^a (Dr), R. Manet^a (Dr), A. Vasiljevic^b (Dr), H. Paris-Refahi^c (Dr), F. Ducray^d (Prof), G. Raverot^c (Prof), E. Jouanneau^a (Prof)

^a Pierre Wertheimer Hospital, HOSPICE CIVIL DE LYON, Pituitary and Skull Base Neurosurgical Department, Reference Center for Rare Pituitary Diseases, Lyon, FRANCE ; ^b Pierre Wertheimer Hospital, HOSPICE CIVIL DE LYON, Department of Pathology, Lyon, FRANCE ; ^c Pierre Wertheimer Hospital, HOSPICE CIVIL DE LYON,Endocrinology Department, Reference Center for Rare Pituitary Diseases HYPO, Lyon, FRANCE ; ^d Pierre Wertheimer Hospital, HOSPICE CIVIL DE LYON, Department of Neuro-Oncology, Lyon, FRANCE

* dr.fcalvanese@gmail.com

Background: The management of craniopharyngiomas invading the hypothalamus is associated with high long-term morbidity and represents a surgical challenge (Apra C. et al 2019). Recently, it has been established that the BRAF V600E mutation plays a central role for the Papillary Craniopharyngioma oncogenesis with encouraging results from targeted therapy (Brastianos PK et al. 2014-2021). However, there are few reported cases in medical literature.

Method: In the last 2 years, four cases of tuberoinfundibular Papillary Craniopharyngiomas have been treated with combined BRAF/MEK inhibitor therapy at our Institute. In three recurrent cases (one solid tumor, one cystic and one mixed), target therapy was administered as adjuvant treatment (i.e after surgery and/or radiotherapy). In one solid tumor, only a tumor biopsy was performed and the combined BRAF/MEK inhibition therapy was administered as pure neo-adjuvant treatment (i.e. before surgery or/and radiotherapy).

Results: The observed efficacy of combined BRAF/MEK inhibitor therapy confirmed the 11 previously published cases in the literature. A drastic and rapid tumor volume reduction was reported in case of solid papillary craniopharyngiomas (i.e. 60% after 2 and 90% after 5 months of treatment) whereas, in cystic form, the rate and magnitude of response is much slower and more modest (new observation). In our neo-adjuvant case, a near total response was obtained which dramatically minimized the target of the radiotherapy. In all cases of solid lesions, the radiological improvement allowed clinical improvement without significant side effects.

Conclusion: Based on our experience and the literature, we confirm the efficacy and good tolerance of BRAF/MEK inhibitors for papillary craniopharyngiomas. The effect seems less encouraging for the cystic component. A change in the current Craniopharyngioma treatment paradigm should be considered to avoid high-risk procedures. In cases of giant or invasive tumors, a simple tumor biopsy could be considered first to select a subset of patients with Papillary craniopharyngiomas harboring BRAF V600E mutation. In such tumors, neoadjuvant combined therapy should be applied to shrink the tumor before considering a curative approach (surgery or radiotherapy/radiosurgery) on smaller target hoping for a reduction in long-term morbidity and a better tumoral control.

The author has declared no conflict of interest.