Sustained Tumor Control With MAPK Inhibition in BRAF V600–Mutant Adult Glial and Glioneuronal Tumors

Abstract

Objective:To assess whether RAF and MEK inhibitors (RAFi/MEKi) can provide long-term clinical benefit in adult patients with BRAF V600-mutant glial and glioneuronal tumors (GGNT), we analyzed tumor response and long-term outcome in a retrospective cohort.Methods:We performed a retrospective search in the institutional databases of six neuroncology departments for adult patients with recurrent or disseminated BRAF V600-mutant GGNT treated with RAFi/MEKi.Results:Twenty-eight adults with recurrent or disseminated BRAF V600-mutant gangliogliomas (n=9), pleomorphic xanthoastrocytomas (n=9), and diffuse gliomas (n=10) were included in the study. At the time treatment with RAFi/MEKi was started, all tumors displayed radiological features of high-grade neoplasms. Thirteen patients received RAFi as single agents [vemurafenib (n=11), dabrafenib (n=2)], and 15 combinations of RAFi/MEKi [vemurafenib+cobimetinib (n=5), dabrafenib+trametinib (n=10)]. Eleven patients achieved a partial or complete response (11/28, 39%), with a median reduction of -78% in their tumor burden. Responders experienced a median increase of 10 points in their Karnofsky Performance Status (KPS) and a median progression-free survival of 18 months, which was longer than achieved with first-line treatment (i.e., 7 months, p=0.047). Responders had better KPS (p=0.018), tended to be younger (p=0.061) and to be treated earlier (p=0.099) compared to non-responders. Five patients were rechallenged with RAFi/MEKi at progression, with novel tumor responses in two. On univariate and multivariate analyses, response to RAFi/MEKi was an independent predictor of overall survival.Conclusions:Our study highlights the clinical benefits of RAFi/MEKi in adult patients with BRAF-mutant GGNT, encourages the systematic screening and rechallenge in responders.

Altered Extracellular Matrix as an Alternative Risk Factor for Epileptogenicity in Brain Tumors

“…The mTOR pathway is involved in a lot of cellular processes that contribute to epileptogenesis, including cell growth, proliferation, cell survival and synaptic strength (reviewed by [ 61 ]). Several studies show a correlation between alterations in these pathways and epileptogenesis, indicating an important role for the mTOR pathway in epileptogenesis and its potential as a therapeutic target [ 60 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 ].…”

Innovating Strategies and Tailored Approaches in Neuro-Oncology

“…Clinical responses may vary from prolonged responses with a remarkable clinical benefit to primary resistance to the targeted therapy. The response rate in BRAF V600E-mutant gliomas exceeds 30%, with associated clinical benefit and prolonged tumor control [ 42 ] ( Figure 1 E–H). Rechallenging with BRAFi +/− MEKi at recurrence in patients initially responding to these targeted therapies may also be effective, as recently reported [ 54 ].…”

“…Panels ( E – H ): tumor response after three cycles of vemurafenib in a 38-year-old patient affected by recurrent BRAF mutant anaplastic ganglioglioma (case already reported in ref. [ 42 ]). Panels ( I – L ): a 53-year-old patient with STRN1-NTRK2 fusion positive high grade glioneuronal tumor treated with larotrectinib and experiencing a complete tumor response (case already reported in ref.…”

“…ongoing phase II multi-indication study (NCT04704154, Table 2), but results are not yet available. [42]). Panels (I-L): a 53-year-old patient with STRN1-NTRK2 fusion positive high grade glioneuronal tumor treated with larotrectinib and experiencing a complete tumor response (case already reported in ref.…”

“…Panels (A-D): tumor response after two cycles of regorafenib in a 49-year-old patient with recurrent IDH wild-type GBM. Panels (E-H): tumor response after three cycles of vemurafenib in a 38-year-old patient affected by recurrent BRAF mutant anaplastic ganglioglioma (case already reported in ref [42]…”