ID #880 Intratumoral and Intracranial Hemorrhage Associated With MAPK-Pathway Targeted Therapy: A Systematic Review

Background

MAPK-pathway inhibitors (BRAF, MEK, and pan-RAF inhibitors) are increasingly used in pediatric and adult CNS tumors as well as systemic malignancies with CNS involvement. Intratumoral and intracranial hemorrhage has emerged as a clinically relevant safety signal, yet drug-specific incidence patterns, clinical contexts, and mechanisms remain incompletely evaluated.

Methods

We performed a systematic review of prior trials, regulatory safety summaries, and case reports describing hemorrhagic events associated with MAPK-pathway targeted therapy. Extracted variables included agent/regimen, population, denominator, hemorrhage phenotype (intratumoral vs intracranial), grade, fatality, and association with therapy and CNS-directed interventions.

Results

Reproducible CNS hemorrhage signals were identified for select agents. In BREAK-MB, intracranial hemorrhage occurred in 10/172 (6%) treated with dabrafenib[1]. In COMBI-MB, a fatal intracranial tumor hemorrhage occurred in 1/125 (0.8%) with dabrafenib + trametinib[2]. In pooled clinical-trial safety data (N = 1087), intracranial hemorrhage occurred in 7/1087 (0.6%), with fatal hemorrhage in 5/1087 (0.5%)[3]. For tovorafenib, hemorrhagic events occurred in 58/137 (42%) in FIREFLY-1 pediatric low-grade glioma patients. Severe hemorrhage (grade 3-4) was reported in 7/137 (5%), including 1/137 (0.7%) grade 5 fatal tumor hemorrhage. Although trial reporting grouped bleeding events collectively, CNS tumor hemorrhages comprised the clinically most relevant severe events. In pooled safety (N = 172), intracranial or intratumoral hemorrhage occurred in 15/172 (9%). Serious bleeding events were reported in 9/172 (5%), including 1/172 (0.6%) grade 5 tumor hemorrhage[4]. Case reports and regulatory data across additional BRAF/MEK combinations showed similar associations[5-8].

Conclusions

MAPK-pathway inhibitors demonstrate a reproducible CNS hemorrhage phenotype, with intracranial bleeding ranging from 7/1087 (0.6%) to 10/172 (6%), and 15/172 (9%) in pediatric tovorafenib datasets. Adult studies comprising primarily dabrafenib-based regimens show similar results and incidences. Standardized hemorrhage definitions, enhanced monitoring in CNS tumor populations, and prospective correlative studies are needed as MAPK inhibitors expand in pediatric neuro-oncology.

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