Intratumoral and intracranial hemorrhage associated with MAPK-pathway targeted therapy: a systematic review and mechanistic synthesis.
Tovorafenib for BRAF-altered low-grade glioma associated with hemorrhage in 42% of patients.
Intratumoral and intracranial hemorrhage associated with MAPK-pathway targeted therapy: a systematic review and mechanistic synthesis.
Intratumoral and intracranial hemorrhage has emerged as a clinically relevant safety signal, but drug-specific incidence estimates, phenotypic definitions, and contributing mechanisms remain incompletely characterized.
MAPK-pathway inhibitors including BRAF, MEK, and type II RAF inhibitors are now integral to treatment of pediatric low-grade glioma (pLGG), BRAF V600-mutant glioma, NF1-associated tumors, and melanoma brain metastases.
We performed a systematic review of PubMed/MEDLINE and Embase from database inception through May 2026, supplemented by FDA prescribing information, to identify studies reporting intratumoral or intracranial hemorrhage with MAPK-pathway targeted agents across tumor types.
hemorrhage in a substantial minority, a real safety signal to watch for
CNS hemorrhage signals were identified across agents.
Dabrafenib-based regimens in melanoma brain metastases produced ICH rates of 6% (BREAK-MB monotherapy) and a fatal hemorrhage in 0.8% (COMBI-MB combination).
Combining BRAF inhibitors with stereotactic radiosurgery was associated with 3-fold higher odds of ICH versus radiosurgery alone (OR 3.16; 95% CI 1.43-6.96).
MAPK-pathway inhibitors are associated with a consistent but heterogeneous CNS hemorrhage signal.
Reported incidence varies by agent, population, and hemorrhage ascertainment method (active imaging-based surveillance versus clinical reporting), from < 1% symptomatic ICH with dabrafenib in adult melanoma to 9% intratumoral hemorrhage in the pooled pediatric tovorafenib safety population.