Tovorafenib (type II RAF inhibitor; BRAF/CRAF) drives 43% ORR in BRAF/RAF1-altered R/R solid tumors

Tovorafenib is an oral, selective, CNS-penetrant type II inhibitor of BRAF and CRAF evaluated as monotherapy in the Phase II FIRELIGHT-1 DAY101-102a substudy (NCT04985604) in recurrent/refractory solid tumors with BRAF fusions or CRAF/RAF1 fusions/amplification (n=23; melanoma n=8; tumor-agnostic n=15; 57% had ≥2 prior lines). Investigator-assessed ORR was 43% overall (10/23), including 50% in melanoma (4/8) and 40% in other tumors (6/15), with median time to response 1.8 months and median duration of response 9.2 months. Tovorafenib received FDA accelerated approval in April 2024 for patients aged six months and older with relapsed/refractory pediatric low-grade glioma harboring a BRAF fusion or rearrangement, or BRAF V600 mutation. FIRELIGHT-1 therefore explores activity beyond that established pediatric glioma indication (note: these outcomes should not be benchmarked against BRAF V600 melanoma targeted therapy, where first-line BRAF/MEK combinations historically deliver ORR ~64%–76% in a different biology/setting). Common treatment-related AEs were anemia (39%), pruritus (30%), increased creatine phosphokinase (26%), and rash (26%); grade ≥3 and discontinuation rates were not reported in this abstract.