Post hoc analysis of rashes reported in patients (pts) with <i>BRAF</i> -altered relapsed/refractory (r/r) pediatric low-grade glioma (pLGG) treated with the type II RAF inhibitor tovorafenib in FIREFLY-1.

10037 Background: Targeted therapies have become a mainstay in the treatment of pLGG. While effective, toxicities, including cutaneous adverse events (AEs), are common. Tovorafenib received accelerated FDA approval in April 2024 for the treatment of BRAF -altered r/r pLGG in pts ≥6 months of age based on FIREFLY-1 (NCT04775485) trial results. Maculopapular rash, dermatitis acneiform, and erythematous rash were the most commonly reported rashes (Kilburn LB, et al. Nat. Med. 2024). An update on the incidence, recurrence, and resolution of rash AEs in pts who received tovorafenib in FIREFLY-1 is provided. Methods: This post hoc analysis included 137 pts with pLGG (arm 1/registrational: 77; arm 2/extension: 60) treated with ≥1 dose of tovorafenib. Treatment-emergent rashes, graded by investigators, were grouped as maculopapular/erythematous/eczematous (M/E/E) or acneiform/pustular (A/P) (May 10, 2024 data cutoff). A rash episode included all rash events occurring over continuous days. A new rash was any subsequent episode occurring a day or more after the prior episode end date. Results: Median duration of tovorafenib treatment was 21.0 months (mos). 93% (128/137) of pts had a treatment-emergent rash. Of those, 59% (76) had only M/E/E rashes, 11% (14), only A/P rashes, and 30% (38), both types. As expected, A/P rashes occurred more often in pts ≥12 years of age (y/a). The rash was graded as G1 in 36% (46), G2 in 50% (64), and G3 in 14% (18) of pts. Most experienced 1 (53% [68]) or 2 (31% [40]) rash episodes. First rash episode median time to onset (TTO) was 0.43 mos, with 47% (60) G1, 41% (52) G2, and 13% (16) G3. First rash episodes resolved for 74% (95/128) of pts within a median of 2.67 mos. Resolution of first rash was more common among pts with M/E/E vs A/P rashes. Among any rash episodes (27% [58/219]) that remained unresolved, final severity was G1 (22% [48/219]) or G2 (5% [10/219]). All G3 rashes resolved. 47% (60) of pts experienced ≥2 rash episodes, of which 82% (49) were the same/lower grade episode. Of the 11 pts with a more severe second episode, 8 (73%) resolved completely. 80% (102) of pts received standard of care (SOC) treatments for rash, primarily topical steroids/antibiotics, oral antihistamines, and emollients. Only 1 (1%) pt had a rash-related tovorafenib discontinuation. 18% (23) of pts had dose interruptions due to rash. 11% (14) of pts had a dose reduction due to rash; of those, 57% (8) required no additional dose reductions due to rash. Conclusions: Rashes were common in pts treated with tovorafenib in FIREFLY-1. They typically occurred early in treatment, most were G1 or G2, resolved within a median of ~3 mos, and were manageable with SOC treatment and/or tovorafenib dose modifications. A/P rashes occurred more frequently in pts ≥12 y/a; there were no other significant trends in rashes experienced between the two age groups. Clinical trial information: NCT04775485 .