Growth recovery in patients with <i>BRAF</i> altered pediatric low-grade gliomas (LGG) after discontinuation of tovorafenib.

Abstract

10029 Background: Tovorafenib is a selective, CNS-penetrant, type II RAF inhibitor that targets BRAF and CRAF. Based on preclinical data, CRAF plays an essential role in chondrocyte maturation, a required step in linear bone growth. Children treated with tovorafenib in early phase studies demonstrate a reversible decrease in growth velocity consistent with CRAF inhibition with no signs of premature closure of growth plates or adverse effects on bone such as fractures or treatment emergent osteopenia. Here we report a combined analysis of off-treatment growth recovery in patients treated with tovorafenib in 3 clinical studies. Methods: Patients aged &lt; 18 years with BRAF altered relapsed/refractory LGG treated with tovorafenib in the Phase 1 PNOC014 study (NCT03429803), Phase 2 FIREFLY-1 study (NCT04775485), or Expanded Access Program (EAP) for patients (NCT05760586) were included. Relevant medical history, neuroendocrine medications, growth parameters, and tovorafenib dosing were collected. Pre- and post-treatment annualized growth velocity (AGV) was calculated for all patients with growth data available ≥90 days post-discontinuation of tovorafenib. Results: As of 17-Jan-2025,38 / 167 (23%) patients were evaluable for growth recovery. Among these evaluable patients, median age at start of treatment was 9.5 yrs (range 3.5 -16.5). Eighteen (47%) patients had a tumor associated endocrinopathy or comorbidity that may affect growth including growth hormone deficiency (8), thyroid disease (8), precocious puberty (6) and panhypopituitarism (4) at baseline. Four (11%) were receiving a gonadotropin-releasing hormone analogue for precocious puberty and 2 (5%) were receiving growth hormone replacement concurrent with tovorafenib. Median baseline height Z-score was -0.13 (range -2.57, 2.64) with 4 patients having Z-score &gt; 2 or &lt; -2. Median on-treatment AGV was 1.7 cm/yr [n = 36, interquartile range (IQR) 0.4 - 2.2] at 12 mo and 2.3 cm/yr (n = 25, IQR 0 - 3.3) at 24 mo. Median age at end of treatment was 11 yrs (range 4.4 - 17.5), and median off-treatment follow up was 10.3 mo (range 3.2 - 37.2). Median off-treatment AGV was 4.3 cm/yr (n = 38; IQR 1.8 - 7.6) at 3 mo, 10.2 cm/yr (n = 26, IQR 2.3 - 13.8) at 6 mo and 7.7cm/yr (n = 5, IQR 4.1 - 13.9) at 12 mo. Thirty-four (89%) patients had recovery of AGV, and 28 (74%) had an increase in Z-score towards baseline indicating catch-up growth. Patients with slow AGV recovery tended to be &gt; 15 years, younger females with precocious puberty/Tanner stage 4, or have only 3 months of off-treatment follow up. Conclusions: Decreases in growth velocity were common during tovorafenib treatment. Majority of patients to date demonstrate AGV recovery as early as 3 months with signs of catchup within 6-12 months after stopping tovorafenib. Preliminary findings indicate tumor-associated precocious puberty/Tanner stage 4 in females may be a risk factor for slow AGV recovery.