10031 Background: Studies have shown the clinical benefits of D and T, in combination and as monotherapy, to treat adult and pediatric patients with BRAF V600 mutation-positive cancers. Here, we report the interim results from a long-term, follow-up study for patients from previously completed clinical trials that assessed the use of D and/or T in pediatric patients with MAPK pathway-activated tumors. Methods: This ongoing, global, open-label, multi-center study evaluated the long-term effects (general health, growth and development) of D and/or T in pediatric patients with tumors with MAPK pathway activation from previous studies that assessed (1) safety, tolerability and pharmacokinetics of D in solid tumors (NCT01677741); (2) pharmacodynamics and clinical activity of T or D+T in cancer or plexiform neurofibromas (NCT02124772); and (3) safety and efficacy of D+T in glioma (NCT02684058). The patients in this study followed the same treatment as at the end of the parent study. The duration of this study is 7 years after the first patient first visit (FPFV) (November 2019). The primary objective is to assess the long-term safety of the treatment. Results: Of a total 165 patients, 157 received the study treatment (D n=28, T n=21, D+T n=108) and 8 patients were for observation only. Most patients with low-grade glioma (LGG) and high-grade glioma (HGG) had BRAF V600 mutation (n=129). The median duration of exposure was approximately 21 months. From FPFV to the data cut-off (October 2024), most of the patients (94.3%) experienced at least one adverse event (AE) with 28% patients experiencing serious AEs. The most common AE was pyrexia (36.9%). AEs leading to treatment discontinuation occurred in 3.8% of total patients (D 3.6%, T 9.5%, D+T 2.8%). One on-treatment death was reported in the D+T arm due to convulsion (not related to the study treatment). No clinically meaningful changes were observed in hematological or biochemical parameters in the D+T arm. Grade ≥ 3 abnormalities were infrequent and were reported in <2% of patients, except creatine kinase increase (5.7%). Assessment of vital signs, growth, electrocardiography, bone age and Tanner staging did not reveal any new safety signals. In the D+T arm, as per investigator assessment, overall response (complete + partial) was 27.7% for patients with BRAF V600E mutation positive LGG (stable disease: 63.9% patients) and 41.2% for patients with BRAF V600E mutation positive HGG. The median progression-free survival and median overall survival were not reached. Conclusions: In this long-term study, reported AEs were in line with established safety profile of D and/or T. Except more than normal increase in weight, no significant impact of D and/or T was observed on growth, sexual maturation and skeletal development. The benefit-risk remained favorable toward D and/or T therapy in pediatric patients with MAPK pathway-activated tumors. Clinical trial information: NCT03975829 .
Bouffet et al. (Wed,) studied this question.