NFB-08. TRAM-01: A Phase 2 study of trametinib for pediatric patients with neurofibromatosis type 1 and plexiform neurofibromas

Abstract

BACKGROUND: Plexiform neurofibromas (PN) are found in up to 50% of patients with neurofibromatosis type 1 (NF1). Trametinib has been used widely to treat PN but limited data has been reported on its efficacy within a clinical trial. METHODS: This ongoing multicenter phase II trial includes patients with pediatric low-grade glioma and PN. The primary objective for PN was to evaluate the overall response rate based on RECIST 1.1 criteria after daily oral trametinib administration for eighteen 28-day cycles. The volumes of PN were centrally quantified using a new semi-automatic 3D segmentation method. RESULTS: As of January 1, 2022, 45 patients with PN were enrolled in the study. Twenty-eight completed treatment and were available for analysis. For these patients, the median age was 11.4 years (range 0.7-19.8) including 16 males (57.1%). The majority did not receive prior systemic therapies (71.4%). The median volume of PN at baseline was 49.5 cm3 (range 2.6 to 469). Among the 28 patients, 25 (89.3%) completed 18 cycles as planned. One patient discontinued due to adverse reaction, one patient refused to continue treatment and one patient discontinued treatment based on physician decision. Median duration of treatment was 15.9 months (range 4.6 to 16.8). Median duration of follow-up was 29.7 months (range 17.7 to 38.1). A total of 32 PN were available for volumetric analysis. Using RECIST evaluation, the overall response rate was 24.1%. Volumetric assessment demonstrated an overall response rate of 60.7% and 62.5% of PN showed a decrease of more than 20% in volume. Median decrease in volume was -30% (range -93.5 to 14.3). Twenty-seven patients (93.1%) had durable response without progression (lasting ≥1 year). CONCLUSION: We report outcome and volumetric quantification of PN treated with trametinib within a large clinical trial. Based on the current results, trametinib appears effective and offers durable response.

Measuring Safety and Outcomes for the Use of Compassionate and Off-Label Therapies for Children, Adolescents, and Young Adults With Cancer in the SACHA-France Study

“…Selumetinib has shown promising single-agent activity in this group of patients 9 and has been approved since October 2020 by the FDA and June 2021 by the EMA for the treatment of inoperable symptomatic plexiform neurofibromas (PNs) in children with NF1 . Additionally, trametinib has shown single-agent activity in this population, 10 but has not been approved for this last indication by the FDA or the EMA. Due to initial lack of access to selumetinib until EMA approval in June 2021, trametinib was prescribed for this indication in Europe until that date.…”

The NF1+/- Immune Microenvironment: Dueling Roles in Neurofibroma Development and Malignant Transformation

“…ERK-dependent target genes are overexpressed in both murine and human PNF, and both MEK and ERK inhibitors have been shown to block PNF growth in vivo [ 45 , 46 ]. Furthermore, multiple phase I and II clinical trials have demonstrated the efficacy of MEK inhibitors (selumetinib, mirdametinib, trametinib, and binimetinib) in the treatment of PNF, resulting in tumor shrinkage, functional benefits, and improvement in patient-reported outcome measures, including pain and quality of life [ 47 , 48 , 49 , 50 , 51 ]. In 2020, the United States Food and Drug Administration (FDA) approved selumetinib for the treatment of symptomatic, inoperable PNF in children 2 years of age and older [ 52 ].…”