(P 163) SELUMETINIB IN JAPANESE PEDIATRIC PATIENTS WITH SYMPTOMATIC INOPERABLE PLEXIFORM NEUROFIBROMA IN NEUROFIBROMATOSIS TYPE 1

Objective: A lifetime risk of developing malignant peripheral nerve sheath tumor (MPNST) in patients with neurofibromatosis type 1 has been reported as high as 15%. Unlike sporadic MPNST, MPNST in NF1 patients develops with malignant transformation of plexiform neurofibroma (PN). It has also been reported that malignant transformation of PN to MPNST in NF1 patients develops through an intermediate tumor (ANNUBP). Because wide excision is the only curative treatment for MPNST, early detection and operation are extremely important.
Selumetinib was allowed to use for patients with symptomatic, inoperable PN in children of neurofibromatosis type 1 (NF1) from November 2022 in Japan. Whereas, single-agent selumetinib has no evidence of efficacy in MPNST, and its efficacy in intermediate- tumor is uncertain. Appropriate use of selumetinib in symptomatic PN is important to ensure that the PN has not become malignant.
Post-approval clinical use experience is critical data to evaluate the safety and efficacy of selumetinib, especially in Asian patients. It is also important to investigate whether selumetinib is used appropriately in non-malignant PN. The purpose of this study is to report the short to middle-term use experience after selumetinib was approved in Japan in November 2022.

Methods: Subjects were patients for whom prescription of selumetinib was started for symptomatic, inoperable plexiform neurofibromas in children with neurofibromatosis type 1 at our institution for 6 months from November 16, 2022 to May 31, 2023. Prescription of selumetinib was determined by appropriately evaluating the following items. (1) symptomatic, inoperable PN: “Symptomatic” was defined as causing ADL/QOL impairment in patients. “Inoperability” was determined by PN site, including orthopedic oncologist, head and neck surgeon, neurosurgeon, and plastic surgeon. Our facility has a multidisciplinary clinical team for NF1 patients Clinical factors of patients, site of symptomatic PN, maximum diameter, dose of selumetinib, administration period, adverse events (AE), presence or absence of dose reduction were investigated. (2) Evaluation of non-malignant transformation: Careful evaluation was performed using contrast-enhanced MRI, diffusion-weighted imaging, and FDG PET-CT, and if necessary, biopsy was performed to confirm intermediate type and no malignant transformation. Clinical factors of patients, site of symptomatic PN, maximum diameter, dose of selumetinib, administration period, adverse events (AE), presence or absence of discontinuation or dose reduction of selumetinib were investigated.

Results: Selumetinib was prescribed to a total of 11 patients, 7 males, mean age 14 years (8-18). The sites of symptomatic PN were the head in 5 patients, the pelvis to the lower extremities in 3 patients, and the paraspinal lesions in 3 patients. The morbidities of the patients were disfigurement in 6 patients, pain and motor dysfunction in 5 patients, and impending spinal cord injury in 1 patient. The median maximum diameter of PN was 91 mm (39-814). The dose of selumetinib was 50 mg/day in 4 patients, 60 mg/day in 4 patients, and 70 mg/day in 3 patient. The median treatment duration was 4 months (range: 1-6 months). Grade 3 or higher AE occurred in only 1 patient, which was elevated ALT. Grade 2 AEs were diarrhea in 4 cases, rash in 1 case, acne in 1 case, and pruritus in 1 case . There were 2 patients of temporary withdrawal of selumetinib due to AE. One is due to Grade 2 diarrhea, and the other is due to more than 10% decreased ejection fraction. Both patients plan to resume oral administration of selumetinib.

Conclusion: Six months have passed since selumetinib was prescribed for symptomatic inoperable PN in children with NF1 in Japan. Despite the short-term results, the prescription was continued in most patients without major AEs. It is necessary to create data on efficacy and safety through patient accumulation.