CHICAGO — Selumetinib appeared effective and safe for the treatment of recurrent or refractory low-grade glioma in children, according to results of a phase 2 clinical trial presented at the ASCO Annual Meeting.
The therapy also showed promise among children with NF-1–associated low-grade glioma and pilocytic astrocytoma harboring BRAF V600E mutation or BRAF-KIAA 1549 fusion.
Researchers of the Pediatric Brain Tumor Consortium evaluated selumetinib (AZD6244/ARRY-142886; AstraZeneca/Array BioPharma) — a potent, highly selective MEK1/MEK2 inhibitor — in children with recurrent/refractory low-grade glioma assigned to one of six strata. Patients received 25 mg/m2 selumetinib twice daily for up to 2 years.
Jason R. Fangusaro, MD, section head of neuro-oncology at Ann & Robert H. Lurie Children’s Hospital of Chicago, and colleagues presented data from three of the six strata; the remaining strata are still enrolling additional patients. Researchers based strata on histology, NF-1 status, tumor location, and absence or presence of common BRAF alterations.
One strata included 25 children with non–NF-1 and nonoptic pathway recurrent or refractory pilocytic astrocytoma who harbored BRAF V600E mutation or BRAF-KIAA 1549 fusion.
Eight of these patients (32%) achieved a partial response and 66% (+/–11%) achieved 2-year PFS.
Two of seven patients with a BRAF V600E mutation and six of 18 patients with a BRAF-KIAA 1549 fusion achieved partial response. Five patients remain on treatment.
“Based on these results and the original statistical study design, the activity of selumetinib in recurrent or refractory BRAF–aberrant pilocytic astrocytomas can be considered promising enough to study further,” Fangusaro said during his presentation.
Another strata included 25 children with NF-1–associated low-grade glioma. Ten of these patients (40%) reached a partial response and 96% (+/–4%) achieved 2-year PFS. One patient experienced disease progression while on treatment. Eighteen patients completed all 26 courses.
“Almost every single person had reduction in the size of their tumor,” Fangusaro said. “Based on these results and the original statistical study design, the activity of selumetinib in recurrent NF-1– driven low-grade gliomas can be considered promising enough to study further.”
The third strata included 16 children with non–NF-1 optic pathway/hypothalamic low-grade glioma. Three patients (18.75%) reached a partial response. Fangusaro noted that these strata expanded to 25 patients and analyses are ongoing.
Researchers evaluated pharmacokinetics samples from 48 patients. The median selumetinib Cmax value for day 1 was 1,207 nM (range, 238-8,171), and the median Tmax value was 1 hour (range, 1-8)
Common grade 1 and grade 2 treatment toxicities included CPK elevation, diarrhea, hypoalbuminemia, elevated aspartate aminotransferase and rash. Grade 3 and grade 4 treatment toxicities — such as elevated CPK, rash, neutropenia, emesis and paronychia — occurred rarely.
“Selumetinib is well tolerated and shows activity in BRAF–aberrant pilocytic astrocytoma and NF-1–associated low-grade glioma,” Fangusaro said. – by Melinda Stevens
Fangusaro J, et al. Abstract 10504. Presented at: ASCO Annual Meeting; June 2-6, 2017; Chicago.
Disclosure: Fangusaro reports no relevant financial disclosures. Please see the abstract for a list of all other researchers’ relevant financial disclosures.