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Selumetinib effective for pediatric low-grade glioma
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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
Reference:
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.
Perspective
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Derek Hanson, MD
This was an important study because we now have a lot more information about the genetics of these low-grade glioma and their certain mutations, which can be quite common in pediatric low-grade glioma. This new class of drugs — called MEK inhibitors — works directly on the pathway that is overactivated by the mutations in these tumors. The thought is by using these MEK inhibitors to target the pathway activation, you will shut down the tumor to prevent it from continuing to grow. These have been tested in adults, but it is something we definitely need in pediatrics to find better ways to treat these tumors. It was an important study from that standpoint — to test these inhibitors in children with these tumors to see the results.
Although there were not complete response rates across the board, the data are encouraging because some of these tumors are very difficult to treat and may not respond to multiple types of chemotherapy. This study shows it is a potential type of drug that can work in these tumors and it important to know as neuro-oncologists that we have this drug as something to offer our patients.
Perspective
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Mark M. Souweidane, MD
This study is highly intriguing not just from a neurosurgical standpoint, but also from a neuro-oncology standpoint. Low-grade tumors — which can be present in a child for decades — can wreak havoc based on continuous slow growth, repeated surgical interventions, radiation therapy and different courses of chemotherapy. These multiple interventions can result in cumulative morbidity and toxicity. To have a phase 2 study like this conducted that demonstrates the ability to target central nervous system tumors in a cohort of patients treated with a MEK inhibitor, and demonstrating real responses — that is phenomenal in and of itself. This demonstrates efficacy of a concept that has gained a lot of attention for good reason.
The other huge implication of this is it takes neurosurgeons further away from the idea of aggressive cytoreductive surgery toward treating upfront with targeted therapy based on biopsy-proven molecular features. These deep-seated and low-grade tumors in children are not reasonable surgical endeavors. There is significant risk and rarely a high potential for surgical cure. It would be a phenomenal step forward and potentially a huge benefit for these children if we could get to the point of limited sampling or biopsy, determine expression of a molecular feature that is druggable, and treat it in an upfront format.
Questions remain on durability and what the responses look like as a function of molecular markers that were not analyzed in this study.
I hope in my lifetime we see the therapeutic strategy that involves limited sampling and using neoadjuvant therapeutic approaches to avoid complex surgery.
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