MEK1/2 Inhibition Is Effective in Subsets of Pediatric Low-Grade Glioma

For patients with pediatric low-grade glioma, surgical resection or standard chemotherapy can improve overall survival; however, the efficacy of these approaches is often limited by disease recurrence and toxicity. Abnormal activation of the MAPK signaling pathway is common among pediatric low-grade gliomas and frequently occurs due to activation of the BRAF oncogene or loss-of-function alterations in the negative regulator NF1. In a phase II clinical trial in pediatric patients with recurrent, refractory, or progressive low-grade glioma, Fangusaro and colleagues assessed the activity of selumetinib, a selective and potent non–ATP-competitive MEK1/2 inhibitor, in two designated patient strata. The primary endpoint was the proportion of patients who achieved and sustained a stratum-specific objective response for at least 8 weeks. Secondary endpoints included progression-free survival, associations between BRAF aberration status and treatment response, MAPK aberrations, and pharmacokinetics. In stratum 1, nine (36%) of 25 patients with BRAF-aberrant grade 1 pilocytic astrocytoma achieved a sustained partial response; in 11 patients who had not had a progression event, the median follow-up since treatment initiation was 36.4 months. Patients with tumors harboring KIAA1549–BRAF fusions experienced longer progression-free survival than patients with BRAF^V600E mutations. In stratum 3, ten (40%) of 25 patients with NF1-associated pediatric low-grade glioma achieved a sustained partial response; median follow-up was 48.6 months among the 17 patients who did not have a progression event. Selumetinib treatment was well tolerated among patients in both strata, with the most common grade 3 adverse events being maculopapular rash and elevated creatine phosphokinase. Taken together, these results support further clinical trials comparing selumetinib to standard chemotherapy and suggest that selumetinib may be an effective therapeutic alternative for subsets of pediatric patients with recurrent low-grade gliomas.

Fangusaro J, Onar-Thomas A, Young Poussaint T, Wu S, Ligon AH, Lindeman N, et al. Selumetinib in paediatric patients with BRAF-aberrant or neurofibromatosis type 1-associated recurrent, refractory, or progressive low-grade glioma: a multicentre, phase 2 trial. Lancet Oncol 2019 May 28 [Epub ahead of print].

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