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Clinical Trial
. 2021 Oct 1;23(10):1777-1788.
doi: 10.1093/neuonc/noab047.

A phase II trial of selumetinib in children with recurrent optic pathway and hypothalamic low-grade glioma without NF1: a Pediatric Brain Tumor Consortium study

Jason Fangusaro  1 , Arzu Onar-Thomas  2 , Tina Young Poussaint  3   4 , Shengjie Wu  2 , Azra H Ligon  5 , Neal Lindeman  5 , Olivia Campagne  6 , Anu Banerjee  7 , Sridharan Gururangan  8 , Lindsay B Kilburn  9 , Stewart Goldman  10   11 , Ibrahim Qaddoumi  12 , Patricia Baxter  13   14 , Gilbert Vezina  15 , Corey Bregman  16 , Zoltan Patay  17 , Jeremy Y Jones  18 , Clinton F Stewart  6 , Michael J Fisher  19   20 , Laurence Austin Doyle  21 , Malcolm Smith  22 , Ira J Dunkel  23   24 , Maryam Fouladi  25
Affiliations
Clinical Trial

A phase II trial of selumetinib in children with recurrent optic pathway and hypothalamic low-grade glioma without NF1: a Pediatric Brain Tumor Consortium study

Jason Fangusaro et al. Neuro Oncol. .

Abstract

Background: Pediatric low-grade gliomas (pLGGs) are the most common childhood brain tumor. Progression-free survival (PFS) is much lower than overall survival, emphasizing the need for alternative treatments. Sporadic (without neurofibromatosis type 1) optic pathway and hypothalamic gliomas (OPHGs) are often multiply recurrent and cause significant visual deficits. Recently, there has been a prioritization of functional outcomes.

Methods: We present results from children with recurrent/progressive OPHGs treated on a PBTC (Pediatric Brain Tumor Consortium) phase II trial evaluating efficacy of selumetinib (AZD6244, ARRY-142886) a MEK-1/2 inhibitor. Stratum 4 of PBTC-029 included patients with sporadic recurrent/progressive OPHGs treated with selumetinib at the recommended phase II dose (25mg/m2/dose BID) for a maximum of 26 courses.

Results: Twenty-five eligible and evaluable patients were enrolled with a median of 4 (1-11) previous therapies. Six of 25 (24%) had partial response, 14/25 (56%) had stable disease, and 5 (20%) had progressive disease while on treatment. The median treatment courses were 26 (2-26); 14/25 patients completed all 26 courses. Two-year PFS was 78 ± 8.5%. Nineteen of 25 patients were evaluable for visual acuity which improved in 4/19 patients (21%), was stable in 13/19 (68%), and worsened in 2/19 (11%). Five of 19 patients (26%) had improved visual fields and 14/19 (74%) were stable. The most common toxicities were grade 1/2 CPK elevation, anemia, diarrhea, headache, nausea/emesis, fatigue, AST and ALT increase, hypoalbuminemia, and rash.

Conclusions: Selumetinib was tolerable and led to responses and prolonged disease stability in children with recurrent/progressive OPHGs based upon radiographic response, PFS, and visual outcomes.

Keywords: MEK-1/2; hypothalamic glioma; optic pathway glioma; pediatric low-grade glioma; selumetinib.

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Figures

Fig. 1
Fig. 1
Kaplan-Meier estimates of PFS (red) and OS (blue) for all eligible and evaluable patients (n = 25). Abbreviations: OS, overall survival; PFS, progression-free survival.
Fig. 2
Fig. 2
Waterfall plot depicting the maximum percentage change in 2D tumor size evaluated on T2-FLAIR imaging by the local institution. The green dashed line represents the 50% reduction required to qualify as a PR. Abbreviation: PR, partial response.
Fig. 3
Fig. 3
Kaplan-Meir comparison of PFS for those patients enrolled on PBTC-029, stratum 3 (NF1-associated), with optic pathway and hypothalamic tumors (n = 15) vs those enrolled on PBTC-029, stratum 4 (non-NF OPHG; n = 25). Abbreviations: NF1, neurofibromatosis type 1; OPHG, optic pathway and hypothalamic glioma; PBTC, Pediatric Brain Tumor Consortium; PFS, progression-free survival.
Fig. 4
Fig. 4
Kaplan-Meir comparison of PFS between PBTC-022, stratum E (limited to the 23 patients with OPHG and thalamic tumors; n = 23) to PBTC-029, stratum 4 (all eligible and evaluable patients; n = 25). Abbreviations: OPHG, optic pathway and hypothalamic glioma, PBTC, Pediatric Brain Tumor Consortium, PFS, progression-free survival.
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