Lgg-08. a Phase Ii Prospective Study of Selumetinib in Children With Recurrent or Refractory Low-grade Glioma (lgg): a Pediatric Brain Tumor Consortium (pbtc) Study
Year: 2017
Type: article
Abstract: A greater understanding of the Ras-MAP kinase-signaling pathway in pediatric low-grade glioma (LGG) has led to the ability to target this pathway with therapeutic intent. The PBTC conducted a multi-institutional phase II study (NCT01089101) evaluating selumetinib (AZD6244, ARRY-142886), a MEK I/II inhibitor, in children with recurrent/refractory LGG assigned to 6 strata and treated at 25 mg/m2/dose PO BID for up to two years. Here we present the data from three of these strata. Stratum I included children with non-NF-1 and non-optic pathway recurrent/refractory pilocytic astrocytoma (PA) harboring BRAF aberrations (BRAF V600e mutation or the BRAF-KIAA 1549 fusion). Eight of 25 (32%) patients achieved a partial response (PR) with 2-year PFS of 66+11%. Two of 7 (29%) patient tumors with a BRAF V600e mutation and 6/18 (33%) with a BRAF KIAA-1549 fusion had a PR. Stratum 3 enrolled NF-1-associated LGG. Tissue for tumor BRAF evaluation was not required for eligibility. Ten of 25 (40%) achieved PR with a 2-year PFS of 96+4%. Only one patient progressed while on treatment. Stratum 4 included children with non-NF-1 optic pathway/hypothalamic LGG. Tissue for tumor BRAF evaluation was not required for eligibility. Two of 16 (12.5%) had a PR with a 2-year PFS of 65+13%. The BRAF aberration status of the responders in strata 3 and 4 is mostly unknown. All responses were confirmed centrally and seven patients remain on treatment. The most common toxicities were grade 1/2 CPK elevation, diarrhea, hypoalbuminemia, elevated AST and rash. Rare grade 3/4 toxicities included elevated CPK, rash, neutropenia, emesis and paronychia. Selumetinib was effective in treating children with recurrent/refractory LGG, including those with NF-1 associated LGG and PA harboring BRAF V600e mutation or BRAF-KIAA 1549 fusion. Larger prospective studies are necessary to determine the future, specific role of this agent in treating children with various LGG molecular subtypes.
Source: Neuro-Oncology
Authors: Jason Fangusaro, Arzu Onar-Thomas, Tina Y Poussaint, Shengjie Wu, Azra H Ligon, Neal Lindeman, Anu Banerjee, Roger J Packer, Lindsay B Kilburn, Ian F Pollack, Regina I Jakacki, Ibrahim Qaddoumi, Paul G Fisher, Girish Dhall, Patricia Baxter, Susan G Kreissman, Clinton F Stewart, Stefan M Pfister, David TW Jones, Gilbert Vezina, Jessica Stern, Ashok Panigrahy, Blaise V Jones, Zoltan Patay, Benita Tamrazi, Jeremy Y Jones, Sofia S Haque, David S Enterline, Soonmee Cha, Laurence A Doyle, Malcolm Smith, James M Boyett, Ira J Dunkel, Maryam Fouladi
Institutions: Lurie Children's Hospital, St. Jude Children's Research Hospital, Boston Children's Hospital, Brigham and Women's Hospital, Harvard University, University of California, San Francisco, Children's National, Children's Hospital of Pittsburgh, AstraZeneca (United States), Stanford Medicine, Children's Hospital of Los Angeles, Texas Children's Hospital, Duke University, Duke Medical Center, German Cancer Research Center, Cincinnati Children's Hospital Medical Center, Memorial Sloan Kettering Cancer Center, National Cancer Institute
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2620179955