Fangusaro Jason, Onar-Thomas Arzu, Poussaint Tina Young, Wu Shengjie, Ligon Azra H, Lindeman Neal, Campagne Olivia, Banerjee Anu, Gururangan Sridharan, Kilburn Lindsay B, Goldman Stewart, Qaddoumi Ibrahim, Baxter Patricia, Vezina Gilbert, Bregman Corey, Patay Zoltan, Jones Jeremy Y, Stewart Clinton F, Fisher Michael J, Doyle Laurence Austin, Smith Malcolm, Dunkel Ira J, Fouladi Maryam
Department of Hematology, Oncology, and Stem Cell Transplantation, Children's Healthcare of Atlanta and Emory University, Atlanta, Georgia, USA.
Department of Biostatistics St. Jude Children's Research Center, Memphis, Tennessee, USA.
Neuro Oncol. 2021 Oct 1;23(10):1777-1788. doi: 10.1093/neuonc/noab047.
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.
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.
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.
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.
儿童低级别胶质瘤（pLGGs）是最常见的儿童脑肿瘤。无进展生存期（PFS）远低于总生存期，这凸显了对替代治疗的需求。散发型（无1型神经纤维瘤病）视路和下丘脑胶质瘤（OPHGs）常多次复发，并导致严重的视觉缺陷。近来，功能结局受到了优先关注。
我们呈现了在一项PBTC（儿童脑肿瘤协作组）II期试验中接受治疗的复发性/进展性OPHGs患儿的结果，该试验评估了MEK-1/2抑制剂司美替尼（AZD6244，ARRY-142886）的疗效。PBTC-029的第4组纳入了散发性复发性/进展性OPHGs患者，这些患者接受司美替尼治疗，剂量为推荐的II期剂量（25mg/m²/剂量，每日两次），最多接受26个疗程。
25名符合条件且可评估的患者入组，他们之前接受治疗的中位数为4次（1 - 11次）。25名患者中有6名（24%）出现部分缓解，14/25（56%）病情稳定，5名（20%）在治疗期间病情进展。治疗疗程的中位数为26次（2 - 26次）；14/25名患者完成了全部26个疗程。两年无进展生存率为78 ± 8.5%。25名患者中有19名可评估视力，其中4/19名患者（21%）视力改善，13/19名患者（68%）视力稳定，2/19名患者（11%）视力恶化。19名患者中有5名（26%）视野改善，14/19名患者（74%）视野稳定。最常见的毒性反应为1/2级肌酸磷酸激酶升高、贫血、腹泻、头痛、恶心/呕吐、疲劳、谷草转氨酶和谷丙转氨酶升高、低白蛋白血症以及皮疹。
基于影像学反应、无进展生存期和视觉结局，司美替尼在复发性/进展性OPHGs患儿中耐受性良好，并能带来缓解且延长疾病稳定期。
