Selumetinib in paediatric patients with BRAF-aberrant or neurofibromatosis type 1-associated recurrent, refractory, or progressive low-grade glioma: a multicentre, phase 2 trial - 30/05/19

Doi : 10.1016/S1470-2045(19)30277-3

Jason Fangusaro, MD ^a,^⁎ , Arzu Onar-Thomas, ProfPhD ^b, Tina Young Poussaint, ProfMD ^f, Shengjie Wu, MS ^b, Azra H Ligon, PhD ^g, Neal Lindeman, MD ^g, Anuradha Banerjee, MD ^h, Roger J Packer, ProfMD ^j, Lindsay B Kilburn, MD ^k, Stewart Goldman, ProfMD ^m, Ian F Pollack, ProfMD ^o, Ibrahim Qaddoumi, MD ^c, Regina I Jakacki, MD ^p, Paul G Fisher, ProfMD ^r, Girish Dhall, MD ^s, Patricia Baxter, MD ^u, Susan G Kreissman, ProfMD ^v, Clinton F Stewart, ProfPharmD ^d, David T W Jones, PhD ^x, Stefan M Pfister, MD ^y, Gilbert Vezina, MD ^l, Jessica S Stern, MD ⁿ, Ashok Panigrahy, ProfMD ^q, Zoltan Patay, ProfMD ^e, Benita Tamrazi, MD ^t, Jeremy Y Jones, MD ^z, Sofia S Haque, MD ^aa, David S Enterline, MD ^w, Soonmee Cha, MD ⁱ, Michael J Fisher, ProfMD ^ac, Laurence Austin Doyle, MD ^ad, Malcolm Smith, MD ^ae, Ira J Dunkel, ProfMD ^ab,^{^{†
Co-senior authors}}, Maryam Fouladi, ProfMD ^af,^{^{†
Co-senior authors}}

^a Department of Hematology, Oncology, and Stem Cell Transplantation, Children’s Healthcare of Atlanta and Emory University, Atlanta, GA, USA

^b Department of Biostatistics, St Jude Children’s Research Hospital, Memphis, TN, USA

^c Department of Oncology, St Jude Children’s Research Hospital, Memphis, TN, USA

^d Department of Pharmaceutical Science, St Jude Children’s Research Hospital, Memphis, TN, USA

^e Department of Diagnostic Imaging, St Jude Children’s Research Hospital, Memphis, TN, USA

^f Department of Radiology, Boston Children’s Hospital, Boston, MA, USA

^g Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

^h Center for Cancer and Blood Disorders, University of California, San Francisco, San Francisco, CA, USA

ⁱ Department of Radiology, University of California, San Francisco, San Francisco, CA, USA

^j Department of Neurology, Children’s National Medical Center, Washington, DC, USA

^k Department of Haematology and Oncology, Children’s National Medical Center, Washington, DC, USA

^l Department of Radiology, Children’s National Medical Center, Washington, DC, USA

^m Department of Haematology, Oncology, Neuro-Oncology, and Stem Cell Transplantation, Ann and Robert H Lurie Children’s Hospital of Chicago, Chicago, IL, USA

ⁿ Department of Radiology, Ann and Robert H Lurie Children’s Hospital of Chicago, Chicago, IL, USA

^o Department of Neurosurgery, Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA

^p Department of Hematology and Oncology, Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA

^q Department of Radiology, Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA

^r Department of Neurology, Stanford University Medical Center, Palo Alto, CA, USA

^s Department of Hematology and Oncology, Children’s Hospital Los Angeles, Los Angeles, CA, USA

^t Department of Radiology, Children’s Hospital Los Angeles, Los Angeles, CA, USA

^u Department of Hematology and Oncology, Texas Children’s Hospital, Houston, TX, USA

^v Department of Hematology and Oncology, Duke University School of Medicine, Durham, NC, USA

^w Department of Radiology, Duke University School of Medicine, Durham, NC, USA

^x Department of Pediatric Glioma Research Group, Hopp Children’s Cancer Center Heidelberg (KiTZ) and German Cancer Research Center (DKFZ), Heidelberg, Germany

^y Department of Pediatric Neuro-Oncology, Hopp Children’s Cancer Center Heidelberg (KiTZ) and German Cancer Research Center (DKFZ), Heidelberg, Germany

^z Department of Radiology, Nationwide Children’s Hospital, Columbus, OH, USA

^aa Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

^ab Department of Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

^ac Department of Pediatric Oncology, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

^ad Investigational Drug Branch, National Cancer Institute and Cancer Therapy Evaluation Program, Bethesda, MD, USA

^ae Clinical Investigation Branch, National Cancer Institute and Cancer Therapy Evaluation Program, Bethesda, MD, USA

^af Department of Haematology and Oncology, Cincinnati Children’s Hospital, Cincinnati, OH, USA

^* Correspondence to: Dr Jason Fangusaro, Departments of Hematology and Oncology and Stem Cell Transplantation, Children’s Healthcare of Atlanta and Emory University, Atlanta, GA 30322, USA Departments of Hematology and Oncology and Stem Cell Transplantation Children’s Healthcare of Atlanta and Emory University Atlanta GA 30322 USA

En prensa. Pruebas corregidas por el autor. Disponible en línea desde el Thursday 30 May 2019

Summary

Background

Paediatric low-grade glioma is the most common CNS tumour of childhood. Although overall survival is good, disease often recurs. No single universally accepted treatment exists for these patients; however, standard cytotoxic chemotherapies are generally used. We aimed to assess the activity of selumetinib, a MEK1/2 inhibitor, in these patients.

Methods

The Pediatric Brain Tumor Consortium performed a multicentre, phase 2 study in patients with paediatric low-grade glioma in 11 hospitals in the USA. Patients aged 3–21 years with a Lansky or Karnofsky performance score greater than 60 and the presence of recurrent, refractory, or progressive paediatric low-grade glioma after at least one standard therapy were eligible for inclusion. Patients were assigned to six unique strata according to histology, tumour location, NF1 status, and BRAF aberration status; herein, we report the results of strata 1 and 3. Stratum 1 comprised patients with WHO grade I pilocytic astrocytoma harbouring either one of the two most common BRAF aberrations (KIAA1549–BRAF fusion or the BRAF^V600E [Val600Glu] mutation). Stratum 3 comprised patients with any neurofibromatosis type 1 (NF1)-associated paediatric low-grade glioma (WHO grades I and II). Selumetinib was provided as capsules given orally at the recommended phase 2 dose of 25 mg/m² twice daily in 28-day courses for up to 26 courses. The primary endpoint was the proportion of patients with a stratum-specific objective response (partial response or complete response), as assessed by the local site and sustained for at least 8 weeks. All responses were reviewed centrally. All eligible patients who initiated treatment were evaluable for the activity and toxicity analyses. Although the trial is ongoing in other strata, enrolment and planned follow-up is complete for strata 1 and 3. This trial is registered with ClinicalTrials.gov, number NCT01089101.

Findings

Between July 25, 2013, and June 12, 2015, 25 eligible and evaluable patients were accrued to stratum 1, and between Aug 28, 2013, and June 25, 2015, 25 eligible and evaluable patients were accrued to stratum 3. In stratum 1, nine (36% [95% CI 18–57]) of 25 patients achieved a sustained partial response. The median follow-up for the 11 patients who had not had a progression event by Aug 9, 2018, was 36·40 months (IQR 21·72–45·59). In stratum 3, ten (40% [21–61]) of 25 patients achieved a sustained partial response; median follow-up was 48·60 months (IQR 39·14–51·31) for the 17 patients without a progression event by Aug 9, 2018. The most frequent grade 3 or worse adverse events were elevated creatine phosphokinase (five [10%]) and maculopapular rash (five [10%]). No treatment-realted deaths were reported.

Interpretation

Selumetinib is active in recurrent, refractory, or progressive pilocytic astrocytoma harbouring common BRAF aberrations and NF1-associated paediatric low-grade glioma. These results show that selumetinib could be an alternative to standard chemotherapy for these subgroups of patients, and have directly led to the development of two Children’s Oncology Group phase 3 studies comparing standard chemotherapy to selumetinib in patients with newly diagnosed paediatric low-grade glioma both with and without NF1.