Sustained Survival Benefit in Recurrent Medulloblastoma by a Metronomic Antiangiogenic Regimen: A Nonrandomized Controlled Trial.

in JAMA oncology by Andreas Peyrl, Monika Chocholous, Magnus Sabel, Alvaro Lassaletta, Jaroslav Sterba, Pierre Leblond, Karsten Nysom, Ingrid Torsvik, Susan N Chi, Thomas Perwein, Neil Jones, Stefan Holm, Per Nyman, Helena Mörse, Anders Öberg, Liesa Weiler-Wichtl, Ulrike Leiss, Christine Haberler, Maresa T Schmook, Lisa Mayr, Karin Dieckmann, Marcel Kool, Johannes Gojo, Amedeo A Azizi, Nicolas André, Mark Kieran, Irene Slavc

TLDR

  • A phase 2 study evaluated the effectiveness of a new combination treatment, MEMMAT, in kids with relapsed medulloblastoma.
  • The study found that MEMMAT achieved disease control in 57.5% of patients and had minimal side effects.

Abstract

Medulloblastoma recurrence in patients who have previously received irradiation has a dismal prognosis and lacks a standard salvage regimen. To evaluate the response rate of pediatric patients with medulloblastoma recurrence using an antiangiogenic metronomic combinatorial approach (Medulloblastoma European Multitarget Metronomic Anti-Angiogenic Trial [MEMMAT]). This phase 2, investigator-initiated, multicenter nonrandomized controlled trial assessed 40 patients with relapsed or refractory medulloblastoma without a ventriculoperitoneal shunt who were younger than 20 years at original diagnosis. Patients were enrolled between April 1, 2014, and March 31, 2021. Treatment consisted of daily oral thalidomide, fenofibrate, celecoxib, and alternating 21-day cycles of low-dose (metronomic) oral etoposide and cyclophosphamide, supplemented by intravenous bevacizumab and intraventricular therapy consisting of alternating etoposide and cytarabine. The primary end point was response after 6 months of antiangiogenic metronomic therapy. Secondary end points included progression-free survival (PFS), overall survival (OS), and quality of life. Adverse events were monitored to assess safety. Of the 40 patients (median [range] age at treatment start, 10 [4-17] years; 25 [62.5%] male) prospectively enrolled, 23 (57.5%) achieved disease control after 6 months of treatment, with a response detected in 18 patients (45.0%). Median OS was 25.5 months (range, 10.9-40.0 months), and median PFS was 8.5 months (range, 1.7-15.4 months). Mean (SD) PFS at both 3 and 5 years was 24.6% (7.9%), while mean (SD) OS at 3 and 5 years was 43.6% (8.5%) and 22.6% (8.8%), respectively. No significant differences in PFS or OS were evident based on molecular subgroup analysis or the number of prior recurrences. In patients demonstrating a response, mean (SD) overall 5-year PFS was 49.7% (14.3%), and for patients who remained progression free for the first 12 months of treatment, mean (SD) 5-year PFS was 66.7% (16.1%). Treatment was generally well tolerated. Grade 3 to 4 treatment-related adverse events included myelosuppression, infections, seizures, and headaches. One heavily pretreated patient with a third recurrence died of secondary acute myeloid leukemia. This feasible and well-tolerated MEMMAT combination regimen demonstrated promising activity in patients with previously irradiated recurrent medulloblastoma. Given these results, this predominantly oral, well-tolerated, and outpatient treatment warrants further evaluation. ClinicalTrials.gov Identifier: NCT01356290.

Overview

  • The study evaluated the response rate of pediatric patients with medulloblastoma recurrence using an antiangiogenic metronomic combinatorial approach.
  • The study included 40 patients with relapsed or refractory medulloblastoma without a ventriculoperitoneal shunt, who were younger than 20 years at original diagnosis.
  • The primary end point was response after 6 months of antiangiogenic metronomic therapy, with secondary end points including progression-free survival, overall survival, and quality of life.

Comparative Analysis & Findings

  • 23 (57.5%) of the 40 patients achieved disease control after 6 months of treatment, with a response detected in 18 patients (45.0%).
  • Median overall survival was 25.5 months (range, 10.9-40.0 months), and median progression-free survival was 8.5 months (range, 1.7-15.4 months).
  • No significant differences in progression-free survival or overall survival were evident based on molecular subgroup analysis or the number of prior recurrences.

Implications and Future Directions

  • The MEMMAT combination regimen demonstrated promising activity in patients with previously irradiated recurrent medulloblastoma and may warrant further evaluation as a standard salvage regimen.
  • Given the high prevalence of medulloblastoma recurrence, future studies should investigate this regimen in earlier stages of disease to potentially improve treatment outcomes.
  • Future studies should also examine the feasibility and efficacy of this regimen in combination with other therapies, such as immunotherapy or targeted therapies.
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