MGMT promoter methylation is a strong prognostic biomarker for benefit from dose-intensified temozolomide rechallenge in progressive glioblastoma: the DIRECTOR trial
Menée sur 103 patients atteints d'un glioblastome ayant progressé après une chimioradiothérapie à l'aide de témozolomide, cette étude évalue l'intérêt d'analyser la méthylation de la séquence promotrice du gène MGMT pour prédire la réponse à une réintroduction du témozolomide
Purpose : Rechallenge with temozolomide (TMZ) at first progression of glioblastoma after temozolomide chemoradiotherapy (TMZ/RT→TMZ) has been studied in retrospective and single-arm prospective studies, applying TMZ continuously or using 7/14 or 21/28 days schedules. The DIRECTOR trial sought to show superiority of the 7/14 regimen.
Patients & Methods : Patients with glioblastoma at first progression after TMZ/RT→TMZ and at least 2 maintenance TMZ cycles were randomized to Arm A (one week on (120 mg/m2 per day) / one week off) or Arm B (three weeks on (80 mg/m2 per day) / one week off). The primary end point was median time to treatment failure (TTF) defined as progression, premature TMZ discontinuation for toxicity, or death from any cause. O6-methylguanine DNA methyltransferase (MGMT) promoter methylation was prospectively assessed by methylation-specific PCR.
Results : Because of withdrawal of support, the trial was prematurely closed to accrual after 105 patients. There was a similar outcome in both arms for median TTF (A: 1.8 months [95% CI 1.8-3.2] versus B: 2.0 months [95% CI 1.8-3.5]) and overall survival (OS) (A: 9.8 months [95% CI 6.7-13.0] versus B: 10.6 months [95% CI 8.1-11.6]). Median TTF in patients with MGMT-methylated tumors was 3.2 months [95% CI 1.8-7.4] versus 1.8 months [95% CI 1.8-2] in MGMT-unmethylated glioblastoma. Progression-free survival rates at six months (PFS-6) were 39.7% with versus 6.9% without MGMT promoter methylation.
Conclusions : TMZ rechallenge is a treatment option for MGMT promoter-methylated recurrent glioblastoma. Alternative strategies need to be considered for patients with progressive glioblastoma without MGMT promoter methylation.
Clinical Cancer Research , résumé, 2015