A phase II, randomised, study of weekly APG101 + reirradiation versus reirradiation in progressive glioblastoma
Menée sur 91 patients atteints d'un glioblastome ayant progressé après une première radiothérapie, cette étude évalue, du point de vue du taux de survie sans progression, l'intérêt d'ajouter à une nouvelle radiothérapie une protéine de fusion inhibant la voie CD95 (APG101)
Purpose : Preclinical data indicate antiinvasive activity of APG101, a CD95-ligand (CD95L)-binding fusion protein, in glioblastoma. Experimental Design : Patients (N=91)with glioblastoma at first or second progression were randomised 1:2 between second radiotherapy (rRT) (36 Gy; 5 times 2 Gy per week; rRT) or rRT+APG101 (400 mg weekly i.v.). Patient characteristics [N=84 (26 patients rRT, 58 patients rRT + APG101)] were balanced. Results : PFS-6 rates were 3.8% (95%-CI: 0.1 - 19.6) rRT and 20.7% (95%-CI: 11.2 - 33.4) for rRT+APG101 (p=0.048). Median PFS was 2.5 (95%-CI: 2.3-3.8) months and 4.5 (95%-CI: 3.7-5.4) months with a hazard ratio (HR) of 0.49 (95% CI: 0.27-0.88, p=0.0162) adjusted for tumour size. Cox regression analysis adjusted for tumour size revealed a HR 0.60 (95% CI: 0.36-1.01)] (p=0.0559) for rRT+APG101 for death of any cause. Lower methylation levels at CpG2 in the CD95L promoter in the tumour conferred a stronger risk reduction (HR=0.19; 95% CI: 0.06-0.58 for treatment with APG101 suggesting a potential biomarker. Conclusions : CD95 pathway inhibition in combination with rRT is an innovative concept with clinical efficacy. It warrants further clinical development. CD95L promoter methylation in the tumour may be developed as a biomarker.