Can OS-6 replace PFS-6 as a primary endpoint in phase II studies on glioblastoma patients given antiangiogenetic drugs?

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2022 Background: In the last decade, progression-free survival (PFS) at 6 months (PFS-6) has been considered the best endpoint in phase II trials on recurrent glioblastoma (GBM). However, since a new standard of care was established by the EORTC/NCIC phase III trial, no data have reported on the PFS-6 or overall survival (OS) obtained with second line treatment following combined RT/TMZ. Moreover, antiangiogenic agents might alter data on response by repairing the blood-brain barrier and diminishing contrast enhancement, thus precluding the accurate assessment of any reduction in the tumor burden. The issue of a robust primary endpoint for phase II studies is therefore still open. The aim of the study was to evaluate outcome endpoints for second line treatment at recurrence. Methods: A retrospective analysis was made using a database on 653 GBM patients (pts) followed prospectively between 5/2001 and 8/2008. Eligibility criteria: age ≥ 18 years; PS 0-2; histological diagnosis of GBM; cytotoxic treatment at disease progression after RT/TMZ. The log-rank test was used to evaluate the significance of the prognostic variables, and the Cox model to ascertain any association between PFS and OS. Results: 150 pts (median age: 52 years, [24–76 y]) were enrolled. MGMT methylation status, evaluable in 110 pts, was present in 38% of cases. Median OS was 18.5 months. At disease progression, 40 pts (27%) received temozolomide, 92 pts (61%), nitrosourea-based chemotherapy, and 18 pts (12%) other treatments. At the time of recurrence, mPFS was 2.5 months (95%CI: 2.0–3.1), PFS-6 15% (95%CI: 9.5%–21.3%, mOS 7.6 months (95%CI: 6.9–8.3) and OS-6 64% (95%CI: 56.6%–72.2%). In the Cox proportional hazard model, PFS with the second line treatment was correlated with OS measured as from the start of the second line treatment (p < 0.0001). Conclusions: The findings made in the present study, the first in literature to evaluate outcome endpoints for a second line treatment after RT/TMZ in GBM pts, confirm that a PFS-6 of 15% should be considered the cut-off for active cytotoxic drugs in phase II studies on recurrent GBM. For antiangiogenic compounds, OS-6 can be considered as a sound endpoint. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb, OncoMethylome Sciences, Roche, Schering-Plough GlaxoSmithKline, Merck Sharp & Dohme, Roche, sanofi-aventis, Schering-Plough