Abstract
11523 Background: Ewing 2008R1 (EudraCT2008-003658-13, Sponsor UKM) was conducted in 12 countries. It evaluated the effect of zolendronic acid (ZOL) maintenance therapy on event-free (EFS, primary endpoint) and overall survival (OS) from randomization in standard risk Ewing Sarcoma (EwS). Methods: Phase III, open label, prospective, multi-center, randomized controlled clinical trial. Eligible patients (pts) had localized EwS with either good histological response to induction chemotherapy and/or small tumors ( < 200ml). Pts received 6 cycles VIDE induction and 8 VAI (male) or 8 VAC consolidation (female) and were randomized to receive either 9 cycles of maintenance ZOL or no further treatment (control;ctrl). ZOL cycles started parallel to the 6th consolidation cycle. Randomization was stratified by tumor site (pelvis/no pelvis). Two-sided adaptive inverse-normal 4-stage design, changed after the 1st interim analysis via Müller-Schäfer method. Initial sample size 448 pts, type I error rate 5%, power 80%. Results: 284 pts were randomized between 2009 and 2018 (142 ZOL / 142 ctrl). With a median follow-up of 3.9 years, the primary endpoint EFS was not significantly different between the ZOL and ctrl group in the adaptive design (HR 0.74, 95% CI 0.43-1.28, intention to treat). 3-year (3y) EFS rates were 84.0% (95% CI 77.7-90.8%) for ZOL vs 81.7% (95% CI 75.2-88.8%) for ctrl. Results were similar in the per protocol collective. Cause-specific HR for local recurrence in ZOL was csHR 0.30 (95% CI 0.08 -1.09; p = 0.07), for metastatic progress/new metastases csHR 1.0 (CI 0.5-2.2), for combined relapse/progress csHR 0.3 (95% CI 0.1-1.7), for second malignancies csHR 4.0 (95% CI 0.45-36.1) compared to ctrl. The 3y OS was 92.8% (95% CI 88.4-97.5%) for ZOL and 94.6% (95% CI 90.9-98.6%) for ctrl. For ZOL the 5y OS was 87.3% (95% CI 80.7-94.5%) and 89% (95% CI 83.7-95.9%) for ctrl. Noticeable more renal, neurological and gut toxicities were observed for ZOL (p < 0.05), with severe renal toxicities occurring more often in the ZOL arm (p = 0.003). Conclusions: In patients with standard risk localized Ewing Sarcoma there is no benefit from maintenance treatment with zoledronic acid, but significant side effects were observed. Clinical trial information: NCT00987636 .
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