Abstract
BACKGROUND: This trial aimed at evaluating the optimal treatment sequence (single agent vs sequential vs combination) of lomustine (LOM) and bevacizumab (BEV) in a randomized phase II design. METHODS: Progressive patients after standard of care were randomized 2:2:2:1 between Arm 1: LOM 90 mg/m2 (max. 160 mg) every 6 weeks plus BEV (10 mg/kg) every 2 weeks until progression, subsequent salvage treatment at the investigators best choice (MD choice); Arm 2: LOM 110 mg/m2 (max. 200 mg) every 6 weeks, at progression switch to BEV every two weeks; Arm 3: BEV every 2 weeks, at progression add LOM 90 mg/m2 (max. 160 mg) every 6 weeks and continue BEV; and Arm 4: LOM single agent 110 mg/m2 (max. 200 mg) every 6 weeks, at progression MD choice (arm 4). Eligibility criteria included performance status 0–2, adequate hematological, liver and renal function, and an interval since the end of radiotherapy of ≥ 3 months to rule out pseudoprogression. The primary endpoint was overall survival at 12 months (OS12), progression free survival (PFS) was measured from the start of study treatment until 1st PD according RANO criteria. RESULTS: Between Oct 2011 and July 2013 274 patients were randomized. Baseline characteristics were well balanced, and all treatment generally well tolerated. In arm 4, 43% received subsequent salvage BEV. Time to first progression was longer in initially BEV treated patients, but survival was similar in all arms: Study treatment (per protocol population) n OS 12 (95% CI) Med OS Med PFS Arm 1: LOM+BEV ◊ MD choice 70 32.9% (25.4, 41.1) 9.1 mo 4.2 mo Arm 2: LOM, ◊ BEV 73 27.4% (20.6, 35.2) 7.8 mo 1.5 mo Arm 3: BEV, ◊ LOM+BEV 70 32.9% (25.4, 41.1) 7.9 mo 2.8 mo Arm 4: LOM, ◊ MD choice 36 41.7% (30.4, 53.7) 9.3 mo 1.6 mo CONCLUSIONS: Initially BEV treated patients had longer PFS, but OS 12 or median OS were similar in the various schedules of BEV and LOM. Agnostic of this data, the emerging BELOB study data triggered this trial to be continued as a phase III comparing LOM versus BEV plus LOM.