Randomized comparisons of bevacizumab (B) and irinotecan (I), added to temozolomide (T), in children with relapsed or refractory high-risk neuroblastoma (RR-HRNB): First survival results of the ITCC-SIOPEN BEACON-Neuroblastoma phase II trial.

10501 Background: BEACON is a randomized phase 2 trial assessing whether inhibiting angiogenesis with bevacizumab adds to the activity of chemotherapy and evaluating chemotherapy regimens for children with RR-HRNB. Methods: Patients with RR-HRNB were eligible. There were randomizations (rand), in a 3x2 factorial design, to: T, IT or topotecan (To)-T, +/- B. Toxicity and response were reported in 2019 (ASCO, ESMO). Survival outcomes – progression-free (PFS) and overall (OS) – for the I and B rands are reported here (To rand is still open). The B rand used a relaxed alpha (1-sided p=0.2) for PFS as its phase 2 success criterion; the I rand was Bayesian. Cox model hazard ratios (HR) <1.0 indicate benefit for I or B. Heterogeneity tests (HT) assessed interactions between B and I. Analysis was intention-to-treat. Results: From 2013-19, 160 patients were randomized to B v. no B, including 121 to I v. no I, with: median age 5.8 years; 113 and 47 measurable and evaluable disease; 67 and 93 refractory and relapsed disease; 35 had MYCN amplification. Median follow-up was 15.4 months. PFS and OS are shown in the table. In the main comparisons (I v. no I, B v. no B), I improved PFS and OS (98% probability that true HR<1.0 for both) and B just met its success criterion (PFS: 1p=0.20; OS: 1p=0.19). However, there was some, but not conclusive, evidence of a positive interaction between B and I for both PFS (HT: p=0.06) and OS (HT: p=0.12). If real, this would suggest that adding either I (IT) or B (BT) to T does not improve outcome, but adding both (BIT) does. Twice as many patients had serious adverse events with BIT (57%) than with T (26%) or IT (27%), with BT at 40%. Conclusions: The BEACON results show that single agent T is suboptimal. Statistical uncertainty about an interaction between I and B means two further interpretations are possible: 1) IT and possibly BT are better than T; 2) IT and BT are not better than T, but I and B together (BIT) are better. Hence, a definitive conclusion on the best combination(s) to take forward is not currently possible and further randomized evaluation is needed. Clinical trial information: ISRCTN40708286. [Table: see text]

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