The efficacy and safety of the addition of bevacizumab to conventional induction chemotherapy in high-risk neuroblastoma-: a multicentric randomized controlled phase-3 trial (BRAVEN Trial)

Despite the use of an intensive multimodal approach, combining induction with multi-agent therapy, the 5-year event-free survival (EFS) rates are dismal. The majority of HR-NB patients do not achieve complete response (CR) and 15%–20% develop refractory and early progressive disease (PD) (Stram et al, 1996). Therefore, the induction regimen is the most critical step in the treatment of HR-NB, because resistant clones may arise during induction, and the persistence of residual resistant disease poses a significant problem (Pearson et al, 1992). Further dose escalation of induction chemotherapy and MAC consolidation followed by auto-HSCT will be limited by toxicity (Dufour 2008). Moreover, extended chemotherapy does not improve the survival outcomes in HR-NB (Berthold et al, 2020). Hence, it is important to evaluate the efficacy and toxicity of adding a new tumor-targeted treatment for HR-NB.

The pro-angiogenic vascular endothelial growth factor (VEGF) and its receptor (VEGFR) are thought to play an important role in the start of tumour angiogenesis (Ferrara et al, 2003). Angiogenesis is a key regulator of NB growth, and tumour vascularity is associated with high-risk illness (Peddinti et al, 2007). Expression of VEGF and VEGFR correlates with a higher stage of NB (Komuro et al, 2001) (Sköldenberg et al, 2009). Bevacizumab is a humanized monoclonal VEGF-neutralizing antibody, which was approved by the Food and Drug Administration (FDA) in 2004 for the treatment of metastatic malignancy treatment regimens (Hurwitz 2005), which has revolutionised the therapy paradigm by enhancing overall and/or progression-free survival, making it the standard of care for a variety of advanced malignancies (Garcia et al, 2020).

§  Recently, the ITCC-SIOPEN BEACON-Neuroblastoma Trial (age 1-21 years) reported improved overall response rate (ORR) and progression-free survival (PFS) (n=106) with the addition of bevacizumab in relapsed/refractory NB in phase-2 study (Moreno et al, 2017). The BERNIE study evaluated the role of bevacizumab as part of the multi-modality treatment of children and adolescents with metastatic soft tissue sarcoma (age 6 months to <18 years) (n=154) and observed that the addition of bevacizumab to chemotherapy was tolerable in patients with metastatic soft tissue sarcoma. There were no treatment-related deaths and no increased incidence of grade 3/4 toxicities with bevacizumab (Chisholm et al, 2017). In another study, De Pasquale et al used bevacizumab in 17 pediatric patients with high-risk malignancies (n=4, stage IV NB) (De Pasquale et al 2011). Modak et al reported a safety profile of bevacizumab in children with refractory/relapsed NB in combination with irinotecan, and temozolomide (Modak et al, 2017).

The main objective of the present study is to investigate an anti-angio-invasive drug with induction regimen in combination. This study aims to evaluate the efficacy and safety of the addition of bevacizumab to conventional induction chemotherapy in patients with high-risk neuroblastoma.