Bevacizumab, Irinotecan, or Topotecan Added to Temozolomide for Children With Relapsed and Refractory Neuroblastoma: Results of the ITCC-SIOPEN BEACON-Neuroblastoma Trial
Authors: Moreno Lucas , Weston Rebekah , Owens Cormac , Valteau-Couanet Dominique , Gambart Marion , Castel Victoria , Zwaan C. Michel , Nysom Karsten , Gerber Nicolas , Castellano Aurora , Laureys Genevieve , Ladenstein Ruth , Rössler Jochen , Makin Guy , Murphy Dermot , Morland Bruce , Vaidya Sucheta , Thebaud Estelle , van Eijkelenburg Natasha , Tweddle Deborah A. , Barone Giuseppe , Tandonnet Julie , Corradini Nadege , Chastagner Pascal , Paillard Catherine , Bautista Francisco J. , Gallego Melcon Soledad , De Wilde Bram , Marshall Lynley , Gray Juliet , Burchill Susan A. , Schleiermacher Gudrun , Chesler Louis , Peet Andrew , Leach Martin O. , McHugh Kieran , Hayes Roisin , Jerome Neil , Caron Hubert , Laidler Jennifer , Fenwick Nicola , Holt Grace , Moroz Veronica , Kearns Pamela , Gates Simon , Pearson Andrew D.J. , Wheatley Keith ,   on behalf of Innovative Therapies for Children with Cancer (ITCC) and European Association for Neuroblastoma Research (SIOPEN), Valteau-Couanet Dominique , José Bautista Francisco , Murphy Dermot , Makin Guy , Thebaut Estelle , van Eijkelenburg Natasha , Hobin Dave , Vaidya Sucheta , Elliott Martin , Schleiermacher Gudrun , Owens Cormac , Barone Giuseppe , Tweddle Deborah , Castel Victoria , Nysom Karsten , Tandonnet Julie , Corradini Nadege , Chastagner Pascal , Gambart Marion , Jannier Sarah , Castellano Aurora , Gallego Soledad , Coze Carole , Auvrignon Anne , Sophie Defachelles Anne , Lopez Almaraz Ricardo , Gerber Nicolas , Ladenstein Ruth , De Wilde Bram , Brichard Benedicte , Luksch Roberto , Zwaan Michel , Popovic Maja Beck , Willis Courtney , Gray Juliet , Hettmer Simone , Schweigerer Lothar , Kontny Udo , Christiansen Holger , Garaventa Alberto , Ng Anthony , Howell Lisa , Yeomanson Daniel 
Published: January 2024

PURPOSE Outcomes for children with relapsed and refractory high-risk neuroblastoma (RR-HRNB) remain dismal. The BEACON Neuroblastoma trial (EudraCT 2012-000072-42) evaluated three backbone chemotherapy regimens and the addition of the antiangiogenic agent bevacizumab (B). MATERIALS AND METHODS Patients age 1-21 years with RR-HRNB with adequate organ function and performance status were randomly assigned in a 3 × 2 factorial design to temozolomide (T), irinotecan-temozolomide (IT), or topotecan-temozolomide (TTo) with or without B. The primary end point was best overall response (complete or partial) rate (ORR) during the first six courses, by RECIST or International Neuroblastoma Response Criteria for patients with measurable or evaluable disease, respectively. Safety, progression-free survival (PFS), and overall survival (OS) time were secondary end points. RESULTS One hundred sixty patients with RR-HRNB were included. For B random assignment (n = 160), the ORR was 26% (95% CI, 17 to 37) with B and 18% (95% CI, 10 to 28) without B (risk ratio [RR], 1.52 [95% CI, 0.83 to 2.77]; P = .17). Adjusted hazard ratio for PFS and OS were 0.89 (95% CI, 0.63 to 1.27) and 1.01 (95% CI, 0.70 to 1.45), respectively. For irinotecan ([I]; n = 121) and topotecan (n = 60) random assignments, RRs for ORR were 0.94 and 1.22, respectively. A potential interaction between I and B was identified. For patients in the bevacizumab-irinotecan-temozolomide (BIT) arm, the ORR was 23% (95% CI, 10 to 42), and the 1-year PFS estimate was 0.67 (95% CI, 0.47 to 0.80). CONCLUSION The addition of B met protocol-defined success criteria for ORR and appeared to improve PFS. Within this phase II trial, BIT showed signals of antitumor activity with acceptable tolerability. Future trials will confirm these results in the chemoimmunotherapy era.