131-iodine-metaiodobenzylguanidine (MIBG) as induction therapy
Clinical trials and pilot studies continue to assess the feasibility and tolerability of incorporating MIBG therapy in induction regimens for patients with high-risk neuroblastoma.[115]Weiss BD, Yanik G, Naranjo A, et al. A safety and feasibility trial of (131) I-MIBG in newly diagnosed high-risk neuroblastoma: a Children's Oncology Group study. Pediatr Blood Cancer. 2021 Oct;68(10):e29117.
http://www.ncbi.nlm.nih.gov/pubmed/34028986?tool=bestpractice.com
[116]Mastrangelo S, Attinà G, Zagaria L, et al. Induction regimen in high-risk neuroblastoma: a pilot study of highly effective continuous exposure of tumor cells to radio-chemotherapy sequence for 1 month. The critical role of iodine-131-metaiodobenzylguanidine. Cancers (Basel). 2022 Oct 21;14(20):5170.
https://pmc.ncbi.nlm.nih.gov/articles/PMC9599979
http://www.ncbi.nlm.nih.gov/pubmed/36291955?tool=bestpractice.com
Lorlatinib
One phase 3 study to determine the effect of the addition of lorlatinib, an ALK/ROS1 inhibitor, to intensive multimodality therapy in patients with high-risk ALK-driven neuroblastoma is active.[117]ClinicalTrials.gov. Testing the addition of 131I-MIBG or lorlatinib to intensive therapy in people with high-risk neuroblastoma (NBL). ClinicalTrials.gov Identifier: NCT03126916. Mar 2025 [internet publication].
https://clinicaltrials.gov/study/NCT03126916
Interim results from an ongoing phase 1 study suggest that lorlatinib, given alone or in combination with chemotherapy, is safe and tolerable in pediatric, adolescent, and adult patients with relapsed or refractory ALK-mutated or ALK-amplified neuroblastoma.[118]Goldsmith KC, Park JR, Kayser K, et al. Lorlatinib with or without chemotherapy in ALK-driven refractory/relapsed neuroblastoma: phase 1 trial results. Nat Med. 2023 May;29(5):1092-102.
https://pmc.ncbi.nlm.nih.gov/articles/PMC10202811
http://www.ncbi.nlm.nih.gov/pubmed/37012551?tool=bestpractice.com
Adavosertib
An investigational inhibitor of WEE1 tyrosine kinase, adavosertib (plus irinotecan) met the protocol-defined efficacy end point (3 objective responses from a cohort of 20 patients) in a phase 2 trial of pediatric patients with recurrent neuroblastoma.[119]Cole KA, Ijaz H, Surrey LF, et al. Pediatric phase 2 trial of a WEE1 inhibitor, adavosertib (AZD1775), and irinotecan for relapsed neuroblastoma, medulloblastoma, and rhabdomyosarcoma. Cancer. 2023 Jul 15;129(14):2245-55.
https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.34786
http://www.ncbi.nlm.nih.gov/pubmed/37081608?tool=bestpractice.com
RIST protocol
In a multicenter, open-label, controlled, phase 2 trial, 129 patients ages 1-25 years with high-risk relapsed or refractory neuroblastoma were randomly assigned to the RIST protocol (comprising metronomic irinotecan plus temozolomide and dasatinib plus rapamycin), or to irinotecan plus temozolomide (control group).[120]Corbacioglu S, Lode H, Ellinger S, et al. Irinotecan and temozolomide in combination with dasatinib and rapamycin versus irinotecan and temozolomide for patients with relapsed or refractory neuroblastoma (RIST-rNB-2011): a multicentre, open-label, randomised, controlled, phase 2 trial. Lancet Oncol. 2024 Jul;25(7):922-32.
https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(24)00202-X/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/38936379?tool=bestpractice.com
At median follow-up of 72 months, median progression-free survival was 11 months in the RIST group and 5 months in the control group.
Chimeric antigen receptor (CAR) T-cell therapy
Clinical trials and studies suggest that disialoganglioside 2 (GD2)-specific CAR T-cell therapy is feasible and safe in patients with high-risk or relapsed/refractory neuroblastoma.[23]Del Bufalo F, De Angelis B, Caruana I, et al. GD2-CART01 for relapsed or refractory high-risk neuroblastoma. N Engl J Med. 2023 Apr 6;388(14):1284-95.
https://www.nejm.org/doi/10.1056/NEJMoa2210859?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed
http://www.ncbi.nlm.nih.gov/pubmed/37018492?tool=bestpractice.com
[121]Li CH, Sharma S, Heczey AA, et al. Long-term outcomes of GD2-directed CAR-T cell therapy in patients with neuroblastoma. Nat Med. 2025 Apr;31(4):1125-9.
http://www.ncbi.nlm.nih.gov/pubmed/39962287?tool=bestpractice.com
[122]Heczey A, Xu X, Courtney AN, et al. Anti-GD2 CAR-NKT cells in relapsed or refractory neuroblastoma: updated phase 1 trial interim results. Nat Med. 2023 Jun;29(6):1379-88.
http://www.ncbi.nlm.nih.gov/pubmed/37188782?tool=bestpractice.com
[123]Yu L, Huang L, Lin D, et al. GD2-specific chimeric antigen receptor-modified T cells for the treatment of refractory and/or recurrent neuroblastoma in pediatric patients. J Cancer Res Clin Oncol. 2022 Oct;148(10):2643-52.
https://pmc.ncbi.nlm.nih.gov/articles/PMC9470713
http://www.ncbi.nlm.nih.gov/pubmed/34724115?tool=bestpractice.com
Grade 3/4 hematological toxicity has been reported.[23]Del Bufalo F, De Angelis B, Caruana I, et al. GD2-CART01 for relapsed or refractory high-risk neuroblastoma. N Engl J Med. 2023 Apr 6;388(14):1284-95.
https://www.nejm.org/doi/10.1056/NEJMoa2210859?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed
http://www.ncbi.nlm.nih.gov/pubmed/37018492?tool=bestpractice.com
[123]Yu L, Huang L, Lin D, et al. GD2-specific chimeric antigen receptor-modified T cells for the treatment of refractory and/or recurrent neuroblastoma in pediatric patients. J Cancer Res Clin Oncol. 2022 Oct;148(10):2643-52.
https://pmc.ncbi.nlm.nih.gov/articles/PMC9470713
http://www.ncbi.nlm.nih.gov/pubmed/34724115?tool=bestpractice.com
Phase 2 trials are ongoing.[124]ClinicalTrials.gov. Neuroblastoma, car-T cell therapy, phase: 2 [internet publication].
https://clinicaltrials.gov/search?cond=Neuroblastoma&intr=Car-T%20Cell%20Therapy&aggFilters=phase:2