Patients with high-risk neuroblastoma (HR-NB) who are unable to achieve a complete response (CR) to induction therapy have worse outcomes. We investigated the combination of humanized anti-GD2 mAb naxitamab (Hu3F8), irinotecan (I), temozolomide (T), and sargramostim (GM-CSF)—HITS—against primary resistant HR-NB. Eligibility criteria included having a measurable chemo-resistant disease at the end of induction (EOI) treatment. Patients were excluded if they had progressive disease (PD) during induction. Prior anti-GD2 mAb and/or I/T therapy was permitted. Each cycle, administered four weeks apart, comprised Irinotecan 50 mg/m2/day intravenously (IV) plus Temozolomide 150 mg/m2/day orally (days 1–5); naxitamab 2.25 mg/kg/day IV on days 2, 4, 8 and 10, (total 9 mg/kg or 270 mg/m2per cycle), and GM-CSF 250 mg/m2/day subcutaneously was used (days 6–10). Toxicity was measured using CTCAE v4.0 and responses through the modified International Neuroblastoma Response Criteria (INRC). Thirty-four patients (median age at treatment initiation, 4.9 years) received 164 (median 4; 1–12) HITS cycles. Toxicities included myelosuppression and diarrhea, which was expected with I/T, and pain and hypertension, expected with naxitamab. Grade ≥3-related toxicities occurred in 29 (85%) of the 34 patients; treatment was outpatient. The best responses were CR = 29% (n = 10); PR = 3% (n = 1); SD = 53% (n = 18); PD = 5% (n = 5). For cohort 1 (early treatment), the best responses were CR = 47% (n = 8) and SD = 53% (n = 9). In cohort 2 (late treatment), the best responses were CR = 12% (n = 2); PR = 6% (n = 1); SD = 53% (n = 9); and PD = 29% (n = 5). Cohort 1 had a 3-year OS of 84.8% and EFS 54.4%, which are statistically significant improvements (EFSp= 0.0041 and OSp= 0.0037) compared to cohort 2. In conclusion, naxitamab-based chemo-immunotherapy is effective against primary chemo-resistant HR-NB, increasing long-term outcomes when administered early during the course of treatment.
高危神经母细胞瘤（HR-NB）患者若在诱导治疗后未能达到完全缓解（CR），其预后往往较差。本研究探讨了人源化抗GD2单克隆抗体那昔妥单抗（Hu3F8）、伊立替康（I）、替莫唑胺（T）与沙格司亭（GM-CSF）联合方案（HITS）对原发性耐药HR-NB的疗效。入组标准包括在诱导治疗结束时仍存在可测量的化疗耐药病灶，若诱导期间出现疾病进展（PD）则予以排除。允许既往接受过抗GD2单抗和/或I/T治疗。治疗方案以四周为一个周期，具体为：伊立替康50 mg/m²/天静脉注射联合替莫唑胺150 mg/m²/天口服（第1-5天）；那昔妥单抗2.25 mg/kg/天静脉注射（第2、4、8、10天，每周期总剂量9 mg/kg或270 mg/m²）；GM-CSF 250 mg/m²/天皮下注射（第6-10天）。采用CTCAE v4.0标准评估毒性反应，并依据修订版国际神经母细胞瘤疗效标准（INRC）评估疗效。34例患者（中位起始治疗年龄4.9岁）共接受164个HITS周期治疗（中位数4个周期，范围1-12）。毒性反应包括I/T方案预期的骨髓抑制与腹泻，以及那昔妥单抗预期的疼痛与高血压。34例患者中29例（85%）出现≥3级相关毒性；治疗在门诊进行。最佳疗效为：完全缓解率29%（10例）；部分缓解率3%（1例）；疾病稳定率53%（18例）；疾病进展率5%（5例）。队列1（早期治疗组）最佳疗效为：完全缓解率47%（8例），疾病稳定率53%（9例）。队列2（晚期治疗组）最佳疗效为：完全缓解率12%（2例）；部分缓解率6%（1例）；疾病稳定率53%（9例）；疾病进展率29%（5例）。队列1的3年总生存率（OS）为84.8%，无事件生存率（EFS）为54.4%，与队列2相比具有统计学显著改善（EFS p=0.0041，OS p=0.0037）。结论：基于那昔妥单抗的化疗-免疫疗法对原发性化疗耐药HR-NB有效，在治疗早期阶段应用可显著改善长期预后。
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