Early Salvage Chemo-Immunotherapy with Irinotecan, Temozolomide and Naxitamab Plus GM-CSF (HITS) for Patients with Primary Refractory High-Risk Neuroblastoma Provide the Best Chance for Long-Term Outcomes

SIMPLE SUMMARY: Patients with high-risk neuroblastoma who are unable to achieve a complete response to induction chemotherapy are known as primary refractory and have poor outcomes. We investigated the combination of chemotherapy (irinotecan (I) and temozolomide (T)) plus anti-GD2 immunotherapy (naxitamab and sargramostim (GM-CSF)), the so-called HITS, against primary resistant high-risk neuroblastoma. Patients were treated when they had measurable chemo-resistant disease at the end of induction treatment but no evidence of progressive disease. Each cycle of HITS comprised Irinotecan 50 mg/m(2)/day intravenously plus Temozolomide 150 mg/m(2)/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/m(2) per cycle), and GM-CSF 250 mg/m(2)/day subcutaneously, for days 6–10 was used. Thirty-four patients received a median of four cycles. Treatment was outpatient and, overall, well tolerated. Patients treated with HITS immediately after induction failure (cohort 1 or early treatment) had a statistically significant improved survival rate compared to patients treated late (cohort 2). In summary, naxitamab-based chemo-immunotherapy is effective against primary chemo-resistant neuroblastoma, significantly improving long-term outcomes when administered early during the course of treatment. ABSTRACT: 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/m(2)/day intravenously (IV) plus Temozolomide 150 mg/m(2)/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/m(2) per cycle), and GM-CSF 250 mg/m(2)/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 (EFS p = 0.0041 and OS p = 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.