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/m2 per 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 (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.