Relapsed or Refractory Neuroblastoma: Addition of Dasatinib/Rapamycin to Irinotecan/Temozolomide

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In a German-Austrian phase II trial (RIST-rNB-2011) reported in The Lancet Oncology, Corbacioglu et al found that the combination of dasatinib plus rapamycin and irinotecan plus temozolomide (RIST) improved progression-free survival vs irinotecan/temozolomide alone in patients with high-risk relapsed or refractory neuroblastoma.

Study Details

In the multicenter open-label trial, 124 evaluable patients aged 1 to 25 years (median = 5.4 years, interquartile range [IQR] = 3.7–8.1 years) were randomly assigned between August 2013 and September 2020 to receive RIST (n = 61) or irinotecan/temozolomide (n = 63).

The RIST group received rapamycin at a loading dose of 3 mg/m² on day 1 and then 1 mg/m² on days 2 to 4, dasatinib at 2 mg/kg per day for 4 days with 3 days off, followed by irinotecan at 50 mg/m² per day and temozolomide at 150 mg/m² per day for 5 days with 2 days off; one course each of rapamycin/dasatinib and irinotecan/temozolomide for four cycles over 8 weeks; then two courses of rapamycin/dasatinib followed by one course of irinotecan/temozolomide for 12 weeks.

The control group received irinotecan/temozolomide alone at the same dosing as in the RIST group.

The primary endpoint was progression-free survival.

Progression-Free Survival

Median follow-up was 72 months (IQR = 31–88 months). Median progression-free survival was 11 months (95% confidence interval [CI] = 7–17 months) in the RIST group vs 5 months (95% CI = 2–8 months) in the control group (hazard ratio [HR] = 0.62, one-sided 90% CI = 0.81, P = .019).

Among 48 patients with amplified MYCN, median progression-free survival was 6 months (95% CI = 4–24 months) in the RIST group vs 2 months (95% CI = 2–5 months) in the control group (HR = 0.45, 95% CI = 0.24–0.84, P = .012). Among 76 patients without amplified MYCN, median progression-free survival was 14 months (95% CI = 9–17 months) in the RIST group vs 8 months (95% CI = 4–15 months) in the control group (HR = 0.84, 95% CI = 0.51–1.38, P = .49).

Among all patients, median overall survival was 20 months (95% CI = 13–30 months) in the RIST group vs 16 months (95% CI = 10–22 months) in the control group (HR = 0.68, 95% CI = 0.45–1.04, P = .073). The hazard ratio for the RIST group vs the control group was significant (0.51, 95% CI = 0.27–0.96, P = .037) among patients with MYCN amplification but not among patients without MYCN amplification (0.91, 95% CI = 0.53–1.57, P = .731).  

Adverse Events

Grade ≥ 3 adverse events in the RIST group and control group were primarily hematologic, including neutropenia (81% vs 82%), thrombocytopenia (67% vs 68%), and anemia (58% vs 63%). Grade ≥ 3 infections occurred in 18% vs 22% of patients; grade ≥ 3 diarrhea occurred in 21% vs 18%. Adverse events led to discontinuation of study therapy in three patients vs two patients. Treatment-related death occurred in one patient in the RIST group (due to multiorgan failure) and in no patients in the control group.

The investigators concluded: “RIST-rNB-2011 demonstrated that targeting of MYCN-amplified relapsed or refractory neuroblastoma with a pathway-directed metronomic combination of a multikinase inhibitor and an mTOR inhibitor can improve progression-free survival and overall survival. This exclusive efficacy in MYCN-amplified, relapsed neuroblastoma warrants further investigation in the first-line setting.”

Selim Corbacioglu, MD, PhD, of the Department of Pediatric Hematology, Oncology, and Stem Cell Transplantation, University Medical Center Regensburg, Regensburg, Germany, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by Deutsche Krebshilfe. For full disclosures of the study authors, visit

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