Irinotecan and temozolomide combined with dasatinib and rapamycin for patients with relapsed or refractory neuroblastoma: Results of the prospective randomized RIST trial.
Authors: Corbacioglu Selim , Lode Holger N. , Jakob Marcus , Suttorp Meinolf , Escherich Gabriele , Gruhn Bernd , Ellinger Susanne , Simon Thorsten , Lang Peter , Rohde Marius , Zeman Florian , Debatin Klaus-Michael , Beilken Andreas , Heiss Peter , Hellwig Dirk , Riemenschneider Markus , Ladenstein Ruth Lydia , Bochennek Konrad , Eggert Angelika , Foell Juergen 
Published: June 2023

10001 Background: Relapsed or refractory neuroblastoma (r/rNB) are associated with a dismal outcome. RIST is the acronym for irinotecan and temozolomide (I/T) as backbone in combination with dasatinib (S) and rapamycin (R) aligned in a molecular targeted, metronomic design. Methods: RIST-rNB-2011, an open label randomised Phase II trial (NCT01467986), compared RIST (experimental arm) with I/T (control arm; CA). Patients with high-risk r/rNB (stage 4 and all MYCN amplified stages; MYCN+) were randomized with a block-wise (block length of 6) randomization stratified by MYCN. RIST treatment consists of courses of R/S (4 days/week) followed by I/T (5 days/week). Phase 1 is defined by 4 cycles with one R/S and one I/T course (8 weeks). In phase 2 each of the 4 cycles comprise 2 R/S and 1 I/T course (12 weeks). CA consisted of I/T courses only.The primary endpoint was progression-free survival (PFS), analysed by a Cox proportional hazards model adjusted for MYCN- to test the null hypothesis of a hazard ratio of 1 assuming proportional hazard rates at a two-sided 5% significance level. A point estimate and a two-sided 95% confidence interval was provided. A sample size of N = 114 patients was calculated. Primary analysis was based on the intention-to-treat principle (ITT). Toxicity was assessed in all participants who received at least one dose of protocol therapy. Results: Subjects (N = 124) eligible for follow-up were enrolled from 08/2012 – 09/2020. Median age was 5.37 years (y) (range 1.1 – 24.6 y). Disease characteristics were relapse in 80% ( < 18 months (m) after diagnosis: 40%) and refractory disease in 20%, MYCN+ was present in 39%. Median overall follow-up was 72 m. In the ITT population median PFS was 11 m in RIST vs 5 m in CA (HR: 0.62 (95%-CI: 0.42, 0.92), p = 0.019), and 16 m in RIST vs 4 m in the CA (HR: 0.53 (95%-CI: 0.31, 0.90), p = 0.018) in the per protocol (PP) population. Subgroup analyses showed a selective effect in the MYCN+ (HR: 0.45 (95%-CI: 0.24, 0.84), p = 0.012) compared to MYCN- patients (HR: 0.84 (95%-CI: 0.51, 1.38), p = 0.492). PFS at 2 y in MYCN+ was 38% vs 8% in CA (ITT) and 50% vs 6% (PP), respectively. In MYCN+ patients with a relapse < 18 m from initial diagnosis (N = 33) PFS remained significantly better (p = 0.048). Median overall survival (OS) for RIST vs CA was 20 m vs 16 m in ITT (HR: 0.68 (95%-CI: 0.45, 1.04), p = 0.073) and 26 m vs 16 m in PP (HR: 0.55 (95%-CI: 0.32, 0.98), p = 0.041). OS was significantly better in MYCN+ patients: 11 m vs 6.5 m in ITT (HR: 0.51 (95%-CI: 0.27, 0.96), p = 0.037) and 17 m vs 5 m in PP (HR: 0.34 (95%-CI: 0.14, 0.83), p = 0.018). In MYCN- no differences were observed neither in PFS nor in OS. R/S did not add additional toxicity to I/T. Conclusions: RIST was well tolerated and led to a significantly improved PFS and OS in MYCN+ patients, allowing a targeted approach for this high-risk population. Clinical trial information: NCT01467986 .