Survival Outcomes with IL-2-Free Dinutuximab Beta Treatment Strategies With or Without 13-cis-Retinoic Acid in Relapsed or Refractory Neuroblastoma: An Exploratory Unanchored, Population-Adjusted Comparison of Two Prospective Cohorts

Background/Objectives: Survival outcomes with IL-2-free dinutuximab beta (DB) treatment strategies with and without 13-cis-retinoic acid (RA) have not been directly compared in a randomized study. We compared event-free survival (EFS) and overall survival (OS) between two study-defined cohorts with relapsed or refractory neuroblastoma receiving DB with or without RA. Methods: We retrospectively reanalyzed individual patient data from APN311-304 study (DB without RA, n = 36) and the experimental arm of APN311-202 V3 study (DB plus RA, n = 44). Eligibility and time zero were harmonized, and overlap-weighted Kaplan–Meier and Cox analyses were performed. An exploratory post-end-of-treatment landmark analysis was conducted among patients who remained alive and EFS-event-free through the landmark. Results: In the primary overlap-weighted analysis, no clear difference was detected between the cohorts for event-free survival (EFS; hazard ratio [HR], 0.92; 95% confidence interval [CI], 0.31–2.73) or overall survival (OS; HR, 1.95; 95% CI, 0.46–8.20). Cohort-specific effective sample sizes were 10.15 for no RA and 15.30 for RA versus nominal sizes of 36 and 44, respectively. Exploratory conditional landmark estimates were also imprecise for EFS (HR, 1.24; 95% CI, 0.37–4.12) and OS (HR, 0.44; 95% CI, 0.07–2.71). Conclusions: This exploratory comparison did not provide evidence of more favorable EFS or OS in the RA cohort than in the no-RA cohort. However, the estimates were highly imprecise and compatible with clinically important benefit or harm. The findings should not be interpreted as evidence of equivalence or as evidence that RA provides no benefit and should not alone guide continuation or omission of RA. Because RA use was perfectly aligned with the source study, the comparison cannot isolate a causal RA effect.