Dexamethasone-free antiemetic prophylaxis with olanzapine in children and adolescents receiving highly emetogenic chemotherapy: A multicenter, phase III non-inferiority randomized trial.

10017 Background: Dexamethasone, with a 5-HT3 receptor antagonist and a neurokinin-1 antagonist, is the guideline-recommended prophylaxis for chemotherapy-induced nausea and vomiting (CINV) in children and adolescents receiving highly emetogenic chemotherapy (HEC), but is associated with clinically relevant toxicities. The role of olanzapine as a dexamethasone-sparing agent for pediatric CINV prophylaxis remains uncertain. Methods: This investigator-initiated, multicenter, open label, phase III randomized non-inferiority (NI) trial (INPHOG-SUPP-22-03) enrolled patients aged 4–18 years receiving single or multi-day HEC. Patients were randomized 1:1 (single chemotherapy cycle) to receive dexamethasone, palonosetron, and fosaprepitant (DEX; standard-of-care) or olanzapine, palonosetron, and fosaprepitant (OLANZ; dexamethasone-free). The primary endpoint was complete response (CR) to vomiting (no vomiting and no rescue anti-emetics) during the overall period (0–120 h after the last chemotherapy dose). A NI margin of −15% was prespecified based on adult dexamethasone-sparing trials. Assuming a control CR rate of 70% from prior pediatric studies, 310 patients provided 80% power at a one-sided α of 0.025, allowing for 5% dropout. Absolute differences in CR rates were analyzed using the Miettinen–Nurminen method; NI was concluded if the lower bound of the 95% confidence interval (CI) was above −15%. Results: Between December 2022 and January 2026, 310 patients were randomized (DEX, n=156; OLANZ, n=154). The per-protocol (PP) population included 299 patients (DEX, n=151; OLANZ, n=148). Median age was 13 years; 62.2% were male, and 56.8% received multi-day HEC. In the PP population, the CR rate for vomiting during the overall period was 56.9% in the DEX arm and 63.5% in the OLANZ arm (absolute difference, 6.6%; 95% CI, −4.5% to 17.7%). Non-inferiority was demonstrated, as the lower 95% CI (−4.5%) was above −15%. Results were consistent in the intention-to-treat population. For secondary endpoints, CR to vomiting during the acute period (0-24 h) was 64.2% vs 68.9%, and during the delayed period (24-120 h) 78.8% vs 79.1%, in the DEX and OLANZ arms, respectively. CR to nausea during the overall period was 54.3% vs 53.4%, during the acute period 59.6% vs 59.5%, and during the delayed period 69.5% vs 68.9%, respectively. Grade ≥2 non-hematologic and hematologic laboratory toxicities were uncommon and similar between arms. Any-grade somnolence was significantly higher with OLANZ than DEX (52.0% vs 25.8%), with all events being ≤ grade 2. Conclusions: A dexamethasone-free antiemetic regimen was non-inferior to standard dexamethasone-based prophylaxis for prevention of vomiting in children and adolescents receiving HEC. These findings support the use of olanzapine as an effective steroid-sparing alternative. Clinical trial information: CTRI/2022/08/045009.