Dexamethasone reduction or omission with NEPA and olanzapine for HEC: A phase III trial.

Abstract

12000 Background: Prolonged dexamethasone (DEX) in antiemetic regimens for highly emetogenic chemotherapy (HEC) may impair immunotherapy efficacy. We evaluated if DEX can be reduced or omitted when combined with NEPA (netupitant/palonosetron) and olanzapine without compromising control. Methods: In this open-label, multicenter, phase III non-inferiority trial, adults receiving HEC were randomized 1:1:1 to: Standard Regimen (NEPA day1, olanzapine days1-4, DEX 12mg day1/8mg days2-4); DEX-sparing Regimen (same, DEX 6mg day1 only); or DEX-free Regimen (same, no DEX). The primary endpoint was overall complete response (CR: no emesis/no rescue) 0-120h. A hierarchical testing sequence (DEX-sparing vs Standard, then DEX-free vs Standard) with a -12% non-inferiority margin controlled type I error (one-sided α=0.025). Results: Among 644 randomized patients (median age 54.9 years; 66.9% female), the overall CR rates were 72.4% for Standard, 72.2% for DEX-sparing (rate difference [RD] -0.19%, 95% CI -8.77 to 8.38; P for non-inferiority = 0.004), and 70.1% for DEX-free (RD -2.24%, 95% CI -10.81 to 6.38; P for non-inferiority = 0.013). Both experimental regimens met the non-inferiority criterion. Acute-phase (0-24 h) CR rates were 81.5%, 82.6%, and 80.8% (intergroup comparison, P＞0.05), and delayed-phase (24-120 h) CR rates were 77.1%, 77.6%, and 73.9% ((P＞0.05), respectively, with no significant differences. For complete nausea control, the DEX-free regimen was inferior beyond 24 hours, whereas the DEX-sparing regimen remained comparable to Standard throughout. Steroid-related adverse events, such as insomnia, were primarily reported in the Standard regimen group. Conclusions: NEPA plus olanzapine with single-day low-dose or no DEX is non-inferior to standard 4-day DEX for CINV prevention in HEC, supporting steroid-sparing strategies relevant for chemo-immunotherapy. Clinical trial information: NCT06331520 . Baseline patient characteristics and chemotherapy regimen. Total(N=644） Standard Regimen(N=217) DEX-sparing Regimen(N=213) DEX-free Regimen(N=214) Age, years 54.9 ±12.0 54.2 ±11.7 55.2±12.0 55.3 ±12.2 Male 219 (34.0) 73 (33.6) 74 (34.7) 72 (33.6) Female 425 (66.0) 144 (66.4) 139 (65.2) 142 (66.4) Breast cancer 280 (43.5) 101 (46.5) 92 (43.2) 87 (40.6) Lung cancer 141 (21.9) 45 (20.7) 50 (23.5) 46 (21.5) AC regimen 148 (23.0) 57 (26.3) 52 (24.4) 39 (18.2) Platinum-based regimen 472 (73.3) 153 (70.5) 152 (71.4) 167 (78.0)