Randomized, double‐blind phase III trial of a dexamethasone‐free regimen for managing highly emetogenic chemotherapy‐induced nausea and vomiting

Chemotherapy‐induced nausea and vomiting (CINV) remains a prevalent treatment complication, often significantly impairing patients' quality of life and reducing adherence to chemotherapy regimens. The standard triplet antiemetic regimen, including either a neurokinin‐1 (NK1) receptor antagonist (RA) or olanzapine, combined with a 5‐hydroxytryptamine type 3 (5‐HT3) RA and dexamethasone (DEX), faces challenges primarily due to DEX‐related adverse effects and its potential to compromise the efficacy of antitumor agents. This study assessed whether omitting DEX (F‐Group: olanzapine + 5‐HT3 RA) is non‐inferior to the standard D‐Group (olanzapine + 5‐HT3 RA + DEX). In this multi‐center, double‐blind, randomized phase III trial, 254 adults with malignant solid tumors (Eastern Cooperative Oncology Group [ECOG] 0–2) scheduled for highly emetogenic chemotherapy (HEC) were randomized 1:1 to the F‐Group or D‐Group. The primary endpoint was the complete response (CR; no emesis/rescue medication) rate over 0–120 h, with a non‐inferiority margin of −15%. Secondary endpoints included CR and complete control (CC; no vomiting/nausea/rescue therapy) rates in acute (0–24 h) and delayed (25–120 h) phases, safety, and quality of life. Overall CR rates were 68.6% (D‐Group) and 69.7% (F‐Group; p = .9658), demonstrating non‐inferiority. Acute phase CR rates were 88.4% versus 86.9% ( p = .8643), and delayed phase CR rates were 69.4% versus 69.7% ( p > .9999). CC rates were comparable across phases, with no new adverse reactions. The combination of a 5‐HT3 RA and olanzapine is as non‐inferior as the standard triplet regimen, providing an alternative option for patients receiving HEC. The trial was registered at ClinicalTrials.gov , number NCT05805800.