The Double-Blind Placebo-Controlled Study Comparing Upfront and Subsequent Netupitant in Addition to Olanzapine-Containing Regimen for Prevention of High-Dose Cisplatin-Induced Nausea/Vomiting.

Background: Addition of olanzapine to NK-1 receptor antagonist regimen improves chemotherapy-induced nausea and vomiting (CINV) prevention for highly emetogenic chemotherapies (HECs). However, the benefit of addition of NK-1 receptor antagonist to olanzapine regimen has not been demonstrated. This study compared the efficacy of upfront and subsequent addition of netupitant- to olanzapine-containing regimen for preventing CINV from high-dose cisplatin (≥ 75 mg/m²).

Patient and methods: The double-blind placebo-controlled trial randomized patients receiving high-dose cisplatin to upfront and subsequent netupitant arms. In upfront netupitant arm, patients received NEPA (a combination of netupitant and palonosetron), dexamethasone, and olanzapine since first cycle. In subsequent netupitant arm, patients received olanzapine, dexamethasone, and ondansetron in first cycle but received NEPA, dexamethasone, and olanzapine in second cycle if no complete response (CR). After preplanned analysis, the initial dexamethasone dose in netupitant regimen was modified from 4 to 8 mg on Days 2-4. The primary endpoint was the overall CR rate of two cycles.

Results: Between January 2019 and December 2020, 51 and 49 patients were randomly assigned to upfront and subsequent netupitant arms, respectively. CR rates in acute (0-24 h), delayed (> 24-120 h), and overall periods were 93.0% versus 77.4% (p = 0.003), 75.5% versus 68.8% (p = 0.31), and 73.3% and 67.7% (p = 0.34) in upfront and subsequent netupitant arms, respectively. After amendment to increase dexamethasone in netupitant regimen, first-cycle CR rates in acute, delayed, and overall periods were 95.2% versus 87.7% (p = 0.34), 85.7% versus 73.5% (p = 0.26), and 85.7% and 69.4% (p = 0.26) in 4-drug and 3-drug groups, respectively. Among 15 patients crossing over to receive netupitant regimen in second cycle, CR was 46.6%.

Conclusion: In this Phase II trial, there was no significant improvement in overall CR when patients received upfront netupitant compared to subsequent addition of netupitant to an olanzapine regimen in patients receiving high-dose cisplatin chemotherapy.