Interpretation of Fosnetupitant vs. Fosaprepitant Noninferiority Trial Results
Fosnetupitant is noninferior to fosaprepitant for preventing nausea and vomiting from highly emetogenic chemotherapy, but the data does not support a claim of superiority despite the numerical advantage.
Understanding the Trial Results
The noninferiority trial comparing fosnetupitant to fosaprepitant for prevention of chemotherapy-induced nausea and vomiting (CINV) showed:
- Primary endpoint: Overall complete response (CR) rate difference of 4.1% (95% CI, -2.1% to 10.3%) 1
- Prespecified noninferiority margin: -10%
- The lower bound of the confidence interval (-2.1%) is above the noninferiority margin (-10%), establishing noninferiority
- However, the confidence interval includes zero (crosses zero), meaning superiority is not established despite the numerical advantage
Proper Interpretation of Noninferiority Trials
- Noninferiority trials are designed to determine if a new treatment is not worse than a standard treatment by more than a prespecified margin
- For superiority to be claimed, the entire confidence interval must exclude zero
- In this case, since the confidence interval (-2.1% to 10.3%) includes zero, we cannot claim that fosnetupitant is superior to fosaprepitant 2
Clinical Implications
- Both fosnetupitant and fosaprepitant are appropriate NK1 receptor antagonists for preventing CINV in highly emetogenic chemotherapy 2
- Current guidelines recommend a three-drug regimen including an NK1 receptor antagonist (such as fosnetupitant or fosaprepitant), a 5-HT3 receptor antagonist, and dexamethasone 3
- Safety profile differences:
- Treatment-related adverse events: 22.2% with fosnetupitant vs. 25.4% with fosaprepitant 1
- Injection site reactions were significantly lower with fosnetupitant (11.0% vs. 20.6%, p<0.001) 1
- Treatment-related injection site reactions were also significantly lower with fosnetupitant (0.3% vs. 3.6%, p<0.001) 1
Additional Considerations
- Extended analysis of the same trial showed numerically higher complete response rates for fosnetupitant across all time intervals, with statistical significance reached for the extended overall phase (0-168 hours): 73.5% vs. 66.9% (p=0.0450) 4
- A pooled analysis of Japanese studies suggested fosnetupitant may have longer-acting antiemetic potency (>120 hours) compared to fosaprepitant 5
Conclusion
Based on the evidence, fosnetupitant has demonstrated noninferiority to fosaprepitant for preventing CINV from highly emetogenic chemotherapy. While there is a numerical advantage favoring fosnetupitant (4.1%), the confidence interval includes zero, meaning we cannot claim superiority. Both agents are appropriate choices as part of the recommended three-drug regimen for CINV prevention, with fosnetupitant potentially offering advantages in terms of fewer injection site reactions.