Interpretation of Fosnetupitant vs. Fosaprepitant Noninferiority Trial Results
Fosnetupitant demonstrated noninferiority to fosaprepitant for preventing nausea and vomiting from highly emetogenic chemotherapy, but did not demonstrate superiority despite a positive numerical difference.
Understanding the Trial Results
The noninferiority trial comparing fosnetupitant with fosaprepitant (n=795) provided the following key findings:
- Primary endpoint: Overall complete response (CR) rate (0-120 hours)
- Prespecified noninferiority margin: -10%
- Difference between treatments: 4.1% (95% CI: -2.1% to 10.3%)
Statistical Interpretation
- The lower bound of the 95% CI (-2.1%) is greater than the noninferiority margin (-10%), confirming noninferiority
- However, the 95% CI includes zero (crosses from negative to positive), meaning superiority cannot be claimed despite the positive point estimate of 4.1%
- The trial specified that superiority would be demonstrated if noninferiority was greater than 0%, but this criterion was not met since the lower bound of the CI was negative (-2.1%)
Evidence-Based Analysis
The CONSOLE trial 1 was the first head-to-head comparison between these two NK-1 receptor antagonists in combination with palonosetron and dexamethasone. The overall CR rate was 75.2% for fosnetupitant versus 71.0% for fosaprepitant, with a difference of 4.1% (95% CI: -2.1% to 10.3%).
Additional findings from the CONSOLE trial showed:
- Similar CR rates in the acute phase (0-24 hours): 93.9% vs. 92.6%
- Numerically higher CR rates for fosnetupitant in the delayed phase (24-120 hours): 76.8% vs. 72.8%
- Potentially better safety profile with fosnetupitant, particularly regarding injection site reactions (11.0% vs. 20.6%, p<0.001)
A subsequent exploratory analysis 2 suggested fosnetupitant might have better efficacy in the extended overall phase (0-168 hours), with CR rates of 73.5% vs. 66.9% (p=0.0450).
Clinical Implications
Both fosnetupitant and fosaprepitant are effective NK-1 receptor antagonists for preventing CINV when used as part of a three-drug regimen. The NCCN guidelines 3 recommend NK-1 antagonists as part of the standard three-drug regimen for highly emetogenic chemotherapy.
Practical Considerations:
- Both agents are effective when combined with a 5-HT3 receptor antagonist and dexamethasone
- Fosnetupitant may offer advantages regarding injection site reactions
- The numerical difference favoring fosnetupitant did not reach statistical significance for superiority
Common Pitfalls in Interpreting Noninferiority Trials
Confusing noninferiority with equivalence: Noninferiority means the new treatment is not worse than the comparator by more than the prespecified margin, not that they are equivalent.
Misinterpreting confidence intervals: For superiority to be demonstrated, the entire confidence interval must be above zero.
Overlooking clinical significance: A statistically noninferior treatment may still have practical advantages (like fewer adverse events).
In conclusion, based on the provided data, fosnetupitant is noninferior to fosaprepitant for preventing CINV from highly emetogenic chemotherapy, but superiority was not demonstrated despite the numerical difference in favor of fosnetupitant.