Interpretation of Noninferiority Trial Results: Fosnetupitant vs. Fosaprepitant
Fosnetupitant is noninferior to fosaprepitant for preventing nausea and vomiting from highly emetogenic chemotherapy, but superiority was not demonstrated despite the numerical difference in favor of fosnetupitant.
Understanding the Trial Results
The noninferiority trial comparing fosnetupitant with fosaprepitant (n=795) for preventing highly emetogenic chemotherapy-induced nausea and vomiting showed:
- Primary endpoint: Overall complete response (CR) rate (no emesis, no rescue medication for 0-120 hours)
- Prespecified noninferiority margin: -10%
- Observed difference: 4.1% (95% CI, -2.1% to 10.3%) in favor of fosnetupitant
Statistical Interpretation:
- The lower bound of the confidence interval (-2.1%) is greater than the noninferiority margin (-10%), confirming noninferiority
- However, the confidence interval crosses zero (includes -2.1%), meaning superiority is not statistically established
- For superiority to be demonstrated, the entire confidence interval would need to be above zero
Evidence Analysis
The CONSOLE trial 1 showed:
- Overall CR rates: 75.2% (fosnetupitant) vs. 71.0% (fosaprepitant)
- The difference of 4.1% favored fosnetupitant numerically
- Noninferiority was clearly demonstrated
- The confidence interval (-2.1% to 10.3%) included zero, preventing a claim of superiority
An exploratory analysis of the same trial 2 found:
- Consistently higher numerical CR rates for fosnetupitant across all time periods
- Statistically significant difference only in the extended overall phase (0-168 hours)
- Complete response rates during the primary overall phase (0-120 hours): 75.5% vs. 71.0% (p = 0.1530)
Safety Considerations
The CONSOLE trial 1 reported:
- Treatment-related adverse events: 22.2% (fosnetupitant) vs. 25.4% (fosaprepitant)
- Injection site reactions: 11.0% vs. 20.6% (p < 0.001)
- Treatment-related injection site reactions: 0.3% vs. 3.6% (p < 0.001)
This suggests a potential safety advantage for fosnetupitant, particularly regarding injection site reactions.
Clinical Context
Both fosnetupitant and fosaprepitant are NK1 receptor antagonists used in combination with 5-HT3 antagonists and dexamethasone for preventing chemotherapy-induced nausea and vomiting, as recommended by clinical guidelines 3.
The American Society of Clinical Oncology guidelines 3 recommend a three-drug combination including an NK1 receptor antagonist for highly emetogenic chemotherapy, with fosaprepitant being an acceptable alternative to oral aprepitant.
Common Pitfalls in Interpreting Noninferiority Trials
Confusing noninferiority with equivalence: Noninferiority only establishes that the new treatment is not worse than the comparator by a prespecified margin.
Misinterpreting numerical differences: A numerical advantage does not automatically mean superiority unless the confidence interval excludes zero.
Overlooking the noninferiority margin: The -10% margin was predetermined as the maximum acceptable difference to still consider the treatments clinically comparable.
Claiming superiority prematurely: For superiority, the entire confidence interval must be above zero, which was not the case here.
Conclusion for Clinical Practice
When interpreting these results for patient care, clinicians should understand that fosnetupitant provides similar efficacy to fosaprepitant for preventing chemotherapy-induced nausea and vomiting, with potentially fewer injection site reactions. The numerical difference in favor of fosnetupitant did not reach statistical significance for superiority in the primary analysis.