Fosnetupitant Outperforms Fosaprepitant in Long-Delayed CINV Control for FOLFIRINOX/FOLFOXIRI Regimens
核心洞察
Fosnetupitant achieved a significantly higher no-vomiting rate (100%) versus fosaprepitant (91.2%) during the long-delayed phase (days 6–7) in a propensity score-matched analysis (p=0.028).
Over the entire 7-day period, the no-vomiting rate was 95.6% with fosnetupitant compared to 83.8% with fosaprepitant (p=0.045), with a hazard ratio of 0.20 for vomiting events.
Injection site reactions were significantly less frequent with fosnetupitant (0.0%) than with fosaprepitant (19.1%, p<0.001), suggesting a more favorable safety profile.
A retrospective, propensity score-matched study conducted at Tokushima University Hospital in Japan has demonstrated that fosnetupitant provides superior control of long-delayed chemotherapy-induced vomiting compared with fosaprepitant in patients receiving FOLFIRINOX or FOLFOXIRI regimens. The findings, published in Cancer Management and Research, address a critical gap in antiemetic prophylaxis for these widely used gastrointestinal cancer regimens, where international guideline classifications remain inconsistent.
The study analyzed 190 eligible patients treated between April 2018 and September 2024, with 68 matched pairs ultimately included after propensity score matching. All patients received triplet antiemetic prophylaxis consisting of an NK1 receptor (搜索) antagonist (either fosnetupitant 235 mg or fosaprepitant 150 mg), palonosetron (0.75 mg), and dexamethasone.
Superior Vomiting Control in the Long-Delayed Phase
The primary endpoint—the proportion of patients with no vomiting during the long-delayed phase (days 6–7)—was met with statistical significance. The fosnetupitant group achieved a 100% no-vomiting rate compared with 91.2% in the fosaprepitant group (p=0.028), yielding a risk difference of 8.8% (95% CI, 2.1% to 15.6%).
Over the entire 7-day observation period, the no-vomiting rate was 95.6% in the fosnetupitant group versus 83.8% in the fosaprepitant group (p=0.045), corresponding to a risk difference of 11.8% (95% CI, 1.7% to 21.8%). The time to first vomiting episode was significantly longer with fosnetupitant (3/68 vs. 11/68 patients, p=0.045). In a Firth-corrected Cox proportional-hazards model, the hazard ratio for vomiting with fosnetupitant compared to fosaprepitant was 0.20 (95% CI, 0.05–0.56).
No significant differences in nausea incidence were observed between the two groups across any phase. This finding is consistent with the known pharmacologic profile of NK1 receptor (搜索) antagonists, which tend to exert stronger effects on vomiting than on nausea.
Pharmacokinetic Rationale
The authors attribute the differential efficacy to pharmacokinetic differences between the active metabolites of the two agents. Aprepitant, the active metabolite of fosaprepitant, has a half-life of approximately 14 hours, whereas netupitant, the active metabolite of fosnetupitant, has a substantially longer half-life of approximately 70 hours. This prolonged exposure may contribute to sustained antiemetic effects in multi-day emetogenic regimens such as FOLFIRINOX and FOLFOXIRI, where the emetogenic stimulus extends beyond the conventional 120-hour assessment window.
Safety: Marked Reduction in Injection Site Reactions
The safety analysis revealed a striking difference in injection site reactions (ISRs). No ISRs were observed in the fosnetupitant group (0.0%), compared with 19.1% in the fosaprepitant group (p<0.001), representing a risk difference of −19.1% (95% CI, −28.5% to −0.1%). All ISR events were grade 1 or 2 in severity, with no grade 3 or higher events reported. The incidences of constipation and hiccups were also numerically lower in the fosnetupitant group, though these differences did not reach statistical significance.
Clinical Context and Guideline Ambiguity
FOLFOXIRI and FOLFIRINOX regimens—combining oxaliplatin, irinotecan, and 5-fluorouracil with leucovorin—are widely used in colorectal and pancreatic cancers. Although each component drug is classified as moderately emetogenic chemotherapy (MEC) by ASCO, MASCC/ESMO, NCCN, and JSCO guidelines, the combination regimens are categorized as highly emetogenic chemotherapy (HEC) in the JSCO guidelines. This classification variability directly influences whether NK1 receptor (搜索) antagonist use is mandated or optional, as well as the optimal duration of dexamethasone administration during the delayed phase.
"Although these regimens are generally classified as MEC, they are frequently associated with a high emetogenic risk," the authors note. "Consequently, inconsistencies in MEC/HEC classification have been reported, with differing recommendations among the ASCO, NCCN, JSCO, and MASCC/ESMO guidelines."
Study Limitations
The authors acknowledge several important limitations. The retrospective, single-center design may limit generalizability, and unmeasured confounders—including psychological distress, dietary factors, history of motion sickness, prior CINV, baseline anxiety, opioid use, and performance status—could not be incorporated into the propensity score model. Nausea was not quantitatively assessed using validated patient-reported outcome measures, and rescue antiemetic use was not systematically captured, precluding evaluation of complete response as an endpoint. Additionally, because fosnetupitant was introduced later in the study period, temporal changes in supportive care practices may have influenced the observed differences.
The limited number of vomiting events, while addressed through Firth-corrected modeling, warrants cautious interpretation of hazard ratio estimates. Secondary endpoints were not adjusted for multiplicity and should be considered exploratory.
The authors conclude that prospective, multicenter studies employing patient diaries or patient-reported outcome measures with complete response as the endpoint are warranted to validate these findings and guide future antiemetic strategies for FOLFIRINOX and FOLFOXIRI regimens.