随机、双盲、III 期 Fosnetupitant 与 Fosaprepitant 预防化疗引起的高度致吐性恶心和呕吐的试验：CONSOLE
objective
We evaluated the efficacy and safety of fonetupitant (FosNTP) versus fosaprepitant (FosAPR) in the prevention of chemotherapy-induced highly emetic nausea and vomiting. This phase III study is the first to make a head-to-head comparison of two different neurokinin-1 receptor antagonists in combination with palonosetron and dexamethasone.
Patients and methods
Patients scheduled to receive cisplatin chemotherapy were randomized in a 1:1 ratio to FosNTP 235 mg or FosAPR 150 mg in combination with palonosetron 0.75 mg and dexamethasone. The primary endpoint was overall (0-120 hours) complete response (CR; No vomiting events and no rescue medication) rate, stratified by sex and age category, to show that FosNTP is not inferior to FosAPR (non-inferiority border, overall CR rate difference of -10%).
outcome
A total of 795 patients were randomized, of whom 785 received the study drug (FosNTP [N = 392] vs FosAPR [N = 393]) and its efficacy and safety were evaluated. Overall CR rates were 75.2% and 71.0%, respectively (Mantel-Haenszel common risk difference, 4.1%; 95% CI, -2.1% to 10.3%), indicating that FosNTP is non-inferior to FosAPR. CR rates were 93.9% and 92.6%, 76.8% and 72.8%, 86.5% and 81.4%, and 73.2% and 66.9% in the acute phase (0-24 hours), delayed phase (24-120 hours), and post-delay phase (120-168 hours), and 0-168 hours, respectively. The rates of treatment-related adverse events for FosNTP and FosAPR were 22.2% versus 25.4%, respectively, while adverse events related to injection site reactions or treatment-related adverse events were 11.0% versus 20.6% (P < .001) and 0.3% versus 3.6% (P <.001), respectively.
conclusion
FosNTP has been shown to be non-inferior to FosAPR, with a good safety profile and a lower risk of injection site reactions. Therefore, FosNTP is valuable in the prevention of nausea and vomiting caused by acute, delayed, and ultra-delayed chemotherapy.
introduce
Chemotherapy-induced nausea and vomiting (CINV) is a frequent toxicity that occurs after chemotherapy for malignancies. Cisplatin-induced CINV, in particular, occurs mainly after several days of chemotherapy and therefore often occurs after discharge, causing severe discomfort to patients beyond the reach of medical staff.
The main objective
For patients receiving cisplatin-based hyperemetic chemotherapy, does fonetupitant (FosNTP) exhibit a non-inferior incidence of injection site reactions to fosapotant (FosAPR) in preventing chemotherapy-induced nausea and vomiting?
Knowledge generation
Overall (0-120 hours; acute phase [0-24 hours] plus delayed phase [24-120 hours]) complete response rate was 75.2% in the FosNTP arm and 71.0% in the FosAPR arm (Mantel-Haenszel common risk difference, 4.1%; 95% CI, -2.1% to 10.3%), indicating that FosNTP is non-inferior to FosAPR. Complete response rates were 93.9% and 92.6%, 76.8% and 72.8%, 86.5% and 81.4%, and 73.2% and 66.9% in the Acute, Delayed, Post-Delayed (120-168 hours), and 0-168 hours in the FosNTP arm, respectively. The incidence of injection site reactions was significantly lower in the FosNTP group than in the FosAPR group.
relevancy
FosNTPs are valuable for the prevention of acute, delayed, and ultra-delayed nausea and vomiting caused by chemotherapy.
Antiemetic guidelines recommend proactive precautions when using anticancer drugs for highly emetic chemotherapy (HEC) or moderately emetic chemotherapy. For most patients treated with HEC and some patients receiving moderately emetogenic chemotherapy, triple therapy consisting of neurokinin-1 (NK 1) receptor antagonists (RAs), serotonin (5-HT3) RA, and dexamethasone (DEX) is considered the basic therapy. In addition, some guidelines recommend quadruple therapy including olanzapine in addition to the above ingredients.
Fosaprepitant (FosAPR), a widely used NK 1 RA, is an injectable prodrug of aprepitant that can be used in patients who have difficulty eating or drinking, thereby improving adherence compared to oral medications. FosAPR has been reported to be associated with a high frequency of injection site reactions (ISRs) with cisplatin administration, leading to clinical concerns and indicating an unmet medical need.
Foonepitant (FosNTP) is an injectable phosphorylated prodrug of netuppitant. Its active form, netuppitant, is characterized by high selectivity and affinity for NK 1 receptors and a longer elimination half-life than aprepitant. In the United States and the European Union, FosNTP 235 mg and palonosetron (PALO; A fixed-dose combination of 5-HT3RA) of 0.25 mg (intravenous [IV] netupitant-palonosetron [NEPA]) is approved for the prevention of CINV.
In Japan, the approach is mainly focused on the development of FosNTP as a single drug. A phase I study confirmed that up to 353 mg of FosNTP has a favorable safety profile and rapidly converts to the active form after administration in healthy adults (archival data). In addition, a clinical pharmacology study on drug interactions between FosNTP and granisetron, a 5-HT3 RA, confirmed that the drug has a good safety profile and that concomitant use with granisetron does not produce drug interactions (archival data).
A double-blind, randomized phase II study in patients treated with cisplatin confirmed that FosNTP 235 mg in combination with PALO 0.75 mg and DEX was administered throughout the phase (0-120 hours after initiation of cisplatin; Complete remission (CR; no vomiting events and no need for rescue medication) was superior to placebo and had a satisfactory safety profile with a very low incidence of ISR. This phase II study extended the efficacy observation period from 120 hours to 168 hours for exploratory evaluation, demonstrating that FosNTP is more efficacious than placebo.
Based on these findings, FosNTP appears to be effective not only for acute and delayed CINV, but also above delayed CINV, and it is possible to overcome the risk of developing ISR with FosAPR treatment. Therefore, we conducted a randomized phase III study to evaluate the efficacy and safety of FosNTP versus FosAPR as a comparator drug in combination with PALO and DEX (JapicCTI-194611).
discuss
To the best of our knowledge, this is the first randomized, double-blind, controlled, phase III head-to-head comparison of the inhibition of CINV by different NK 1 RA in combination with PALO 0.75 mg and DEX in patients treated with HEC.
This study demonstrates that FosNTP is non-inferior to FosAPR in terms of overall CR rate (primary endpoint). In the clinical studies of CINV that have been reported to date, the evaluation period for CINV is set at 120 hours. However, a recent observational study of CINV investigated the occurrence of nausea or vomiting after 120 hours. The study reported that a certain number of patients developed CINV after 120 hours, suggesting that it is important to monitor for delayed CINV after 120 hours. In our study, efficacy assessments continued up to 168 hours, indicating that all efficacy parameters of FosNTP were higher than FosAPR during the delay and overall phases and during the observation period including 168 hours. It is conceivable that the main reason for this may be the difference in the pharmacokinetic profile of the two drugs - the difference in the plasma elimination half-life of the active form.
In the phase III study of IV NEPA in patients treated with HEC (approximately 96% of patients treated with cisplatin), the overall CR rate in the IV NEPA arm was 76.8%, comparable to our findings (75.2%). One of the main differences between the two studies was the dose of PALO taken at the same time (0.25 mg versus 0.75 mg). The systematic review reported no statistically significant difference in efficacy between the two PALO doses. Therefore, the efficacy results of our study are considered reliable.
This study demonstrated that FosNTP has a favorable safety profile and that the observed TRAEs are reported NK 1 RA events and are manageable. With the exception of ISR, the security of FosNTP and FosAPR is similar. The proportion of ISR-related AEs and TRAEs in patients using FosNTPs was significantly lower than in patients using FosAPR. The proportion of patients who develop ISR-related TRAEs in this study (0.3%) is similar to the proportion of patients treated with cisplatin reported in the phase II study (1.0%) of FosNTP and the phase III study of IV NEPA (0%). In addition, no ISR-related TRAEs were observed in the FosNTP and IV NEPA PHASE III safety studies in patients treated with doxorubicin-cyclophosphamide or epirubicin-cyclophosphamide who were known to be at high risk of ISR with FosAPR. These data suggest that the risk of ISR due to FosNTP is very low. In addition, FosNTP showed a favorable safety profile, with no increase in ISR-related events in patients treated with multi-cycle FosNTP.
Our study implemented simultaneous administration of FosNTP, PALO, and DEX in one infusion bag with no risk of incompatibility, which can reduce the total infusion time compared to sequential dosing of FosAPR, PALO, and DEX. Therefore, it is considered advantageous to mix co-administered drugs in an intravenous bag in a clinical setting. More recently, this convenience of administration was also found in the trial of Ottoboni et al., although the trial was not designed to evaluate the mixing of aprepitant injection emulsion with PALO and DEX.
ASCO and United States National Comprehensive Cancer Network guidelines recommend quadruple therapy. However, in Japan guidelines, triple therapy is recommended for patients treated with HEC and with caution for quadruple therapy including olanzapine in appropriate patients. A limitation of this study is the lack of comparisons with quadruple therapy including olanzapine.
In conclusion, the overall CR rate of FosNTP was not lower than that of FosAPR in patients treated with HEC in combination with PALO and DEX. The proportion of patients with FosNTP who developed ISR was significantly lower than that of patients with FosAPR, which confirmed the good safety profile of FosNTP. FosNTP is valuable in the prevention of acute, delayed, and ultra-delayed CINV.
Randomized, Double-Blind, Phase III Study of Fosnetupitant Versus Fosaprepitant for Prevention of Highly Emetogenic Chemotherapy-Induced Nausea and Vomiting: CONSOLE - PubMedTwitterFacebookLinkedInGitHubTwitterSM-FacebookSM-Youtube