Randomized, Double-Blind, Phase III Study of Fosnetupitant Versus Fosaprepitant for Prevention of Highly Emetogenic Chemotherapy-Induced Nausea and Vomiting: CONSOLE

Abstract

PURPOSE We evaluated the efficacy and safety of fosnetupitant (FosNTP) versus fosaprepitant (FosAPR) for preventing highly emetogenic chemotherapy-induced nausea and vomiting. This phase III study was the first head-to-head comparison between two different neurokinin-1 receptor antagonists in combination with palonosetron and dexamethasone. PATIENTS AND METHODS Patients scheduled to receive cisplatin-based chemotherapy were randomly assigned 1:1 to FosNTP 235 mg or FosAPR 150 mg in combination with palonosetron 0.75 mg and dexamethasone. The primary end point was overall (0-120 hours) complete response (CR; no emetic event and no rescue medication) rate, stratified by sex and age category, to show the noninferiority of FosNTP to FosAPR (noninferiority margin, –10% for the difference in the overall CR rate). RESULTS Overall, 795 patients were randomly assigned, of whom 785 received the study drug (FosNTP [N = 392] v FosAPR [N = 393]) and were evaluated for efficacy and safety. The overall CR rate was 75.2% versus 71.0%, respectively (Mantel-Haenszel common risk difference, 4.1%; 95% CI, –2.1% to 10.3%), demonstrating noninferiority of FosNTP to FosAPR. The CR rates in the acute (0-24 hours), delayed (24-120 hours), and beyond delayed (120-168 hours) phases, and at 0-168 hours were 93.9% versus 92.6%, 76.8% versus 72.8%, 86.5% versus 81.4%, and 73.2% versus 66.9%, respectively. The incidence rates of treatment-related adverse events with FosNTP versus FosAPR were 22.2% versus 25.4%, whereas adverse events or treatment-related adverse events relevant to injection site reactions were 11.0% versus 20.6% ( P < .001) and 0.3% versus 3.6% ( P < .001), respectively. CONCLUSION FosNTP demonstrated noninferiority to FosAPR, with a favorable safety profile and lower risk for injection site reactions. Thus, FosNTP is valuable in the prophylaxis of acute, delayed, and beyond delayed chemotherapy-induced nausea and vomiting.

Exploratory Analysis Comparing Fosnetupitant Versus Fosaprepitant for Prevention of Highly Emetogenic Chemotherapy-Induced Nausea and Vomiting (CINV): A Randomized, Double-Blind, Phase 3 Study (CONSOLE)

“…For the primary analysis of the primary endpoint in this study [18], differences in the overall 0-120 h complete response rate were analyzed by comparing the complete response rates of fosnetupitant with that of fosaprepitant stratified by age category and sex and calculated on the basis of the Mantel-Haenszel method in the full analysis set (FAS; which includes only patients who received the study drug, PALO, DEX, and cisplatin on day 1). A two-sided 95% confidence interval (CI) was also calculated using Newcombe's method.…”

“…Contrary to this LOCF approach, the original analysis on the FAS considered any patient who did not complete the study as a treatment failure. In addition, the purpose of the original analysis [18] was to test for both non-inferiority and superiority between the two arms, whereas the null hypothesis in this analysis was that there was no difference in the proportion of patients with complete response between the two arms. So, in addition to differences in the approach to handling missing values, the null hypotheses between the original study analysis and this one were also different.…”

“…In the full publication of this study, we reported the non-inferiority of fosnetupitant to fosaprepitant for the primary endpoint of complete response during the overall 0-120 h phase [fosnetupitant 75.2% vs. fosaprepitant 71.0%, difference of 4.1% (95% CI -2.1% to 10.3%)] [18]. All secondary efficacy endpoints/time intervals of delayed, beyond delayed, and extended overall phases tended to be higher with fosnetupitant than with fosaprepitant.…”

“…Inclusion/exclusion criteria are presented in detail in the primary publication of this study [18]. Key eligibility criteria were that patients were C 20 years, naı ¨ve to chemotherapy or had received prior chemotherapy classified as low/ minimal emetic risk, and scheduled to receive cisplatin-based (C 70 mg/m 2 ) chemotherapy for the treatment of a confirmed solid tumor malignancy.…”

“…The primary analysis of the CONSOLE study has been published [18]. Non-inferiority of fosnetupitant and fosaprepitant was demonstrated for the primary endpoint of overall (0-120 h) complete response (no emetic event and no rescue medication).…”