The oral NK1 antagonist aprepitant for the prevention of acute and delayed chemotherapy-induced nausea and vomiting: Pooled data from 2 randomised, double-blind, placebo controlled trials

doi:10.1016/j.ejca.2005.01.024

European Journal of Cancer

Volume 41, Issue 9, June 2005, Pages 1278-1285

https://doi.org/10.1016/j.ejca.2005.01.024 Get rights and content

Abstract

In this work, data from two phase III studies were pooled to further evaluate the NK₁ antagonist aprepitant for prevention of cisplatin induced nausea and vomiting.

One thousand and forty three patients receiving cisplatin (⩾70 mg/m²) were randomised to receive either a control regimen (32 mg intravenous ondansetron [O] and 20 mg oral dexamethasone [D] on day 1; 8 mg D twice daily on days 2–4) or an aprepitant (A) regimen (125 mg A plus 32 mg O and 12 mg D on day 1, 80 mg A and 8 mg D once daily on days 2–3, and 8 mg D on day 4). The primary endpoint was no emesis and no rescue therapy. Potential correlations between acute and delayed emesis were assessed, as were frequency of emetic episodes by time interval and effects on nausea and quality of life as measured by the functional living index emesis (FLIE) questionnaire. In the aprepitant group, there was statistically significantly less nausea over the study period as well as higher functioning on the FLIE questionnaire in both the nausea and vomiting domains. Patients without acute emesis were more likely to have no emesis in the delayed phase. Compared with control, the aprepitant regimen improved prevention of delayed emesis by 16% points in patients without acute emesis, and by 17% points in patients with acute emesis. Among patients who did not have complete response, the frequency of emesis at various intervals over 5 days was consistently lower in patients receiving aprepitant.

Analyses of this combined Phase III population further characterized the clinical profile of the aprepitant regimen, showing that delayed emesis is correlated with, but not entirely dependent on, the presence of acute emesis, and that aprepitant has a favorable effect against nausea throughout 5 days postchemotherapy. In addition, even among patients who had emesis or needed rescue therapy, aprepitant was associated with a lower frequency of these events compared with the control regimen.

Introduction

Two identically designed Phase III trials have been previously reported describing the addition of the NK₁ antagonist aprepitant to a control regimen (a 5HT₃ antagonist and dexamethasone) for the prevention of cisplatin-based chemotherapy induced nausea and vomiting (CINV) [1], [2]. The aprepitant regimen was significantly superior to the control regimen in the overall 5-day study period, the first 24 h postchemotherapy (day 1, the acute phase of CINV), and particularly days 2–5 (the delayed phase). The reports of the individual phase III studies established that aprepitant was generally well tolerated and made a large impact on the likelihood of vomiting following high dose cisplatin. The impact of NK₁ receptor antagonists on the important symptom of nausea, however, was less clear. There was a statistically significant difference in the proportion of patients with no nausea in only one of the two phase III trials. Non-statistically significant trends were reported for the proportion of patients with nausea visual analog scores less than 25 mm. No tests of statistical significance were reported for the functional living index emesis (FLIE) questionnaire, nor were the results for the nausea and vomiting domains of that questionnaire reported separately. This paper aims to expand upon the results for the nausea outcomes in the pooled dataset.

Another topic that appears in the antiemetic literature is the relationship between acute and delayed emesis. Consistent with current belief that the most important risk factor for delayed emesis is poor control of acute emesis [3], in both phase III studies, the likelihood of delayed emesis was lower in patients who had not experienced acute emesis [1], [2]. It has been suggested that the pharmacologic benefit of aprepitant in the delayed phase is not strictly a carryover effect from the acute phase [4], [5]. In this study, we have analysed data pooled from the Phase III studies to determine the extent to which the results in the first 24 h predict the results in the delayed phase.

Section snippets

Design

Two identically designed multicenter, randomised, double-blind, parallel-group, placebo-controlled trials were conducted. Written informed consent to participate was obtained from every patient, and was approved by the Institutional Review Board of each participating site. Detailed descriptions of the design (including enrollment criteria), as well as the primary efficacy and tolerability results of the individual studies, are published elsewhere [1], [2].

Patients

The studies enrolled cisplatin-naı¨ve

Patients

Details of patient accounting for the individual studies are published elsewhere [1], [2]. Combined data from 1099 patients were assessed for baseline characteristics (Table 1). As shown in the table, baseline characteristics were similar between the treatment groups. A total of 1043 patients (520 in the aprepitant group and 523 in the control group) were included in the efficacy analyses.

Efficacy

Fig. 1 and Table 2 show results of the efficacy analyses. No statistically significant interaction between

Discussion

The efficacy of currently recommended therapeutic regimens, which include a 5HT₃ antagonist combined with a corticosteroid, has been well established for the acute phase of CINV (especially up to about 16 h post cisplatin), but these agents have not been nearly as effective in the delayed phase [3], [13], [14].

As anticipated, based on the consistency of results between the individual studies [1], [2], the present efficacy findings based on the pooled Phase III data confirmed that the aprepitant

Conflict of interest statement

Drs. Carides, Evans, and Horgan are employees of Merck Research Laboratories. Drs. Warr, Grunberg, Gralla, Hesketh, Roila, and de Wit have received funding from Merck Research Laboratories for the conduct of clinical studies of aprepitant. The studies described in this paper were funded by Merck Research Laboratories, manufacturers of aprepitant.

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Superiority of aprepitant, an oral NK1 antagonist, over standard antiemetic therapy: reducing the impact of nausea and vomiting on patients’ daily lives
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The oral NK1 antagonist aprepitant for the prevention of acute and delayed chemotherapy-induced nausea and vomiting: Pooled data from 2 randomised, double-blind, placebo controlled trials

Abstract

Introduction

Section snippets

Design

Patients

Patients

Efficacy

Discussion

Conflict of interest statement

Eur J Cancer

Eur J Cancer

Eur J Cancer

The oral NK1 antagonist aprepitant for the prevention of chemotherapy induced nausea and vomiting: a multinational, randomized, double-blind, placebo-controlled trial in patients receiving high-dose cisplatin

J Clin Oncol

Addition of the NK1 receptor antagonist aprepitant to standard antiemetic therapy improves control of chemotherapy induced nausea and vomiting: results from a randomized, double-blind, placebo controlled trial in Latin America

Cancer

Recommendations for the use of antiemetics: evidence-based, clinical practice guidelines. American Society of Clinical Oncology

J Clin Oncol

The oral NK₁ antagonist aprepitant for the prevention of acute and delayed chemotherapy-induced nausea and vomiting: Pooled data from 2 randomised, double-blind, placebo controlled trials