Prevention of cisplatin‐induced acute and delayed emesis by the selective neurokinin‐1 antagonists, L‐758,298 and MK‐869

Abstract

BACKGROUND Recent studies have suggested that antiemetic therapy with a triple combination of the neurokinin‐1 receptor antagonist MK‐869, a serotonin (5‐HT3) antagonist, and dexamethasone provides enhanced control of cisplatin‐induced emesis compared with standard therapy regimens. The authors compared the antiemetic activity of a dual combination of MK‐869 and dexamethasone with that of a standard dual combination of ondansetron and dexamethasone to characterize further the efficacy and tolerability profile of MK‐869. METHODS This was a multicenter, double‐blind, randomized, active agent‐controlled study of 177 cisplatin‐naïve patients with malignant disease. On Day 1, MK‐869 was given intravenously as its water‐soluble prodrug, L‐758,298. Patients were randomized to one of three groups as follows. Group I received L‐758,298 100 mg intravenously (i.v.), then dexamethasone 20 mg i.v., and cisplatin ≥ 70 mg/m2 on Day 1 followed by 300 mg MK‐869 (tablet) orally on Days 2–5; Group II received L‐758,298 100 mg i.v., then dexamethasone 20 mg i.v., and cisplatin ≥ 70 mg/m2 on Day 1 followed by placebo on Days 2–5; and Group III received ondansetron 32 mg i.v., then dexamethasone 20 mg i.v., and cisplatin ≥ 70 mg/m2 on Day 1 followed by placebo on Days 2–5. Emesis was recorded over Days 1–5 in a diary. Nausea was assessed every 24 hours by visual analog scale. Additional medication was available for emesis or nausea at any time. The primary efficacy parameters of interest were the proportion of patients without emesis and the proportion without emesis or rescue therapy on Day 1 (acute phase) and on Days 2–5 (delayed phase). RESULTS No serious adverse events were attributed to L‐758,298 or MK‐869. On Day 1, the proportions of patients with no emesis and no use of rescue medication were 44% of patients in Group I, 36% of patients in Group II, 40% of patients in Groups I and II combined, and 83% of patients in Group III (P < 0.001 for Group III vs. the combined Groups I and II). The proportions of patients with no emesis and no use of rescue medication on Days 2–5 were 59% of patients in Group I, 46% of patients in Group II, and 38% of patients in Group III (P < 0.05 for Group I vs. Group III). The proportions of patients who were without emesis on Day 1 were 49% of patients in Group I, 47% of patients in Group II, and 84% of patients in Group III (P < 0.01 for Group I or II vs. Group III). On Days 2‐5, however, the proportions of patients who were without emesis on Days 2–5 were 65% of patients in Group I, 61% of patients in Group II, and 41% of patients in Group III (P < 0.05 for Group I or II vs. Group III). Nausea scores in the acute phase were lower for Group III than for Group I, Group II, or Groups I and II combined (P < 0.05), although there was no significant difference among groups either for the delayed phase or overall for Days 1–5. CONCLUSIONS Although the L‐758,298 and dexamethasone combination reduced acute (Day 1) emesis compared with historic rates, dual therapy with ondansetron and dexamethasone...

Consensus recommendations for the prevention of vomiting and nausea following high-emetic-risk chemotherapy

“…Furthermore, the addition of dexamethasone consistently improved efficacy compared to a 5-HT 3 receptor antagonist alone, establishing this combination as a standard for patients receiving cisplatin-based therapy [25,49]. Dose-ranging studies of these agents demonstrate a dose-response curve consistent with the conclusions discussed earlier [16,17,34,35,38,49,54,57,59]. There are conflicting data regarding the optimal single dose of ondansetron for prevention of acute emesis from cisplatin.…”

“…The dose-ranging study of Van Belle and the comparative trial by Marty both support a 5-mg single-dose administration of tropisetron as effective in highly emetogenic cisplatin-based chemotherapy, with the study of Van Belle suggesting no further improvement in efficacy at dose levels up to 40 mg [43,59]. Dose-ranging studies of dolasetron did not define the lowest effective dose while the subsequent comparative trial of Hesketh supports a dose level of 1.8 mg/kg as effective, with no evidence of clinically significant improvement in efficacy at 2.4 mg/kg [27,36,57].…”

“…Although other aprepitant doses may be appropriate, the 125-mg oral aprepitant dose tested in two phase III studies [28,48] is recommended. An intravenous (IV) formulation of aprepitant, fosaprepitant, is available at a dose of 115 mg [8,40,59]. …”

Current position of 5HT3 antagonists and the additional value of NK1 antagonists; a new class of antiemetics

“…More recently, the preceding proof of concept studies conducted with L-745,030, and its water-soluble intravenous prodrug L-758,298, were published (Cocquyt et al, 2001;Van Belle et al, 2002). The rationale for combining NK 1 antagonists with 5HT 3 antagonists is based upon the results of these phase II studies.…”

“…Further data to support triple therapy with a 5HT 3 antagonist, dexamethasone plus an NK 1 antagonist were obtained in a randomised study involving 177 cisplatin-naive patients (Van Belle et al, 2002). Patients were randomized to one of three groups as follows: group I received L-758,298 intravenously plus dexamethasone before cisplatin on day 1, followed by L-745,030 orally on days 2 -5; group II received L-758,298 plus dexamethasone on day 1, followed by placebo on days 2 -5; and group III received ondansetron i.v.…”