Prevention of cisplatin-induced emesis by the oral neurokinin-1 antagonist, MK-869, in combination with granisetron and dexamethasone or with dexamethasone alone

Purpose: The NK1-receptor antagonist MK-869 (L-754,030) has demonstrated an tiemetic activity in humans receiving chemotherapy. Objectives of the prese nt trial included the first assessment of oral MK-869 plus dexamethasone co mpared with a 5HT(3) antagonist plus dexamethasone for prevention of acute and delayed emesis after high-dose cisplatin. Furthermore, the study sought to confirm that addition of MK-869 to a 5HT(3) antagonist plus dexamethaso ne was more effective than just the 5HT(3) antagonist plus dexamethasone fo r prevention of acute and delayed emesis. Patients and Methods: This multicenter, double-blind, parallel-group trial in 351 cisplatin-naive patients evaluated prevention of acute (0 to 24 hour s) and delayed emesis (primary efficacy parameter; days 2 to 5) after cispl atin (greater than or equal to 70 mg/m(2)). Patients were randomized to fou r groups (1 to IV) (n = number randomized; number evaluable): granisetron ( 10 mug/kg intravenously) pre-cisplatin followed by placebo on days 2 to 5 ( group I) (n = 90; 90); granisetron and MK-869 (400 mg PO [by mouth]) pre-ci splatin, followed by MK-869 (300 mg PO) on days 2 to 5 (group II) (n = 86; 84); MK-869 (400 mg PO) the evening before and pre-cisplatin, followed by M K-869 (300 mg PO) on days 2 to 5 (group III) (n = 89; 88); or MK-869 (400 m g PO) pre-cisplatin, followed by MK-869 (300 mg PO) on days 2 to 5 (group I V) (n = 86; 84). All patients also received dexamethasone (20 mg PO) before cisplatin. Additional medication wets available to treat emesis or nausea at any time. Results: In the acute period, 57%, 80%, 46%, and 43% of patients were witho ut emesis in groups I, II, III, and IV, respectively (P < .01 for group II v group I). In the delayed period, the proportion of patients without emesi s in groups I, II, III, and IV was 29%, 63%, 51%, and 57%, respectively (P < .01 for groups It, III, and IV v group I). The distribution of nausea sca res in the delayed period was lower when comparing group II with group I (P < .05 for days 1 to 5 and days 2 to 5). One serious adverse event (dizzine ss) was rated as possibly related to MK-869. Conclusion: Once daily oral administration of MK-869 was effective in reduc ing delayed emesis and nausea after high-dose cisplatin. However, the combi nation of the 5HT3 antagonist plus dexamethasone was numerically superior t o MK-869 plus dexamethasone in reducing acute emesis. Confirming and extend ing previous findings, the triple combination of a 5HT(3) antagonist, MK-86 9, and dexamethasone provided the best control of acute emesis. <(c)> 2001 by American Society of Clinical Oncology.