Use of an NK1 Receptor Antagonist to Prevent Delayed Emesis After Cisplatin

Despite the use of serotonin antagonists, most patients continue to experience vomiting with chemotherapy, particularly delayed emesis. Substance P, a regulatory peptide (1), induces vomiting (2) and binds to the NK1 neuroreceptor. Compounds that block the NK1 receptor (3–6) lessen emesis after cisplatin, ipecac, copper sulfate, apomorphine, and radiation therapy (4,5). This broad activity suggests that substance P and the receptor may play central roles in emesis. We evaluated the NK1 receptor antagonist CP-122,721 in 17 cancer patients receiving cisplatin (⩾80 mg/m2 over <3 hours) that induces acute vomiting in 98% of the patients not receiving antiemetics (7) and delayed vomiting in 89% (8). CP-122,721 (1 mg/kg) prevented emesis after cisplatin in the ferret model that predicted the activity and dose of serotonin antagonists (9,10). All 17 patients had a normal electrocardiogram, bilirubin level, and creatinine level and provided written informed consent. A single oral dose of CP-122,721 (50 mg [n = 3], 100 mg [n = 4], and 200 mg [n = 10]) was administered 30 minutes before cisplatin. Patients were observed for 24 hours for emesis, nausea (11), and side effects and were contacted later about delayed vomiting. Statistical tests were two-sided. The initial 10 patients received prophylactic antiemetics together with CP- 122,721. Eight patients had emesis with prior cisplatin and each received the same antiemetics. Seven patients, four who had not received cisplatin previously, received CP-122,721 alone as prophylaxis. Patient characteristics and results are shown in Table 1. Among the 10 patients receiving single CP-122,721 doses of 50-200 mg with antiemetics, 100% had no acute emetic episodes. Eighty percent reported no delayed emesis. Among the nine patients who had received cisplatin previously, 78% experienced no acute emesis in the prior course, and delayed emesis prevention rose from 11% to 78% with CP-122,721 (P = .007). Five of the seven patients who received 200 mg of CP-122,721 alone as prophylaxis had two or fewer episodes, a significant difference compared with historical controls (P = .0001) (7). With the use of the same control subjects (7), those receiving CP-122,721 alone had fewer vomiting episodes (mean, two versus seven) (P = .007). Six (86%) of the seven patients who received one dose of CP-122,721 alone as prophylaxis reported no delayed emesis. Acute emesis and delayed emesis were similar among the CP- 122,721 doses. No adverse effects of CP-122,721 occurred. This trial reports the first use of a substance-P antagonist to prevent cisplatin- induced emesis. The most dramatic finding was the prevention of delayed vomiting in 83% of the patients given a single prophylactic dose of CP- 122,721. Only 17% of previously treated individuals had no delayed emesis in their prior course (P = .006). This observation that NK1 receptor blockade prevents delayed emesis suggests that substance P may, in part, mediate this reflex. In patients receiving CP-122,721 alone as prophylaxis for acute cisplatininduced emesis, vomiting was lessened compared with historical data (7), showing activity against acute emesis. For patients who had experienced acute emesis with a serotonin antagonist and dexamethasone in prior cycles, control during a subsequent cycle with CP-122,721 did not decline as expected (12). These data suggest that NK1 antagonists may provide additive acute control. Further study of NK1 receptor antagonists provides a singular opportunity to improve our understanding and control of emesis.