NK1 Receptor Boosts Benefits of Standard Antiemetic Therapy

ORLANDO—When combined with standard antiemetic therapy, the neurokinin-1 (NK1) receptor antagonist aprepitant (MK-869[M]) protects against acute and delayed chemotherapy-induced nausea and vomiting, according to two separate studies (ASCO abstracts 1467 and 1467).

"We have been working with NK1 antagonists for over a decade, but until now, there really were no new agents.

Now we have a once-daily oral agent that adds to existing medications," Ronald de Wit, MD, PhD, told Oncology News International. He is director of the inpatient department of medical oncology at Rotterdam Cancer Institute and Erasmus Medical Center of University Hospital in Rotterdam, the Netherlands. "In phase III clinical studies, aprepitant added 10% to 15% to emesis relief in the early phase and about 25% in the later phase, at days 2 to 5 after the start of chemotherapy," Dr. de Wit explained.

Before Cisplatin Therapy

Before receiving their first dose of a chemotherapy regimen including cisplatin (Platinol) greater than 70 mg/m², 202 patients between ages 20 and 82 were randomized to one of three treatment groups. Group I received aprepitant, 375 mg on day 1 and 250 mg on days 2 to 5. Group II received aprepitant, 125 mg on day 1 and 80 mg on days 2 to 5. Group III received placebo on days 1 to 5.

All patients received standard antiemetic therapy with intravenous ondansetron (Zofran) at 32 mg, and oral dexamethasone (Decadron) at 20 mg, before receiving cisplatin on day 1, and dexamethasone on days 2 to 5. Because of pharmacokinetic data from healthy volunteers, the group I regimen was discontinued, and efficacy evaluations were based on only groups II and III.

Compared with standard therapy alone, triple combination therapy including aprepitant provided 34% better protection against chemotherapy-induced nausea and vomiting throughout multiple chemotherapy cycles. Although standard therapy decreased in efficacy after three cycles, the triple combination regimen maintained efficacy during all six cycles.

For cycles five and six, 59% of patients receiving triple combination therapy and 3% of patients receiving standard therapy had a complete response, defined as no vomiting and no use of rescue therapy. Results for cycles one through four showed a trend favoring aprepitant but were not statistically significant.

Patients generally tolerated aprepitant well, with similar dropout rates to those in the placebo group.

"Not only is protection against emesis important in the first cycle, but it is even more important at the end of chemotherapy," Dr. de Wit said. "With this agent, the protective effect is magnified at the end of chemotherapy, which makes a difference to patients to be able to tolerate their entire treatment."

Early and Late Effects

In a separate study, aprepitant combined with the 5HT3 receptor antagonist, granisetron (Kytril) protected against acute and delayed chemotherapy-induced nausea and vomiting.

"We were trying to get a better understanding of the mechanism of chemotherapy-induced emesis," said Paul J. Hesketh, MD, professor of medicine at Tufts University, and chief of hematology/oncology at St. Elizabeth’s Medical Center in Boston. "Findings from this study strongly suggest that both serotonin and substance P-dependent mechanisms are operative, with serotonin more important during the first 16 hours after cisplatin therapy, and NK1 receptors subsequently. Using antagonists of both results in a better outcome than with either class alone."

In this multicenter, double-blind, parallel-group study, 351 patients scheduled for their first dose of chemotherapy including cisplatin were randomized to one of four treatment groups. Group I received granisetron on day 1 and placebo on days 2 to 5. Group II received aprepitant and granisetron on day 1, followed by aprepitant on days 2 to 5. Group III received 2 doses of aprepitant 12 hours apart on day 1 and then single doses on days 2 to 5. Group IV received aprepitant on days 1 to 5. All patients also received dexamethasone before cisplatin and could take additional medication to treat nausea and vomiting at any time.

"There is a 23% difference from the current standard of care in the acute phase, or 24 hours, and this agent also has great potential for delayed emesis," Dr. Hesketh said. "Up to 5 days following initiation of chemotherapy, reduction in emesis is more than 20% better in the groups receiving aprepitant (groups II, III, and IV), than in the group receiving placebo (group I)."

The percentage of patients without emesis in the acute period was 57% for the group receiving granisetron (group I), 80% for granisetron plus aprepitant (group II), and 46% and 43% for groups receiving aprepitant alone (groups III and IV). Corresponding percentages for patients without emesis in the delayed period were 29%, 63%, 51%, and 57%, respectively (P < .01 for group I relative to each other group). One serious adverse event, dizziness, was rated as possibly related to aprepitant.

"You see the effect of aprepitant both early and late," Dr. Hesketh said. "It’s a useful addition to our current armamentarium. It does not replace any currently used agents, but considerably boosts the antiemetic effect when used in combination."