Abstract & Commentary
By William B. Ershler, MD
Synopsis: Current strategies to prevent chemotherapy-induced nausea and vomiting frequently include a 3-day course of aprepitant. In a multicenter trial from Japan, administration of a single dose of the aprepitant prodrug fosaprepitant, when used in combination with granisetron and dexamethasone, was shown to provide significant improvement when compared to placebo plus granisetron/dexamethasone. Thus, single-dose fosaprepitant may offer a more convenient and less complicated approach in the regimen to prevent nausea and vomiting.
Source: Saito H, et al. Efficacy and safety of single-dose fosaprepitant in the prevention of chemotherapy-induced nausa and vomiting in patients receiving high-dose cisplatin: A multicenter, randomized, double-blind, placebo-controlled phase 3 trial. Ann Oncol 2013;24:1067-1073.
Chemotherapy-induced nausea and vomiting (CINV) remains a major concern for cancer patients, particularly those treated with highly emetogenic chemotherapy such as cisplatin. Traditional antiemetic agents for CINV have included serotonin 5-HT3 receptor antagonists, corticosteroids, and dopamine receptor antagonists. A more recent development has been the neurokinin-1 (NK1) receptor antagonists. The first of these to reach clinical application was aprepitant, which was shown to provide additive control on CINV in combination with existing antiemetics. However, due to formulation issues, aprepitant is only available for oral administration. Fosaprepitant, a prodrug of aprepitant, was introduced to the market in 2008 as an intravenous bioequivalent to aprepitant.
In the current report, Saito and colleagues throughout Japan evaluated the efficacy and safety of single-dose fosaprepitant in combination with intravenous granisetron and dexamethasone. The research was funded by Ona Pharmaceuticals, Osaka, Japan.
Patients treated at any of 68 participating centers who were receiving chemotherapy including cisplatin (≥ 70 mg/m2) were considered eligible. Between August and December 2009, a total of 347 patients were enrolled. Of these, 21% had previously received cisplatin with associated vomiting. Patients previously treated with cisplatin without associated vomiting were not considered eligible. Enrolled subjects were randomized to receive the fosaprepitant regimen (fosaprepitant 150 mg, intravenous, on day 1 in combination with granisetron, 40 μg/kg, intravenous, on day 1 and dexamethasone, intravenous, on days 1-3) or the control regimen (placebo plus intravenous granisetron and dexamethasone). Aprepitant (the active form of fosaprepitant and a CYP3A4 inhibitor) is known to increase plasma dexamethasone concentrations when used in combination with dexamethasone (CYP3A4 substrate).1,2 To achieve comparable plasma levels of dexamethasone in the fosaprepitant and placebo groups, the dose of dexamethasone in the fosaprepitant group was half of that in the placebo group on days 1 and 2.
The primary endpoint was the percentage of patients who had a complete response (no emesis and no need for rescue therapy) over the entire treatment course (0-120 h). The percentage of patients with a complete response was significantly higher in the fosaprepitant group than in the control group (64% vs 47%, P = 0.0015). The fosaprepitant regimen was more effective than the control regimen in both the acute (0-24 h post chemotherapy) phase (94% vs 81%, P = 0.0006) and the delayed (24-120 h post chemotherapy) phase (65% vs 49%, P = 0.0025).
The efficacy of the 3-day regimen of oral aprepitant in combination with ondansetron and dexamethasone has been demonstrated in a series of Phase 3 trials in patients treated with highly emetogenic chemotherapy.3,4 There is some indication that single-dose aprepitant may be sufficient to control CINV in some patients.5,6
In the current multicenter trial conducted in Japan, it was demonstrated that single-dose intravenous fosaprepitant (150 mg) used in combination with granisetron and dexamethasone was well-tolerated and effective in preventing CINV in patients receiving highly emetogenic cancer chemotherapy, including high-dose cisplatin. The trial was conducted before aprepitant was approved in Japan, and thus it was not possible to determine from this work whether a single dose of fosaprepitant could substitute for the current standard of 3 days of aprepitant used in combination with ondansetron and dexamethasone. However, a subsequent Phase 3 study demonstrated comparable (i.e., non-inferior) efficacy of single-dose fosaprepitant when compared to the 3 days of aprepitant in the prevention of CINV in patients treated with highly emetogenic chemotherapy when used with ondansetron and dexamethasone.7
Thus, single-dose fosaprepitant is likely equally effective in preventing CINV as the 3-day course of aprepitant, and may be a less complicated and more convenient approach. Yet, there remains the one-third or more of patients who experience significant nausea and vomiting in this setting, and new drugs or treatment schedules need to be developed.
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2. McCrea JB, et al. Clin Pharmacol Ther 2003;74:17-24.
3. Hesketh PJ, et al. J Clin Oncol 2003;21:4112-4119.
4. Poli-Bigelli S, et al. Cancer 2003;97:3090-3098.
5. Herrington JD, et al. Cancer 2008;112:2080-2087.
6. Navari RM, et al. N Engl J Med 1999;340:190-195.
7. Grunberg S, et al. J Clin Oncol 2011;29:1495-1501.