FDA Approves Single-Dose Fosaprepitant for CINV

The FDA approved single-dose fosaprepitant dimeglumine (Emend for injection) in combination with other antiemetic agents for the prevention of delayed chemotherapy-induced nausea and vomiting (CINV) following moderately emetogenic chemotherapy (MEC), according to Merck, the developer of the drug.

The approval is primarily based on the phase III MK-0517-031 study, in which adding single-dose fosaprepitant to ondansetron and dexamethasone induced a complete response (CR) during the delayed phase (25 -120 hours after treatment initiation) in nearly 80% of patients receiving MEC. The CR rate with fosaprepitant was about 15% higher than the rate with ondansetron and dexamethasone alone.

“Despite significant advances in supportive care, nausea and vomiting has remained a challenge for many cancer patients undergoing moderately emetogenic chemotherapy and has historically required multiday antiemetic therapy,” Stuart Green, MD, vice president of Clinical Research at Merck Research Laboratories, said in a statement. “Today’s approval of an expanded indication for Emend for injection means that physicians now have a new single-dose intravenous option, combined with other antivomiting medicines, for the prevention of delayed nausea and vomiting in these patients.”

In the pivotal, randomized double-blind MK-0517-031 trial, 1000 patients receiving MEC were randomized in a 1:1 ratio to fosaprepitant as a single IV infusion combined with ondansetron and dexamethasone (n = 502) or the control regimen of ondansetron and dexamethasone alone (n = 498). On day 1, patients received 150 mg of fosaprepitant or placebo, along with ondansetron and dexamethasone. Patients in the control arm received ondansetron on days 2 and 3.

Patients were scheduled to receive IV treatment with at least 1 MEC agent when beginning treatment. Overall, baseline characteristics were well balanced between the 2 study arms. The majority of patients were female, Caucasian, and aged ≥50 years.

The primary endpoint was complete response (no vomiting and no use of rescue therapy) in the delayed phase. Secondary endpoints included CR in the overall (0-120 hours after starting MEC) and acute (0-24 hours after starting MEC) phases, and no vomiting in the overall phase.

In the delayed phase, patients in the fosaprepitant arm had a 78.9% CR rate compared with 68.5% in the control arm (P <.001). The CR rate was also significantly improved in the overall phase (77.1% vs 66.9%; P <.001). However, in the acute phase, there was not a significant CR rate improvement at 93.2% versus 91.0%, respectively (P = .184).

In the overall phase, the rate of individuals with no vomiting was 82.7% in the fosaprepitant arm versus 72.9% in the control arm (P <.001). The rate of patients without significant nausea was also improved with fosaprepitant at 83.2% versus 77.9% with ondansetron and dexamethasone alone (P = .030).

The safety profiles were similar between the fosaprepitant and control arms. All-grade adverse events were reported in 8.5% and 9.1% of the fosaprepitant and control arms, respectively. There were no reported cases of severe infusion-site pain, erythema, or induration. Three patients receiving fosaprepitant had infusion-site thrombophlebitis compared with no patients in the control regimen.

The most frequently occurring adverse events in the fosaprepitant versus the control arm were fatigue (15% vs 13%), diarrhea (13% vs 11%), neutropenia (8% vs 7%), asthenia (4% vs 3%), anemia (3% vs 2%), peripheral neuropathy (3% vs 2%), leukopenia (2% vs 1%), dyspepsia (2% vs 1%), urinary tract infection (2% vs 1%), and pain in extremity (2% vs 1%).

Fosaprepitant is an IV prodrug of the oral agent aprepitant, an NK1 receptor antagonist. When injected, fosaprepitant rapidly converts to aprepitant.

In 2008, the FDA initially approved fosaprepitant as part of a 3-day combination regimen with other antiemetic agents for the prevention of acute and delayed CINV following MEC or highly emetogenic chemotherapy. The original approved regimen included 115 mg of fosaprepitant on day 1 and 80 mg of aprepitant on days 2 and 3, along with a corticosteroid and a 5-HT3 antagonist.

Weinstein C, Jordan K, Green SA, et al. Single-dose fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with moderately emetogenic chemotherapy: results of a randomized, double-blind phase III trial. Ann Oncol. 2016;27(1):172-178.