FDA Expands Aprepitant's CINV Indication

The FDA has approved aprepitant capsules (Emend) in combination with other antiemetic agents for the prevention of acute and delayed nausea and vomiting in patients aged 12 to 17 and for those under the age of 12 who weigh at least 30 kg who are receiving highly emetogenic chemotherapy (HEC) or moderately emetogenic chemotherapy (MEC).

The extension to the aprepitant indication was based on findings from a phase III clinical trial that examined aprepitant plus ondansetron compared with placebo and ondansetron. The study enrolled 302 patients between the age of 6 months and 17 years. In those between the age of 12 and 17 or under 12 and at least 30 kg (n = 132), an acute or delayed complete response (CR), defined as no vomiting or retching, was achieved for 34.9% of patients treated with the combination versus 13% with ondansetron monotherapy.

A CR in the delay phase, defined as 25 to 120 hours following the initiation of chemotherapy, was experienced by 49.2% of patients treated with the aprepitant/ondansetron combination compared with 18.8% with ondansetron alone. In the first 24 hours following treatment (acute phase), 55.6% of patients treated with the combination had a CR versus 37.7% with ondansetron alone.

“The FDA approval of this expanded indication for Emend is the result of our commitment to fully realizing the potential of our therapies to help as many patients as possible,” Stuart Green, MD, vice president, clinical research, Merck Research Laboratories, said in a statement. “Historically, significant improvements in pediatric medicine have been slow due to many challenges such as clinical trial size. However, at Merck, these obstacles have invigorated our efforts to bring forward a new option for these patients.”

In the phase III clinical trial, treatment with the NK-1 receptor antagonist aprepitant was administered at 125 mg on the first day of treatment followed by 80 mg on day 2 and 3. The 5-HT3 receptor antagonist ondansetron was administered prior to chemotherapy on day 1 in both arms. Intravenous dexamethasone was permitted, with a 50% dose reduction required in the aprepitant arm. Across the full study, 30% of patients received dexamethasone in the first cycle.

Following the first cycle, patients were allowed to receive open-label aprepitant in cycles 2 to 6. The primary endpoint of the study was CR in the delayed phase. Secondary outcome measures included CR in the acute and overall phase along with safety and tolerability.

Across the full study, 152 patients were treated in the aprepitant group and 150 were enrolled in the control arm. According to findings published in the Lancet Oncology for the full population of the study, the CR rate in the delayed phase was 50.7% with aprepitant plus ondansetron and 26% with ondansetron alone (P <.0001). In the acute phase, the CR rates were 66.4% and 52% with and without aprepitant, respectively (P <.05). The overall CR rate across phases was 40.1% with aprepitant and 20% with ondansetron alone.

All-grade adverse events (AEs) were seen in 79% of patients treated with aprepitant versus 77% with ondansetron alone. The most frequently observed grade 3/4 AEs with aprepitant plus ondansetron versus ondansetron alone, respectively, were febrile neutropenia (15% vs 14%), anemia (9% vs 17%), and decreased neutrophil count (7% vs 11%). Febrile neutropenia was the most common serious AE, and occurred in 15% of patients in each arm.

For patients under the age of 12 who weighed less than 30 kg, an appropriate commercially available dose of aprepitant is not yet available. In the phase III study, an investigational powder for suspension formulation was examined for those below 30 kg; however, under the Pediatric Research Equity Act (PREA), an application for this formulation is still pending for pediatric patients.

Kang HJ, Loftus S, Taylor A, et al. Aprepitant for the prevention of chemotherapy-induced nausea and vomiting in children: a randomised, double-blind, phase 3 trial. Lancet Oncol. 2015;16(4):385—394.