NEPA Combination for Prevention of CINV Proves Noninferior to Aprepitant Regimen


The novel combination of a neurokinin-1 (NK-1) receptor antagonist and the 5-HT3 receptor antagonist palonosetron (Aloxi), NEPA (Akynzeo) had non-inferior efficacy compared to a conventional aprepitant regimen for preventing chemotherapy-inducted nausea and vomiting (CINV).

Li Zhang, MD

Li Zhang, MD

Li Zhang, MD

A head-to-head study demonstrated that NEPA (Akynzeo)—a novel combination of a neurokinin-1 (NK1) receptor antagonist and the 5-HT3 receptor antagonist palonosetron (Aloxi)—had non-inferior efficacy compared to a conventional aprepitant regimen for preventing chemotherapy-induced nausea and vomiting (CINV).1 This trial focused on Asian patients receiving cisplatin-based highly emetogenic chemotherapy (HEC) as first-line treatment, and showed promising activity in this patient population.

NEPA can provide a near-immediate positive effect on patients receiving HEC, and since it is a single-dose oral drug, it can facilitate patients taking anti-CINV medication as prescribed. “The availability of an oral antiemetic targeting 2 antiemetic pathways in a convenient single capsule can make chemotherapy less burdensome for patients with cancer, especially those undergoing HEC regimens,” said Li Zhang, MD, of the Sun Yat-sen University Cancer Center in Guangzhou, China. Zhang also was the primary investigator for the trial, and presented the data at the 2017 Multinational Association of Supportive Care in Cancer Annual Meeting in Washington, DC.

The double-blind, phase III study randomized 828 chemotherapy-naïve Asian patients receiving cisplatin-based HEC to either receive a single oral dose of NEPA (netupitant given at a dose of 300 mg and palonosetron at 0.5 mg) or a 3-day oral aprepitant/granisetron regimen (125 mg of oral aprepitant combined with 3 mg of intravenous granisetron). Both arms also received oral dexamethasone.

Patients who had an ECOG performance status of 0, 1, or 2, and who were scheduled to receive their first course of cisplatin-based chemotherapy were eligible for the study.

In the NEPA arm (n = 413), 70.7% of patients were male, the mean age was 54.6 years, and the median dose of cisplatin received was 73 mg/m2.In the aprepitant/granisetron arm (n = 416), 71.4% of patients were male, the median age was 54.5 years, and the median dose of cisplatin received was 72 mg/m2. ECOG performance statuses were balanced between the NEPA and aprepitant/granisetron arms (Table). In both arms, the most common cancer type was lung cancer.1

Table. ECOG Performance Status at Baseline for Patients in Each Treatment Arm

ECOG Performance Status


Aprepitant/ Granisetron Arm


175 (42.5%)

171 (41.1%)


231 (56.1%)

236 (56.7%)


7 (1.7%)

9 (2.2%)

The primary endpoint was complete response (CR), defined as patients having no emesis and no need for rescue medication for CINV. Secondary endpoints for analysis included patients having no emesis or significant nausea, and the daily rates of CINV events.

The CR rates were assessed in 3 time frames: acute (CINV events occurring in 0-24 hours), delayed (25-120 hours), and overall (0-120 hours). Rates were similar between the 2 arms, with CR rates in the acute period at 84.5% in the NEPA arm and 87.0% in the aprepitant/granisetron arm, 77.9% and 74.3% in the delayed period, respectively, and 73.8% and 72.4% overall, respectively.1

Notably, although the overall CR rates were similar for the 2 arms, the daily rates of patients experiencing CINV remained between 13% and 15% for the aprepitant/granisetron arm over 5 days, yet declined from 16% to 8% for NEPA.1

This study was not powered to demonstrate the superiority of NEPA to aprepitant/granisetron, and only could demonstrate noninferiority, there is clear potential for NEPA rising above aprepitant/granisetron. “The selectivity and convenient dosing of NEPA should make it an attractive option for many patients undergoing HEC,” Zhang commented.

Incidence of treatment-related adverse events (TRAEs) was similar in the 2 arms (18.4% for NEPA vs 14.4% for aprepitant/granisetron), as was the incidence of serious TRAEs (0.5% in both arms), according to Zhang. The most common TRAEs were constipation (8.0% in the NEPA arm vs 6.3% in the aprepitant/granisetron arm) and hiccups (2.7% vs 1.4%, respectively).

Part of what makes NEPA such a promising regimen is its mechanism of action as a combination therapy. “For patients receiving HEC, optimal control of CINV requires co-administration of antiemetics that inhibit multiple molecular pathways. One of the more commonly recommended regimens for preventing and treating CINV is one that combines a selective 5-HT3 receptor antagonist, an NK1 receptor antagonist, and a corticosteroid,” Zhang explained.

Chemotherapy causes nausea and vomiting by stimulating the release of serotonin from the enterochromaffin cells of the small intestine. Serotonin then activates 5-HT3 receptors located on the terminals of the vagus nerve, which reflexively causes vomiting. The development of acute emesis depends on serotonin, and its 5-HT3 receptors have been shown to selectively stimulate the emetic response.2

Netupitant is a selective antagonist of NK1 receptors. The other component of NEPA, palonosetron, is a 5-HT3 receptor antagonist with a strong binding affinity for this receptor and little or no affinity for other receptors. Palonosetron prevents nausea and vomiting during the acute phase of CINV, and netupitant prevents nausea and vomiting during both the acute and delayed phases after chemotherapy.2

Oral NEPA has been approved in the United States and Europe after demonstrating superior efficacy in preventing CINV compared to palonosetron alone in patients taking cisplatin chemotherapy. The earlier trial was a multicenter, randomized, double-blind, parallel-group study comparing oral NEPA (n = 135) to oral palonosetron (n = 136) in patients receiving high-dose cisplatin chemotherapy. Ninety percent of patients treated with NEPA achieved a CR, versus 77% in palonosetron group.3

Almost all patients treated with NEPA experienced a complete response during the acute phase of CINV, compared to 90% of patients receiving palonosetron (P = 0.002). Additionally, 90% of patients in the NEPA group achieved a CR during the delayed phase of CINV, versus 80% in the oral PALO group (P = 0.032).3

Despite these positive results, a study comparing NEPA to other treatments had not previously been done. “Prior to our study, none of the NK1 receptor antagonist-containing regimens had been compared to each other in a head-to-head phase III trial. That is why we chose to compare oral NEPA to aprepitant/granisetron,” Zhang said.

In terms of future research, Zhang noted that they plan to conduct some prespecific analyses of this study, such as for different tumor types and different ethnic groups.


  • Zhang L, Lu S, Feng J, et al. Phase 3 study of NEPA versus 3-day aprepitant regimen for prevention of chemotherapy-induced nausea and vomiting (CINV) in highly emetogenic chemotherapy (HEC) setting. Abstract presented at: 2017 Multinational Association of Supportive Care in Cancer Annual Meeting; June 22-24, 2017; Washington, DC. Abstract PS049.
  • Akynzeo [prescribing information]. Lugano, Switzerland: Helsinn Group; December 2016. Accessed July 26, 2017.
  • Hesketh PJ, Rossi G, Rizzi G, et al. Efficacy and safety of NEPA, an oral combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy: a randomized dose-ranging pivotal study. Ann Oncol. 2014;25(7):1340-1346. doi: 10.1093/annonc/mdu110.

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