A phase III study evaluating the safety and efficacy of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting over repeated cycles of chemotherapy

Abstract

Background: Safe, effective and convenient antiemetic regimens that preserve benefit over repeated cycles are needed for optimal supportive care during cancer treatment. NEPA, an oral fixed-dose combination of netupitant, a highly selective NK1 receptor antagonist (RA), and palonosetron (PALO), a distinct 5-HT3 RA, was shown to be superior to PALO in preventing chemotherapy-induced nausea and vomiting after a single cycle of highly (HEC) or moderately (MEC) emetogenic chemotherapy in recent trials. This study was designed primarily to assess the safety but also to evaluate the efficacy of NEPA over multiple cycles of HEC and MEC.

Patients and methods: This multinational, double-blind, randomized phase III study (NCT01376297) in 413 chemotherapy-naïve patients evaluated a single oral dose of NEPA (NETU 300 mg + PALO 0.50 mg) given on day 1 with oral dexamethasone (DEX). An oral 3-day aprepitant (APR) regimen + PALO + DEX was included as a control (3:1 NEPA:APR randomization). In HEC, DEX was administered on days 1-4 and in MEC on day 1. Safety was assessed primarily by adverse events (AEs), including cardiac AEs; efficacy by complete response (CR: no emesis, no rescue).

Results: Patients completed 1961 total chemotherapy cycles (76% MEC, 24% HEC) with 75% completing ≥4 cycles. The incidence/type of AEs was comparable for both groups. Most frequent NEPA-related AEs included constipation (3.6%) and headache (1.0%); there was no indication of increasing AEs over multiple cycles. The majority of AEs were mild/moderate and there were no cardiac safety concerns based on AEs and electrocardiograms. The overall (0-120 h) CR rates in cycle 1 were 81% and 76% for NEPA and APR + PALO, respectively, and antiemetic efficacy was maintained over repeated cycles.

Conclusions: NEPA, a convenient single oral dose antiemetic targeting dual pathways, was safe, well tolerated and highly effective over multiple cycles of HEC/MEC.

Keywords: CINV; NEPA; multiple chemotherapy cycles; netupitant; neurokinin-1 receptor antagonist; palonosetron.

Figure 1.

Consort diagram of the disposition of patients. One patient randomized/allocated to NEPA received APR + PALO throughout the study. Following the intent-to-treat principle, this patient was analyzed in the NEPA group for the full analysis set (FAS; N = 309) and the APR + PALO group for the safety population (N = 104). One patient randomized/allocated to APR + PALO did not receive any treatment and was therefore excluded from both the FAS (N = 103) and safety population. *The vast majority discontinued due to the study closure which occurred when the last patient enrolled had completed his/her final chemotherapy cycle; these patients were allowed to complete their current cycle but not enter any further cycles.

Figure 2.

Primary analysis: complete response (no emesis, no rescue medication) (overall 0–120 h). Full analysis population.