A randomized phase III study evaluating the efficacy and safety of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy

M Aapro, H Rugo, G Rossi, G Rizzi, M E Borroni, I Bondarenko, T Sarosiek, C Oprean, S Cardona-Huerta, V Lorusso, M Karthaus, L Schwartzberg, S Grunberg, M Aapro, H Rugo, G Rossi, G Rizzi, M E Borroni, I Bondarenko, T Sarosiek, C Oprean, S Cardona-Huerta, V Lorusso, M Karthaus, L Schwartzberg, S Grunberg

Abstract

Background: Antiemetic guidelines recommend co-administration of agents that target multiple molecular pathways involved in emesis to maximize prevention and control of chemotherapy-induced nausea and vomiting (CINV). NEPA is a new oral fixed-dose combination of 300 mg netupitant, a highly selective NK1 receptor antagonist (RA) and 0.50 mg palonosetron (PALO), a pharmacologically and clinically distinct 5-HT3 RA, which targets dual antiemetic pathways.

Patients and methods: This multinational, randomized, double-blind, parallel group phase III study (NCT01339260) in 1455 chemotherapy-naïve patients receiving moderately emetogenic (anthracycline-cyclophosphamide) chemotherapy evaluated the efficacy and safety of a single oral dose of NEPA versus a single oral dose (0.50 mg) of PALO. All patients also received oral dexamethasone (DEX) on day 1 only (12 mg in the NEPA arm and 20 mg in the PALO arm). The primary efficacy end point was complete response (CR: no emesis, no rescue medication) during the delayed (25-120 h) phase in cycle 1.

Results: The percentage of patients with CR during the delayed phase was significantly higher in the NEPA group compared with the PALO group (76.9% versus 69.5%; P = 0.001), as were the percentages in the overall (0-120 h) (74.3% versus 66.6%; P = 0.001) and acute (0-24 h) (88.4% versus 85.0%; P = 0.047) phases. NEPA was also superior to PALO during the delayed and overall phases for all secondary efficacy end points of no emesis, no significant nausea and complete protection (CR plus no significant nausea). NEPA was well tolerated with a similar safety profile as PALO.

Conclusions: NEPA plus a single dose of DEX was superior to PALO plus DEX in preventing CINV following moderately emetogenic chemotherapy in acute, delayed and overall phases of observation. As a fixed-dose antiemetic drug combination, NEPA along with a single dose of DEX on day 1 offers guideline-based prophylaxis with a convenient, single-day treatment.

Keywords: CINV; NEPA; moderately emetogenic; netupitant; neurokinin-1 receptor antagonist; palonosetron.

© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology.

Figures

Figure 1.
Figure 1.
Consort diagram of the disposition of patients.
Figure 2.
Figure 2.
Complete response (no emesis, no rescue medication).
Figure 3.
Figure 3.
Proportion of patients with no impact on daily living (NIDL) based on Functional Living Index-Emesis (FLIE): Overall 0–120 h.

References

    1. Frame DG. Best practice management of CINV in oncology patients: I. physiology and treatment of CINV. Multiple neurotransmitters and receptors and the need for combination therapeutic approaches. J Support Oncol. 2010;8(1):5–9.
    1. Feyer P, Jordan K. Update and new trends in antiemetic therapy: the continuing need for novel therapies. Ann Oncol. 2011;22(1):30–38.
    1. Roila F, Herrstedt J, Aapro M, et al. Guideline update for MASCC and ESMO in the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting: results of the Perugia consensus conference. Ann Oncol. 2010;21(5):232–243.
    1. Warr DG, Hesketh PJ, Gralla RJ, et al. Efficacy and tolerability of aprepitant for the prevention of chemotherapy-induced nausea and vomiting in patients with breast cancer after moderately emetogenic chemotherapy. J Clin Oncol. 2005;23(12):2822–2830.
    1. Aapro M, Molassiotis A, Dicato M, et al. The effect of guideline-consistent antiemetic therapy on chemotherapy-induced nausea and vomiting (CINV): the Pan European Emesis Registry (PEER) Ann Oncol. 2012;23(8):1986–1992.
    1. Rojas C, Slusher BS. Pharmacological mechanism of 5-HT3 and tachykinin NK-1 receptor antagonism to prevent chemotherapy-induced nausea and vomiting. Eur J Pharmacol. 2012;684(1–3):1–7.
    1. Stathis M, Pietra C, Rojas C, et al. Inhibition of substance P-mediated responses in NG108-15 cells by netupitant and palonosetron exhibit synergistic effects. Eur J Pharmacol. 2012;689(1–3):25–30.
    1. Hesketh P, 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;25:1340–1346.
    1. Lanzarotti C, Rossi G. Effect of netupitant, a highly selective NK1 receptor antagonist, on the pharmacokinetics of midazolam, erythromycin, and dexamethasone. Support Care Cancer. 2013;21:2783–2791.
    1. Boccia R, Grunberg S, Franco-Gonzales E, et al. Efficacy of oral palonosetron compared to intravenous palonosetron for prevention of chemotherapy-induced nausea and vomiting associated with moderately emetogenic chemotherapy: a phase 3 trial. Support Care Cancer. 2013;21(5):1453–1460.
    1. Aapro M, Fabi A, Nole F, et al. Double-blind, randomized, controlled study of the efficacy and tolerability of palonosetron plus dexamethasone for 1 day with or without dexamethasone on days 2 and 3 in the prevention of nausea and vomiting induced by moderately emetogenic chemotherapy. Ann Oncol. 2010;21:1083–1088.
    1. Basch E, Prestrud AA, Hesketh PJ, et al. Antiemetics: ASCO Clinical Practice Guideline Update. J Clin Oncol. 2012;29(31):4189–4198.
    1. Gralla R, Bosnjak S, Honsta A, et al. A phase 3 study evaluating the safety and efficacy of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting (CINV) over repeated cycles of chemotherapy. Ann Oncol. 2014;25:1333–1339.

Source: PubMed

Sponzoři a spolupracovníci

Zdravotní podmínky

Drogové intervence

3
Předplatit