Top

24-11-2016 | Nausea and vomiting | Article

NEPA, a fixed oral combination of netupitant and palonosetron, improves control of chemotherapy-induced nausea and vomiting (CINV) over multiple cycles of chemotherapy: results of a randomized, double-blind, phase 3 trial versus oral palonosetron

Journal: Supportive Care in Cancer

Authors: Matti Aapro, Meinolf Karthaus, Lee Schwartzberg, Igor Bondarenko, Tomasz Sarosiek, Cristina Oprean, Servando Cardona-Huerta, Vincent Hansen, Giorgia Rossi, Giada Rizzi, Maria Elisa Borroni, Hope Rugo

Publisher: Springer Berlin Heidelberg

Abstract

Purpose

Antiemetic guidelines recommend co-administration of targeted prophylactic medications inhibiting molecular pathways involved in emesis. NEPA is a fixed oral combination of a new NK₁ receptor antagonist (RA), netupitant (NETU 300 mg), and palonosetron (PALO 0.50 mg), a pharmacologically distinct 5-HT₃ RA. NEPA showed superior prevention of chemotherapy-induced nausea and vomiting (CINV) compared with oral PALO in a single chemotherapy cycle; maintenance of efficacy/safety over continuing cycles is the objective of this study.

Methods

This study is a multinational, double-blind study comparing a single oral dose of NEPA vs oral PALO in chemotherapy-naïve patients receiving anthracycline/cyclophosphamide-based chemotherapy along with dexamethasone 12 mg (NEPA) or 20 mg (PALO) on day 1. The primary efficacy endpoint was delayed (25–120 h) complete response (CR: no emesis, no rescue medication) in cycle 1. Sustained efficacy was evaluated during the multicycle extension by calculating the proportion of patients with overall (0–120 h) CR in cycles 2–4 and by assessing the probability of sustained CR over multiple cycles.

Results

Of 1455 patients randomized, 1286 (88 %) participated in the multiple-cycle extension for a total of 5969 cycles; 76 % completed ≥4 cycles. The proportion of patients with an overall CR was significantly greater for NEPA than oral PALO for cycles 1–4 (74.3 vs 66.6 %, 80.3 vs 66.7 %, 83.8 vs 70.3 %, and 83.8 vs 74.6 %, respectively; p ≤ 0.001 each cycle). The cumulative percentage of patients with a sustained CR over all 4 cycles was also greater for NEPA (p < 0.0001). NEPA was well tolerated over cycles.

Conclusions

NEPA, a convenient, guideline-consistent, fixed antiemetic combination is effective and safe over multiple cycles of chemotherapy.

Hesketh PJ, Bohlke K, Lyman GH et al (2016) Antiemetics: ASCO clinical practice focused guideline update. J Clin Oncol 34(4):381–386CrossRef

Aapro M, et al. MASCC/ESMO Antiemetic Guideline, version 1.1 2016 - Multinational Association of Supportive Care in Cancer. Available at: http://www.mascc.org

Aapro M, Molassiotis A, Dicato M et al (2012) The effect of guideline-consistent antiemetic therapy on chemotherapy-induced nausea and vomiting (CINV): the pan European emesis registry (PEER. Ann Oncol 23(8):1986–1992CrossRef

Gilmore JW, Peacock NW, Gu A et al (2014) Antiemetic guideline consistency and incidence of chemotherapy-induced nausea and vomiting in US community oncology practice: INSPIRE study. J Oncol Pract 10(1):68–74CrossRef

Affronti ML, Schneider SM, Schlundt S et al (2014) Adherence to antiemetic guidelines in patients with malignant glioma: a quality improvement project to translate evidence into practice. Support Care Cancer 22(7):1897–1905CrossRef

Feyer P, Jordan K (2011) Update and new trends in antiemetic therapy: the continuing need for novel therapies. Ann Oncol 22(1):30–38CrossRef

Rojas C, Slusher BS (2012) Pharmacological mechanism of 5-HT3 and tachykinin NK-1 receptor antagonism to prevent chemotherapy-induced nausea and vomiting. Eur J Pharmacol 684(1–3):1–7CrossRef

Stathis M, Pietra C, Rojas C, Slusher BS (2012) Inhibition of substance P-mediated responses in NG108-15 cells by netupitant and palonosetron exhibit synergistic effects. Eur J Pharmacol 689(1–3):25–30CrossRef

Thomas AG, Stathis M, Rojas C et al (2014) Netupitant and palonosetron trigger NK1 receptor internalization in NG 108-15 cells. Exp Brain Res 232(8):2637–2644CrossRef

10.

Hesketh PJ, Rossi G, Rizzi G et al (2014) 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 25:1340–1346CrossRef

11.

Gralla R, Bosnjak S, Hontsa A et al (2014) 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 25:1333–1339CrossRef

12.

Herrstedt J, Muss HB, Warr DG et al (2005) Efficacy and tolerability of aprepitant for the prevention of chemotherapy-induced nausea and emesis over multiple cycles of moderately emetogenic chemotherapy. Cancer 104(7):1548–1555CrossRef

13.

Aapro M, Rugo H, Rossi G et al (2014) A randomized phase 3 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. Ann Oncol 25:1328–1333CrossRef

14.

Ewer M, Grunberg S, Ranganathan S et al (2009) Cardiac safety data for casopitant, an NK-1 receptor antagonist, given with anthracycline. Support Care Cancer 17:857–1039CrossRef

15.

Morrow G, Roscoe JA, Hickok JT et al (1998) Initial control of chemotherapy-induced nausea and vomiting in patient quality of life. Oncology (Williston Park) 12:32–37

16.

Cohen L, de Moor CA, Eisenberg P et al (2007) Chemotherapy-induced nausea and vomiting: incidence and impact on patient quality of life at community oncology settings. Support Care Cancer 15:497–503CrossRef

17.

Rapoport BL, Jordan K, Boice JA et al (2010) Aprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with a broad range of moderately emetogenic chmotherapis and tumor types: a randomized, double-blind study. Supp Care Cancer 18(4):423–431CrossRef

18.

Warr DG, Hesketh PJ, Gralla RJ et al (2005) 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 23(12):2822–2830CrossRef

19.

Poli-Bigelli S, Rodribues-Perelra J, Carides AD et al (2003) Addition of the neurokinin 1 receptor antagonist aprepitant to standard antiemetic therapy improves control of chemotherapy-induced nausea and vomiting. Cancer 97(12):3090–3098CrossRef

20.

Hesketh PJ, Grunberg SM, Gralla RJ et al (2003) The oral neurokinin-1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a multinational, randomized, double-blind, placebo-controlled trial in patients receiving high-dose cisplatin—the aprepitant protocol 052 study group. J Clin Oncol 21:4112–4119CrossRef

21.

Schmoll HJ, Aapro MS, Poli-Bigelli S et al (2006) Comparison of an aprepitant regimen with a multiple-day ondansetron regimen, both with dexamethasone, for antiemetic efficacy in high-dose cisplatin treatment. Ann Oncol 17(6):1000–1006CrossRef