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

Paul J. Hesketh, G. Rossi, G. Rizzi, M. Palmas, A. Alyasova, I. Bondarenko, A. Lisyanskaya, Richard J. Gralla

Research output: Contribution to journalArticle

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Abstract

Background: NEPA is a novel oral fixed-dose combination of netupitant (NETU), a new highly selective neurokinin-1 (NK<inf>1</inf>) receptor antagonist (RA) and palonosetron (PALO), a pharmacologically and clinically distinct 5-hydroxytryptamine type 3 (5-HT<inf>3</inf>) RA. This study was designed to determine the appropriate clinical dose of NETU to combine with PALO for evaluation in the phase 3 NEPA program. Patients and methods: This randomized, double-blind, parallel group study in 694 chemotherapy naïve patients undergoing cisplatin-based chemotherapy for solid tumors compared three different oral doses of NETU (100, 200, and 300 mg) + PALO 0.50 mg with oral PALO 0.50 mg, all given on day 1. A standard 3-day aprepitant (APR) + IV ondansetron (OND) 32 mg regimen was included as an exploratory arm. All patients received oral dexamethasone on days 1-4. The primary efficacy endpoint was complete response (CR: no emesis, no rescue medication) during the overall (0-120 h) phase. Results: All NEPA doses showed superior overall CR rates compared with PALO (87.4%, 87.6%, and 89.6% for NEPA<inf>100</inf>, NEPA<inf>200</inf>, and NEPA<inf>300</inf>, respectively versus 76.5%PALO; P < 0.050) with the highest NEPA<inf>300</inf> dose studied showing an incremental benefit over lower NEPA doses for all efficacy endpoints. NEPA<inf>300</inf> was significantly more effective than PALO and numerically better than APR + OND for all secondary efficacy endpoints of no emesis, no significant nausea, and complete protection (CR plus no significant nausea) rates during the acute (0-24 h), delayed (25-120 h), and overall phases. Adverse events were comparable across groups with no dose response. The percent of patients developing electrocardiogram changes was also comparable. Conclusions: Each NEPA dose provided superior prevention of chemotherapy-induced nausea and vomiting (CINV) compared with PALO following highly emetogenic chemotherapy; however, NEPA<inf>300</inf> was the best dose studied, with an advantage over lower doses for all efficacy endpoints. The combination of NETU and PALO was well tolerated with a similar safety profile to PALO and APR + OND.

Original languageEnglish (US)
Article numbermdu110
Pages (from-to)1340-1346
Number of pages7
JournalAnnals of Oncology
Volume25
Issue number7
DOIs
StatePublished - 2014

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Nausea
Vomiting
Safety
aprepitant
Drug Therapy
Ondansetron
Neurokinin-1 Receptor Antagonists
palonosetron
netupitant
Receptors, Serotonin, 5-HT3
Dexamethasone
Cisplatin
Electrocardiography

Keywords

  • CINV
  • Highly emetogenic
  • NEPA
  • Netupitant
  • Neurokinin-1 receptor antagonist
  • Palonosetron

ASJC Scopus subject areas

  • Oncology
  • Hematology
  • Medicine(all)

Cite this

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. / Hesketh, Paul J.; Rossi, G.; Rizzi, G.; Palmas, M.; Alyasova, A.; Bondarenko, I.; Lisyanskaya, A.; Gralla, Richard J.

In: Annals of Oncology, Vol. 25, No. 7, mdu110, 2014, p. 1340-1346.

Research output: Contribution to journalArticle

Hesketh, Paul J. ; Rossi, G. ; Rizzi, G. ; Palmas, M. ; Alyasova, A. ; Bondarenko, I. ; Lisyanskaya, A. ; Gralla, Richard J. / 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. In: Annals of Oncology. 2014 ; Vol. 25, No. 7. pp. 1340-1346.
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title = "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",
abstract = "Background: NEPA is a novel oral fixed-dose combination of netupitant (NETU), a new highly selective neurokinin-1 (NK1) receptor antagonist (RA) and palonosetron (PALO), a pharmacologically and clinically distinct 5-hydroxytryptamine type 3 (5-HT3) RA. This study was designed to determine the appropriate clinical dose of NETU to combine with PALO for evaluation in the phase 3 NEPA program. Patients and methods: This randomized, double-blind, parallel group study in 694 chemotherapy na{\"i}ve patients undergoing cisplatin-based chemotherapy for solid tumors compared three different oral doses of NETU (100, 200, and 300 mg) + PALO 0.50 mg with oral PALO 0.50 mg, all given on day 1. A standard 3-day aprepitant (APR) + IV ondansetron (OND) 32 mg regimen was included as an exploratory arm. All patients received oral dexamethasone on days 1-4. The primary efficacy endpoint was complete response (CR: no emesis, no rescue medication) during the overall (0-120 h) phase. Results: All NEPA doses showed superior overall CR rates compared with PALO (87.4{\%}, 87.6{\%}, and 89.6{\%} for NEPA100, NEPA200, and NEPA300, respectively versus 76.5{\%}PALO; P < 0.050) with the highest NEPA300 dose studied showing an incremental benefit over lower NEPA doses for all efficacy endpoints. NEPA300 was significantly more effective than PALO and numerically better than APR + OND for all secondary efficacy endpoints of no emesis, no significant nausea, and complete protection (CR plus no significant nausea) rates during the acute (0-24 h), delayed (25-120 h), and overall phases. Adverse events were comparable across groups with no dose response. The percent of patients developing electrocardiogram changes was also comparable. Conclusions: Each NEPA dose provided superior prevention of chemotherapy-induced nausea and vomiting (CINV) compared with PALO following highly emetogenic chemotherapy; however, NEPA300 was the best dose studied, with an advantage over lower doses for all efficacy endpoints. The combination of NETU and PALO was well tolerated with a similar safety profile to PALO and APR + OND.",
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author = "Hesketh, {Paul J.} and G. Rossi and G. Rizzi and M. Palmas and A. Alyasova and I. Bondarenko and A. Lisyanskaya and Gralla, {Richard J.}",
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TY - JOUR

T1 - Efficacy and safety of NEPA, an oral combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy

T2 - A randomized dose-ranging pivotal study

AU - Hesketh, Paul J.

AU - Rossi, G.

AU - Rizzi, G.

AU - Palmas, M.

AU - Alyasova, A.

AU - Bondarenko, I.

AU - Lisyanskaya, A.

AU - Gralla, Richard J.

PY - 2014

Y1 - 2014

N2 - Background: NEPA is a novel oral fixed-dose combination of netupitant (NETU), a new highly selective neurokinin-1 (NK1) receptor antagonist (RA) and palonosetron (PALO), a pharmacologically and clinically distinct 5-hydroxytryptamine type 3 (5-HT3) RA. This study was designed to determine the appropriate clinical dose of NETU to combine with PALO for evaluation in the phase 3 NEPA program. Patients and methods: This randomized, double-blind, parallel group study in 694 chemotherapy naïve patients undergoing cisplatin-based chemotherapy for solid tumors compared three different oral doses of NETU (100, 200, and 300 mg) + PALO 0.50 mg with oral PALO 0.50 mg, all given on day 1. A standard 3-day aprepitant (APR) + IV ondansetron (OND) 32 mg regimen was included as an exploratory arm. All patients received oral dexamethasone on days 1-4. The primary efficacy endpoint was complete response (CR: no emesis, no rescue medication) during the overall (0-120 h) phase. Results: All NEPA doses showed superior overall CR rates compared with PALO (87.4%, 87.6%, and 89.6% for NEPA100, NEPA200, and NEPA300, respectively versus 76.5%PALO; P < 0.050) with the highest NEPA300 dose studied showing an incremental benefit over lower NEPA doses for all efficacy endpoints. NEPA300 was significantly more effective than PALO and numerically better than APR + OND for all secondary efficacy endpoints of no emesis, no significant nausea, and complete protection (CR plus no significant nausea) rates during the acute (0-24 h), delayed (25-120 h), and overall phases. Adverse events were comparable across groups with no dose response. The percent of patients developing electrocardiogram changes was also comparable. Conclusions: Each NEPA dose provided superior prevention of chemotherapy-induced nausea and vomiting (CINV) compared with PALO following highly emetogenic chemotherapy; however, NEPA300 was the best dose studied, with an advantage over lower doses for all efficacy endpoints. The combination of NETU and PALO was well tolerated with a similar safety profile to PALO and APR + OND.

AB - Background: NEPA is a novel oral fixed-dose combination of netupitant (NETU), a new highly selective neurokinin-1 (NK1) receptor antagonist (RA) and palonosetron (PALO), a pharmacologically and clinically distinct 5-hydroxytryptamine type 3 (5-HT3) RA. This study was designed to determine the appropriate clinical dose of NETU to combine with PALO for evaluation in the phase 3 NEPA program. Patients and methods: This randomized, double-blind, parallel group study in 694 chemotherapy naïve patients undergoing cisplatin-based chemotherapy for solid tumors compared three different oral doses of NETU (100, 200, and 300 mg) + PALO 0.50 mg with oral PALO 0.50 mg, all given on day 1. A standard 3-day aprepitant (APR) + IV ondansetron (OND) 32 mg regimen was included as an exploratory arm. All patients received oral dexamethasone on days 1-4. The primary efficacy endpoint was complete response (CR: no emesis, no rescue medication) during the overall (0-120 h) phase. Results: All NEPA doses showed superior overall CR rates compared with PALO (87.4%, 87.6%, and 89.6% for NEPA100, NEPA200, and NEPA300, respectively versus 76.5%PALO; P < 0.050) with the highest NEPA300 dose studied showing an incremental benefit over lower NEPA doses for all efficacy endpoints. NEPA300 was significantly more effective than PALO and numerically better than APR + OND for all secondary efficacy endpoints of no emesis, no significant nausea, and complete protection (CR plus no significant nausea) rates during the acute (0-24 h), delayed (25-120 h), and overall phases. Adverse events were comparable across groups with no dose response. The percent of patients developing electrocardiogram changes was also comparable. Conclusions: Each NEPA dose provided superior prevention of chemotherapy-induced nausea and vomiting (CINV) compared with PALO following highly emetogenic chemotherapy; however, NEPA300 was the best dose studied, with an advantage over lower doses for all efficacy endpoints. The combination of NETU and PALO was well tolerated with a similar safety profile to PALO and APR + OND.

KW - CINV

KW - Highly emetogenic

KW - NEPA

KW - Netupitant

KW - Neurokinin-1 receptor antagonist

KW - Palonosetron

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U2 - 10.1093/annonc/mdu110

DO - 10.1093/annonc/mdu110

M3 - Article

C2 - 24608196

AN - SCOPUS:84903748544

VL - 25

SP - 1340

EP - 1346

JO - Annals of Oncology

JF - Annals of Oncology

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