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

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. This randomized, double-blind, parallel group study in 694 chemotherapy na < 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. All NEPA doses showed superior overall CR rates compared with PALO (87.4%, 87.6%, and 89.6% for NEPA(100), NEPA(200), and NEPA(300), respectively versus 76.5% PALO; P < 0.050) with the highest NEPA(300) dose studied showing an incremental benefit over lower NEPA doses for all efficacy endpoints. NEPA(300) 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. Each NEPA dose provided superior prevention of chemotherapy-induced nausea and vomiting (CINV) compared with PALO following highly emetogenic chemotherapy; however, NEPA(300) 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.