Background: Management of CINV has been refined over the past several decades and CINV can now be managed with targeted prophylactic medications aimed at inhibiting several molecular pathways involved in emesis. NEPA, a fixed-dose combination of netupitant (NETU), a new NK₁ receptor antagonist (RA) and palonosetron (PALO), a pharmacologically distinct 5-HT₃RA, targets these dual antiemetic pathways and has been shown to uniquely work synergistically in vitro. Methods: This was a multinational, randomized, double-blind, parallel group study assessing the efficacy and safety of a single oral dose of NEPA (NETU 300mg + PALO 0.50 mg) versus a single oral 0.50 mg dose of PALO in 1,455 chemotherapy-naive patients (pts) receiving anthracycline-based chemotherapy (all pts received oral dexamethasone (DEX) 12 mg (NEPA) or 20 mg (PALO) on Day 1). The primary efficacy endpoint was complete response (CR: no emesis, no rescue medication) during the delayed (25-120h) phase. Results: Treatment groups had comparable demographic characteristics with the majority of the population being female (98%) and white (80%), with a mean age of 54 yrs; 97% pts had breast cancer. NEPA showed superior CR rates compared to PALO during the delayed, acute, and overall phases. NEPA was also superior to PALO during the delayed/overall phases for complete protection, no emesis, and no significant nausea. Most frequently reported study drug-related adverse events (AEs) for NEPA included headache (3.3%) and constipation (2.1%). The majority of adverse events for NEPA-treated pts were mild/moderate and there were very few (0.7%) severe drug-related AEs. The type and frequency of AEs were comparable between NEPA and PALO. There was no evidence of any cardiac safety concerns for NEPA or PALO. Conclusions: NEPA, a novel single-day fixed-dose combination targeting dual antiemetic pathways, is superior to PALO (both associated with DEX) in preventing CINV in pts receiving MEC. Clinical trial information: NCT01339260.