Gralla, R., Bosnjak, S., Hontsa, A., Balser, C., Rizzi, G., Rossi, G., ... Jordan, K. (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 over repeated cycles of chemotherapy. Annals of Oncology, 25(7), 1333–1339.  

DOI Link

Study Purpose

To assess the safety and evaluate the efficacy of ​a fixed-dose combination of netupitant and palonosetron (NEPA) over multiple cycles of highly emetogenic chemotherapy (HEC) and moderately emetogenic chemotherapy (MEC)

Intervention Characteristics/Basic Study Process

Oral NEPA (​netupitant [NETU] 300 mg + palonosetron [PALO] 0.50 mg) + dexamethasone (DEX) versus oral aprepitant (APR) (125 mg Day 1; 80 mg Days 2–3) + oral PALO 0.50 mg Day 1 + DEX (for HEC, DEX Days 1–4; for MEC, DEX Day 1 only)

Sample Characteristics

  • N = 412  
  • AVERAGE AGE = 58 years 
  • MALES: 50%, FEMALES: 50%
  • KEY DISEASE CHARACTERISTICS: Eligible patients were ≥ 18 years, diagnosed with a malignant tumor, naïve to chemotherapy, and scheduled to receive repeated, consecutive courses of chemotherapy (HEC/MEC). A single intravenous (IV) dose of one or more of the intervention versus control agents was administered on Day 1. Single-day chemotherapy was necessary for inclusion. ECOG ≤ 2.
  • OTHER KEY SAMPLE CHARACTERISTICS: Non-AC chemotherapy, no previous NK1RA use, no CYP3A4 inducer use within four weeks, no bone marrow transplant or stem cell rescue therapy, no known hypersensitivity of or contradiction to 5-HT3RA or dexamethasone.

Setting

  • SITE: Multi-site    
  • SETTING TYPE: Outpatient    
  • LOCATION: Multinational including Bulgaria, Czech Republic, Germany, Hungary, India, Poland, Russia, Serbia, Ukraine, and the United States

Phase of Care and Clinical Applications

  • PHASE OF CARE: Active antitumor treatment

Study Design

Phase 3 multinational, double-blind, double-dummy, parallel group study design

Measurement Instruments/Methods

  • Safety: Treatment-emergent adverse events (TEAEs), labs, physical exams, vital signs, ECGs, cardiac troponin I (cTnl), and left ventricular ejection fraction (LVEF)
  • Efficacy: Diary (Days 1–6) recorded the onset and duration of emetic episodes and nausea severity (Visual Analog Score [VAS] 0–100). They also recorded the achievement of complete response (CR, no emesis, no rescue medication) or no significant nausea (VAS score of < 25 mm) during the acute (0–24 hour), delayed (25–120 hour), and overall (0–120 hour) phases after the start of chemotherapy.

Results

Overall CR rates in cycle 1 were 81% for NEPA and 76% for APR + PALO, and antiemetic efficacy was maintained over repeated cycles (with NEPA showing a consistent numerical advantage over APR + PALO; 2%–7%). The NEPA group demonstrated similar CR with HEC and MEC, whereas the APR + PALO group showed lower CR in HEC than MEC. Proportions of patients with no significant nausea were high and similar (with NEPA showing an advantage over APR + PALO).
 
The majority of TEAEs were of mild to moderate intensity; 25.0% (NEPA) and 32.7% (APR + PALO) experienced severe TEAEs. There was no indication of increasing adverse events over multiple cycles. The proportion of patients experiencing adverse events that were considered study drug-related was 10.1% for NEPA and 5.8% for APR + PALO. The most frequent adverse events for NEPA were constipation (3.6%) and headache (1.0%). Two serious TEAEs related to NEPA were ventricular systoles and acute psychosis (possibly related to DEX). There were no cardiac safety concerns based on adverse events and ECGs. 

Conclusions

NEPA, a convenient, single oral-dose antiemetic targeting dual pathways, was safe, well tolerated, and highly effective over multiple cycles of HEC and MEC.

Limitations

  • Baseline sample/group differences of import
  • Subject withdrawals ≥ 10%  
  • Other limitations/explanation: Patients participated in up to six cycles (98% completed one cycle, 75% completed four cycles, and 40% completed six cycles). 

Nursing Implications

NEPA could be used as a safe alternative for guideline-recommended antiemetic regimens (APR + PALO).
 
As the CR rates in the NEPA group were similar in HEC and MEC, the benefits of NEPA in both types of chemotherapy regimens were supported. Constipation and headache need to be considered as possible adverse events for patients receiving NEPA, and interventions need to be provided. Ventricular systoles and acute psychosis need to be understood as possible serious adverse events related to NEPA use.