Hesketh, P.J., Rossi, G., Rizzi, G., Palmas, M., Alyasova, A., Bondarenko, I., ... Gralla, R.J. (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. Annals of Oncology, 25(7), 1340–1346. 

DOI Link

Study Purpose

To determine the best dose of netupitant (NEPA) used in combination with palonosteron for chemotherapy-induced nausea and vomiting (CINV) by evaluating the efficacy and safety of three different doses of netupitant (100 mg, 200 mg, and 300 mg)

Intervention Characteristics/Basic Study Process

Patients were stratified by gender and then randomized to one of five treatment groups.
  • Day 1: Oral PALO 0.50 mg + Oral DEX 20 mg + placebo; Days 2–4: Oral DEX 8 mg bid
  • Day 1: Oral NEPA 100 mg + Oral PALO 0.50 mg + Oral DEX 12 mg; Days 2–4: Oral DEX 4 mg bid
  • Day 1: Oral NEPA 200 mg + Oral PALO 0.50 mg + Oral DEX 12 mg; days 2–4: Oral DEX 4 mg bid
  • Day 1: Oral NEPA 300 mg + Oral PALO 0.50 mg + Oral DEX 12 mg; days 2–4: Oral DEX 4 mg bid
  • Day 1: Oral PR 125 mg + IV OND 32 mg + Oral DEX 12 mg; Days 2–3: Oral APR 80 mg in morning + oral DEX 4 mg bid; Day 4: oral DEX 4 mg bid (exploratory arm)
Rescue medication was permitted although considered a treatment failure. No antiemetic or systemic corticosteroids were allowed in the 72 hours preceding the start of chemotherapy, and patients were excluded if they had any vomiting or more than mild nausea in the 24 hours preceding chemotherapy. Patients could not use any CYP3A4 substrates or inhibitors within the one week prior to therapy or any CYP3A4 inducers four weeks prior to chemotherapy. 

Sample Characteristics

  • N = 677  
  • MEDIAN AGE (of all groups) = 53–55 years
  • MALES: 57%, FEMALES: 43%
  • KEY DISEASE CHARACTERISTICS: All groups were primarily patients with lung disease followed by head and neck and then ovarian cancer.
  • OTHER KEY SAMPLE CHARACTERISTICS: All groups received cisplatin primarily with another emetogenic chemotherapy agent although patients were not eligible if they were due to receive moderately or highly emetogenic chemotherapy on subsequent days. Karnofsky Performance Status Scale scores were primarily 90% among all groups, and the majority of group members reported no alcohol consumption.

Setting

  • SITE: Multi-site    
  • SETTING TYPE: Not specified    
  • LOCATION: 29 sites in Russia, and 15 sites in Ukraine

Phase of Care and Clinical Applications

  • PHASE OF CARE: Active antitumor treatment
  • APPLICATIONS:  Palliative care 

Study Design

Phase 2, multi-center, randomized, double-blind, double-dummy, parallel group

Measurement Instruments/Methods

Efficacy was measured by a patient diary of 120 hours that consisted of emetic episodes (timing and duration), severity of nausea (reported daily on 100 mm on the Visual Analog Scale [VAS]), concomitant medications, and patients' overall satisfaction. The primary efficacy endpoint was reported as complete response (CR, defined as no emesis and no rescue medication) overall. Secondary efficacy endpoints were reported as CR rates during the acute phase (0–24 hours) and during the delayed phase (25–120 hours), no emesis, no significant nausea (VAS < 25 mm), and complete protection (CR + no significant nausea).
 
Safety was measured by adverse events, laboratory evaluations, vital signs, physical exam findings, and ECGs (no information on how these data were gathered or by whom). 

Results

All NEPA groups had statistically better overall and delayed-phase CR rates in comparison to the palonosetron group (NEPA 100 mg = 87.4%, NEPA 200 mg = 87.6%, NEPA 300 mg = 89.6%, PALO alone = 76.5%, p < 0.050). During the acute phase, only the NEPA 300 group had significantly better CR rates than the palonosetron group (p < 0.01). 
 
The NEPA 300 group was statistically better for a complete response than palonosetron alone in the acute (p < 0.01), delayed (p < 0.05), and overall (p < 0.01) phases. It was better for no emesis in the acute, delayed, and overall phases (p < 0.01 for all three) and for no significant nausea in the acute (p < 0.05), delayed (p < 0.01), and overall (p < 0.05) phases. NEPA 300 mg was significantly better than PALO alone for complete protection in the acute (p < 0.01), delayed (p < 0.05), and overall (p < 0.01) phases. 
 
The NEPA 200 group was significantly better than palonosetron alone for complete response in the delayed (p < 0.01) and overall phases (p < 0.05), for no emesis in the delayed (p < 0.01) and overall (p < 0.05) phases, for no significant nausea in the delayed phase (p < 0.05), and for complete protection in the delayed (p < 0.01) and overall (p < 0.05) phases. 
 
The NEPA 100 mg was significantly better than PALO alone for complete response in the delayed and overall phases (p < 0.05 for both) and for no emesis in the delayed and overall phases (p < 0.05 for both). 
 
APR + OND was significantly better than PALO in complete response in the delayed and overall phases (p < 0.05 for both) and in no emesis in the delayed and overall phases (p < 0.05 for both). 
 
There was no significant difference in adverse events among all groups; 15% (n = 106) had at least one adverse event with the most common being hiccups and headache. Changes in 12-lead ECGs were consistent across all treatment groups.  

Conclusions

NEPA is better than palonosetron in treating chemotherapy-induced nausea and vomiting with the 300 mg dosing showing consistently better outcomes than 200 mg and 100 mg dosing with no apparent safety issues. NEPA 300 mg had better outcomes in complete response, no emesis, no significant nausea, and complete protection in the acute, delayed, and overall phases when compared to PALO alone.

Limitations

  • Measurement/methods not well described
  • Other limitations/explanation: Although the efficacy measurements were adequately described, there was a lack of detail regarding how safety was measured. Furthermore, not all of the safety measurements were reported in the results section (missing information about laboratory evaluations, vital signs, and physical exam findings). There were no reports of missing data.

Nursing Implications

At this time, NEPA is not approved by the FDA for use in CINV; however, it shows promising results in alleviating CINV in patients receiving highly emetogenic chemotherapy for cancer treatment. Nurses should be aware that NEPA 300 mg was superior to the NEPA 100 mg and 200 mg dose for alleviating CINV in all phases after chemotherapy.