Netupitant-Palonosetron Combination (NEPA)

STUDY PURPOSE: To identify the best triple drug antiemetic regimen for cisplatin-induced nausea and vomiting

TYPE OF STUDY: Meta-analysis and systematic review

DATABASES USED: Not stated

INCLUSION CRITERIA: All were double-blind randomized controlled trials.

EXCLUSION CRITERIA: Not cisplatin-based therapy, no triple-drug regimen used, non-English language

• FINAL NUMBER STUDIES INCLUDED = 10
• TOTAL PATIENTS INCLUDED IN REVIEW = 7,317
• SAMPLE RANGE ACROSS STUDIES: 174–2,322 patients
• KEY SAMPLE CHARACTERISTICS: All were receiving cisplatin-based chemotherapy.

PHASE OF CARE: Active antitumor treatment

Pairwise meta-analysis was done to rank treatments for effectiveness in terms of complete response (CR) rate. Ranking for best results was: (a) netupitant, palonosetron, and dexamethasone (NEPA); (b) fosaprepitant, ondansetron, and dexamethasone; (c) palonosetron and dexamethasone; (d) fosaprepitant, granisetron, and dexamethasone. However, comparisons did not reach statistical significance. NEPA also ranked highest in percentage of cases with no nausea. The regimen of aprepitant, granisetron, and dexamethasone ranked highest in the side effect of constipation. The regimen of rolapitant, ondansetron, and dexamethasone ranked highest for delayed nausea control and fewest side effects. No significant differences existed across regimens in side effects.

Findings suggest that triple drug regimens, including NEPA, may be most effective in chemotherapy-induced nausea and vomiting (CINV) prevention and the prevention of delayed nausea, though actual differences across all triple drug regimens were not statistically significant.

The authors noted that some evidence reveals that the efficacy of various triple drug regimens may depend upon the tumor type rather than the antiemetic regimen. In general, all triple drug antiemetic regimens are shown to be effective for CINV management, and variation across regimens exists regarding their efficacy for nausea and response in the delayed phase, in particular. Further research is needed to identify comparative effectiveness for various regimens with analysis by tumor type as well as type of chemotherapy. In practice, given potential differences in effect, regimens for individual patients should be planned according to individual patient responses and risks.

To compare the efficacy and safety of netupitant plus palonosetron (NEPA) compared to palonosetron alone in preventing chemotherapy-induced nausea and vomiting (CINV)

Chemotherapy-naïve patients receiving anthracycline- or cyclophosphamide-based chemotherapy were randomized to receive a single dose of PO NEPA (300 mg netupitant plus 0.50 mg palonosetron) and 12 mg dexamethasone or a single dose of 0.5 mg PO palonosetron and 20 mg dexamethasone on day 1, cycle 1, of their chemotherapy. Delayed (25-120 hours post chemotherapy) CINV was evaluated as the primary end point.

• N = 1,455 (participated in a total of 5,969 chemotherapy cycle extension)   
• MEDIAN AGE = 54 years
• MALES: 2%, FEMALES: 98%
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: Solid tumor cancer, 98% with breast cancer
• OTHER KEY SAMPLE CHARACTERISTICS: Aged older than 18 years; chemotherapy-naïve; anthracycline- or cyclophosphamide-based chemotherapy; European Cooperative Oncology Group (ECOG) score of 0, 1, or 2; not receiving prolonged chemotherapy from day 1-5; not receiving abdominal radiotherapy; no bone marrow transplantation; did not received any antiemetics 24 hours before chemotherapy and did not experience anticipatory nausea and vomiting

• SITE: Multi-site   
• SETTING TYPE: Outpatient    
• LOCATION: Multinational

PHASE OF CARE: Active antitumor treatment

Double-blind, randomized

• Diary: Emesis episodes and rescue medications used from 0-120 hour each cycle
• Visual analog scale (VAS) for nausea from 0 (no nausea) to 100 (nausea as bad as it could be)
• Proportion of patients with complete response (0-120 hours)
• Review treatment emergent adverse effects, ECG, troponin levels

Participants who received NEPA and dexamethasone reported complete remission (no emesis or rescue antiemetics) significantly more than participants who received palonosetron and dexamethasone (p ≤ 0.001).

NEPA and dexamethasone may offer more control over CINV compared to palonosetron and dexamethasone.

• Measurement validity/reliability questionable
• Using VAS for nausea and vomiting

Combination antiemetic therapies have been shown to provide more relief from CINV compared to single agents. The results of this study demonstrated that NEPA given with dexamethasone did prevent CINV better than palonosetron and dexamethasone.

To evaluate the safety and efficacy of NEPA (a combination of netupitant plus palonosetron) compared to palonosetron (PALO) alone

During cycle 1 of moderately emetogenic chemotherapy, patients received either a single dose of NEPA (a combination of 300 mg netupitant and 0.50 mg palonosetron) plus 12 mg dexamethasone, or a single dose of 0.50 mg palonosetron (PALO) plus 20 mg dexamethasone. Patients were randomized and stratified by region. Matching placebos were used for blinding in all groups. Metoclopramide tablets were provided for breakthrough, though treating physicians could select another medication. Data were collected daily on days 1–6 after chemotherapy (0–120 hours).

• N = 1449  
• MEDIAN AGE = 54 years
• MALES: 1.9%, FEMALES: 98.1%
• KEY DISEASE CHARACTERISTICS: Primarily breast cancer (97.5%)
• OTHER KEY SAMPLE CHARACTERISTICS: Chemotherapy-naïve patients receiving moderately emetogenic chemotherapy with an ECOG performance status ≤ 2

• SITE: Multi-site    
• SETTING TYPE: Not specified    
• LOCATION: Multinational

PHASE OF CARE: Active antitumor treatment

Phase 3 trial, multicenter, randomized, double-blind, double-dummy, parallel group design

• Patient diary (timing and duration of emetic episode, severity of nausea, rescue medications needed)
• Visual analog scale (VAS) of pain
• The Functional Living Index-Emesis (FLIE) 
• Primary endpoint: Complete response (CR)

A significant number of patients in the NEPA group achieved CR when compared to patients in the PALO group overall (p = 0.001), in the delayed phase of treatment (p = 0.001), and during the acute phase of treatment (p = 0.047).

NEPA, the combination of netupitant and palonosetron, was demonstrated to be safe and more effective than palonosetron alone in producing CR during the acute, delayed, and overall phases of treatment in patients receiving cycle 1 of moderately emetogenic therapy.

• Risk of bias (sample characteristics)
• Other limitations/explanation: More than 98% of the participants in the study were women. Of those, more than 97% were diagnosed with breast cancer.

Chemotherapy-induced nausea and vomiting (CINV) guidelines recommend antiemetic therapies targeting multiple pathways involved in emesis. NEPA, the novel combination of netupitant and palonosetron, uses an NK1 receptor antagonist and a 5-HT3 receptor antagonist to maximize CINV control. NEPA was shown to be more effective than palonosetron alone in producing CR during the acute, delayed, and overall phases of cycle 1 of moderately emetogenic therapy. The majority of this sample, however, were women diagnosed with breast cancer. The findings may not be generalizable to males or to other types of cancer.

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)

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)

• 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.

• 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: Active antitumor treatment

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

• 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.

• 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). 

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)

• 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)

• 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.

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

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

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

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.

• 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.

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.

RESOURCE TYPE: Evidence-based guideline

Not provided

Nothing has been listed regarding the updated antiemetic guidelines and the used databases.

Nurses should know about pharmaceutical antiemetics advancement, assess patients' nausea and vomiting, and discuss the efficacy of the antiemetics with physicians if it is not within the recommended guidelines. Although some differences across guidelines exist, evidence and most guidelines support triplet therapy for HEC. It is unclear in these guidelines why multiday HEC recommendations do not include an NK₁.

PHASE OF CARE: Active antitumor treatment

Three studies were included in the review.

The oral combination of NEPA and dexamethasone is an option for patients receiving highly emetogenic chemotherapy (including anthracycline and cyclophosphamide) to meet recommendations for triple-drug therapy.

• Focused guideline update only to include NEPA
• Studies reviewed did not specifically show that pediatric patients were included.

NEPA is a new drug that can be combined with NK1 and 5HT3 drugs. This drug provides both recommended agents in a single, oral medication. Patients who take NEPA rather than a typical regimen will not need IV administration, which can result in increased cost to the patient depending on individual insurance coverage.

RESOURCE TYPE: Evidence-based guideline

PHASE OF CARE: Multiple phases of care

One hundred seventy-one articles were retrieved via aPubMed search. No information was provided regarding which articles were selected as relevant to these guidelines, and no discussion of any method used for rating the quality of included evidence exists.

Limited database used. Recommendations are a combination of evidence- and consensus-based suggestions, and most nonpharmacologic interventions are by consensus.

Provides multiple evidence- and consensus-based recommendations for prophylaxis and the management of nausea and vomiting due to chemotherapy or radiation therapy. Recommendations provide a list of chemotherapy agents, including oral agents and categorization as to emetic potential.