NEPA (netupitant and palonosetron)

NEPA is an oral fixed-combination drug containing 300mg netupitant (NETU), an NK₁ receptor antagonist, and 0.50mg palonosetron (PALO), a second-generation 5-HT₃ receptor antagonist that has molecular characteristics different from the first-generation 5-HT₃ receptor antagonist class, which includes ondansetron and granisetron (Rojas and Slusher 2012, Thomas et al 2014, Schilling et al 2020). Netupitant has been shown to have longevity in its effect (half-life of ≈3.75 days) due to its inhibition of substance P (Aapro et al 2014, Thomas et al 2014). PALO has a longer half-life (≈2 days) than the first-generation 5-HT₃ receptor antagonists, inhibits the 5-HT₃ receptor with high affinity binding, and leads to prolonged internalisation of the PALO-5-HT₃ receptor complex into the cell. Therefore, PALO produces long-lasting inhibition of the 5-HT₃ receptor. As a result, NEPA, with its fixed combination of NETU and PALO, provides prevention against acute and delayed CINV, especially during the delayed phase (Zhang et al 2018).

Three pivotal trials of NEPA have demonstrated that one NEPA dose per cycle of chemotherapy plus 12mg dexamethasone before treatment prevented CINV during the acute and delayed phase and was well-tolerated by patients (Aapro et al 2014, Gralla et al 2014, Hesketh et al 2014). Since clinical trials have stringent criteria regarding the patients recruited and are often conducted in specialised settings, it can be difficult to make generalisations from their results (Sherman et al 2016). Therefore, real-world evidence is essential to understand whether the results of rigorously controlled clinical trials are replicated in everyday clinical practice.

In the UK, NEPA is licensed in adults for the prevention of acute and delayed CINV associated with cisplatin-HEC or MEC (Chugai Pharma UK Ltd 2020). However, real-world UK data concerning the effectiveness, acceptability and potential benefits of a single oral dose of NEPA per cycle of chemotherapy among patients receiving HEC or MEC are limited. The authors of this article conducted a service evaluation – an assessment of the current care of patients, without randomisation or allocation to an intervention (Health Research Authority 2017) – in two UK centres to assess patient-reported effectiveness, safety and satisfaction with NEPA in preventing CINV in multiple cycles of chemotherapy (HEC, including anthracycline and cyclophosphamide combination (AC) and cisplatin, or MEC). This article reports data for patients taking NEPA to prevent CINV in up to three cycles of chemotherapy.

Participating centres

Two centres participated in this service evaluation: Southampton General Hospital and Kent and Canterbury Hospital. To be eligible, centres were required to have NEPA on their NHS trust formulary or to have made a decision to add it to their formulary before the start of the service evaluation. Centres were also required to have had NEPA as a treatment option for oncology patients receiving cisplatin-HEC and some MEC regimens and to have decided to make NEPA the standard of care for these regimens before, and independently of, the initial contact regarding their involvement in the service evaluation. The protocol was approved as a service evaluation by each of the NHS trusts and was reviewed by the appropriate personnel at each site, ensuring adherence to all necessary governance standards. A patient information leaflet, developed by Chugai Pharma UK Ltd, was approved for use in both centres.

Patient recruitment

Patients were recruited prior to their first chemotherapy cycle by a consultant nurse, an advanced nurse practitioner or a lead oncology pharmacist. To be eligible, patients had to:

As this was a service evaluation, patients’ treatment had been determined by their healthcare professional prior to their participation and there were no requirements for treatments to be changed. The service evaluation was designed to evaluate patients’ current care without reference to a standard (Health Research Authority 2017).

Patients were excluded if they were pregnant; had received any drugs with potential antiemetic efficacy within 24 hours, or any systemic corticosteroids within 72 hours, of Day 1 of the chemotherapy cycle; and/or had a history of serious cardiovascular disease or a predisposition to cardiac conduction abnormalities (with the exception of incomplete right bundle branch block), a brain tumour or symptomatic brain metastases. Patients were also excluded if they had experienced vomiting, retching or anything more than mild nausea within 24 hours of Day 1 of the first chemotherapy cycle.

All potential patients were given a patient information leaflet before recruitment to help them decide whether to participate in the service evaluation. The leaflet explained the purpose of the service evaluation, what data would be collected via a web-based app designed for the evaluation, how personal data would be collected and anonymised (all data entered in the online diaries were encrypted, so no personal information was visible in the data outputs), how to complete the daily online diary and how to report side effects of NEPA. The leaflet also included the contact details of the patient’s nurse or pharmacist if they needed to ask questions about how to complete the online diary.

Patient registration

Chugai Pharma UK Ltd developed a web-based app to facilitate consent, recruitment, documentation of baseline characteristics and data collection. Patients provided informed consent at the time of recruitment, which was captured by the recruiting healthcare professional by checking a tick box within the app in the presence of the patient.

Once consent had been obtained and captured, the recruiting healthcare professional recorded baseline characteristics including gender, cancer diagnosis and/or tumour type and stage, performance status (Oken et al 1982), previous chemotherapy exposure, previous antiemetic treatments and scheduled chemotherapy regimen. Baseline characteristics also included whether the patient had any of the following risk factors for CINV: <55 years of age, history of nausea and vomiting (including during pregnancy), history of motion sickness and low alcohol intake (<14 units of alcohol per week).

As part of the registration process, the recruiting healthcare professional asked the patient whether they had experienced nausea and/or vomiting (yes/no) in the preceding 24 hours. Based on their clinical judgement and using version 4 of the Common Terminology Criteria for Adverse Events grades (National Cancer Institute 2009), the healthcare professional then recorded the patient’s baseline levels of nausea and vomiting. If a patient had experienced anything more than mild nausea and/or vomiting in the preceding 24 hours, they were not eligible for inclusion.

Completion of online diary

Patients were asked to use the app to complete a daily online diary from Day 1 to the morning of Day 5 of each cycle of chemotherapy. At 10am on Days 1-5 of each cycle, patients received an automated daily reminder to complete the diary in the form of a text message. Diary entries were reviewed by the patient with their nurse or pharmacist at the next chemotherapy appointment, any data gaps were discussed and entries were completed if necessary. This article reports data from diaries kept by patients for up to three cycles of chemotherapy.

Effectiveness, safety and satisfaction measures

To assess the effectiveness of NEPA in preventing CINV, patients were asked, on Days 1-5 of each cycle, to:

‘No significant nausea’ was defined as a patient-rated degree of nausea <3. This is consistent with the measurements in the three pivotal trials of NEPA mentioned above, which used a visual analogue scale that ranged from 0mm to 100mm (Aapro et al 2014, Gralla et al 2014, Hesketh et al 2014). The proportion of patients reporting nausea was calculated among patients with and without risk factors for CINV, who had completed one cycle of chemotherapy.

Patients were asked to report any adverse events they experienced as soon as they occurred (yes/no; and if yes, patients could provide more detail in a free-text box). When an adverse event was reported via the app, an automated text message was immediately sent to the nurse or pharmacist to prompt them to review the adverse event. At the next chemotherapy visit, the nurse or pharmacist ensured that the adverse event had been correctly reported by the patient and confirmed, based on their clinical judgement, whether the adverse event was related to NEPA and not to chemotherapy. All adverse events were reported to Chugai Pharma UK Ltd’s pharmacovigilance department within 24 hours of the healthcare professional becoming aware of them.

To evaluate patients’ satisfaction with the effectiveness and convenience of NEPA, the diary included the questions from the Treatment Satisfaction Questionnaire for Medication (Atkinson et al 2005) on Day 5 of each cycle. This gave patients the option to rate their satisfaction on a seven-point Likert scale as ‘extremely dissatisfied’, ‘very dissatisfied’, ‘dissatisfied’, ‘somewhat satisfied’, ‘satisfied’, ‘very satisfied’ or ‘extremely satisfied’.

Baseline patient characteristics

Between 5 March 2018 and 11 February 2019, 37 patients were recruited to take part in the service evaluation and registered on the app. Among those 37 patients:

Baseline patient characteristics are summarised in Table 1. Among the recruited patients, almost three quarters were female; the most common tumour types were breast and lung tumours; there were high levels of functioning (performance status of 0 or 1); and the most common risk factors for CINV were low alcohol intake, being <55 years of age and having a history of nausea and vomiting (including during pregnancy). Previously used antiemetic drugs were metoclopramide hydrochloride (n=2), ondansetron (n=3), cyclizine (n=1), aprepitant (n=1) and domperidone (n=1).

Number of diary entries and reasons for withdrawal

Thirty-one (83.8%) of the 37 recruited patients received oral NEPA and at least one cycle of their scheduled chemotherapy. Among these 37 patients, 24 (64.9%) provided a complete online diary (five days of diary entries) after receiving their first cycle of chemotherapy (Cycle 1); 14 (37.8%) provided a complete online diary of their second cycle (Cycle 2); 7 (18.9%) provided a complete online diary after receiving their third cycle (Cycle 3). In total, 238 daily diary entries were recorded from 60 chemotherapy cycles.

Reasons for withdrawal from the service evaluation included general non-compliance with the diary entry (n=8, 21.6% of recruited patients) and treatment change and/or discontinuation (n=16, 43.2% of recruited patients). General non-compliance included difficulties accessing or using the app. Treatment change and/or discontinuation included patients who received rescue medication (antiemetics other than NEPA) or changed and/or discontinued their chemotherapy treatment.

Patient-reported effectiveness

All patients had ‘no significant nausea’ (nausea <grade 3) at baseline, as rated by the recruiting healthcare professional using the Common Terminology Criteria for Adverse Events grades. Figure 2 shows daily patient reports of the degree of nausea experienced. In all three cycles of chemotherapy, substantial proportions of patients experienced ‘no nausea’ (nausea score = 0) across all five days of each cycle.

Figure 1.

Patient disposition flow chart

Figure 2.

Daily patient reports of the degree of nausea experienced*

Figure 3 shows daily patient reports of ‘no significant nausea’ (nausea score <3) and ‘no vomiting’ (0 episodes of vomiting reported). Across all five days of the three cycles, the vast majority of patients reported ‘no significant nausea’ (89.1%) and ‘no vomiting’ (97.1%). In Cycles 1 and 2, the proportions of patients reporting ‘no significant nausea’ and ‘no vomiting’ tended to be higher during the delayed phase (Days 2-5). In Cycle 3, all patients reported ‘no significant nausea’ and ‘no vomiting’.

Figure 3.

Daily patient reports of ‘no significant nausea’ and ‘no vomiting’*

Table 2 shows the proportion of patients with and without significant nausea among those with and without risk factors for CINV (<55 years, low alcohol intake, history of motion sickness, and history of nausea and vomiting) who completed Cycle 1. The majority of patients with a history of nausea and vomiting experienced significant nausea (nausea score ≥3) in Cycle 1.

Table 2.

Nausea among patients with and without risk factors for chemotherapy-induced nausea and vomiting who completed Cycle 1 (n=24)

Patient-reported adverse events

Nine out of the 31 treated patients (29.0%) reported at least one adverse event in 39 diary entries. The most commonly reported adverse events were:

Two (6.5%) of the treated patients reported more than one episode of vomiting within one day and were hospitalised, one of whom had low sodium levels that were deemed to be related to chemotherapy by the clinical team.

Patient-reported satisfaction

In total, 46 responses to the Treatment Satisfaction Questionnaire for Medication were provided. Almost all patients were ‘satisfied’, ‘very satisfied’ or ‘extremely satisfied’ with:

Throughout the service evaluation, few patients were ‘dissatisfied’ or ‘somewhat satisfied’ with the ability of NEPA to prevent CINV (n=2) or with the way NEPA relieved symptoms (n=3). However, these patients reported no episodes of vomiting throughout the service evaluation and only one of them reported experiencing significant nausea (nausea score ≥3) more than once.

No patients replied that they were ‘extremely dissatisfied’ or ‘very dissatisfied’ in response to any of the questions in the Treatment Satisfaction Questionnaire for Medication.

Limitations

One limitation of this service evaluation was the small sample of patients throughout the cycles, which should be considered when interpreting these data. The number of patients who did not comply with diary completion was another limitation. The overall attrition limits the extrapolation of the results to other patient groups and the data should be interpreted with caution.

Using self-reporting of adverse events is appropriate for a real-world service evaluation, since subjective symptoms such as pain and nausea may be best described by the patient. However, these data should only be considered in the real-world context and cannot be directly compared with the rigorously defined adverse events reported in clinical trials.