Advice

Key points from the evidence

Key points from the evidence

The content of this evidence summary was up-to-date in March 2016. See summaries of product characteristics (SPCs), British national formulary (BNF) or the MHRA or NICE websites for up-to-date information.

Summary

Netupitant/palonosetron shows statistically significant benefits compared with palonosetron alone (both in combination with dexamethasone) in people receiving emetogenic chemotherapy, mainly in the prevention of delayed nausea and vomiting. There are limited data comparing netupitant/palonosetron with other neurokinin‑1 receptor antagonists (such as, aprepitant) and 5‑HT3 receptor antagonists (such as ondansetron or granisetron) given in combination. Netupitant/palonosetron capsules are given as a single dose prior to each chemotherapy cycle.

Regulatory status: Netupitant/palonosetron capsules (Akynzeo) received a UK marketing authorisation in May 2015 and were launched in the UK in September 2015.

Effectiveness

  • During the delayed phase of the first cycle of an anthracycline plus cyclophosphamide chemotherapy regimen, statistically significantly more participants taking netupitant/palonosetron 300 mg/500 microgram had a complete response (no emesis and no rescue medication) and no significant nausea compared with palonosetron 500 microgram (complete response: 76.9% compared with 69.5%; and no significant nausea: 76.9% compared with 71.3% respectively) [1 RCT; n=1455].

  • During the overall phase of the first cycle of a cisplatin‑based chemotherapy regimen, statistically significantly more participants taking netupitant/palonosetron 300 mg/500 microgram had a complete response (no emesis and no rescue medication) compared with palonosetron 500 microgram (89.6% compared with 76.5%) [1 RCT; dose ranging study n=694 in total; n=135 and n=136 for the netupitant/palonosetron 300 mg/500 microgram and palonosetron groups respectively].

Safety

  • The European public assessment report (EPAR) concluded that netupitant/palonosetron was well tolerated with many adverse reactions likely to be associated with either the underlying condition or associated cytotoxic treatments.

  • Netupitant/palonosetron is contraindicated in pregnancy. Severe constipation and complications due to constipation may also occur (summary of product characteristics [SPC]). In‑line with the other 5‑HT3 receptor antagonists the SPC also includes warnings and precautions on the risk of serotonin syndrome and QT prolongation.

  • The SPC lists headache, constipation and fatigue as common adverse reactions (occurring in 1 in 100 or more to less than 1 in 10 people).

Patient factors

  • Netupitant/palonosetron capsules are given as a single dose prior to each chemotherapy cycle. This may simplify the treatment regimen and be preferable for some people.

Resource implications

  • Netupitant/palonosetron costs £69.00 for each chemotherapy cycle.

  • Costs for other 5‑HT3 receptor antagonist and neurokinin‑1 receptor antagonist treatment regimens range from approximately £48 to £103 for each chemotherapy cycle.

Introduction and current guidance

Chemotherapy regimens vary in the extent to which they cause nausea and vomiting, usually classed as having a minimal, low, moderate or high degree of emetogenicity. People can also vary in their susceptibility to drug‑induced nausea and vomiting; those affected more often include women, people under 50 years of age, people with anxiety and those who have motion sickness. Guidelines including the Multinational Association for Supportive Care in Cancer (MASCC) and the European Society of Medical Oncology (ESMO) antiemetic guidelines recommend regimens including both a 5‑HT3 receptor antagonist and a neurokinin‑1 receptor antagonist for the prevention of nausea and vomiting in people receiving highly emetogenic or anthracycline plus cyclophosphamide based chemotherapy regimens.

Full text of introduction and current guidance.

Product overview

Akynzeo capsules contain 300 mg netupitant (a neurokinin‑1 receptor antagonist) and 500 micrograms palonosetron (a 5‑HT3 receptor antagonist). Netupitant/palonosetron (Akynzeo) is licensed in adults for the prevention of acute and delayed nausea and vomiting associated with highly emetogenic cisplatin‑based cancer chemotherapy or moderately emetogenic cancer chemotherapy. The dose recommended in the SPC is one netupitant/palonosetron 300 mg/500 microgram capsule to be taken approximately 1 hour before the start of each chemotherapy cycle.

Full text of product overview.

Evidence review

This evidence summary discusses the best available evidence on the safety and efficacy of netupitant/palonosetron. This is a phase 3 RCT comparing netupitant/palonosetron with palonosetron in 1455 adults (the majority were women with breast cancer) having anthracycline plus cyclophosphamide based chemotherapy (Aapro et al. 2014) and a phase 3 RCT that assessed the safety of netupitant/palonosetron in 308 people having moderately or highly emetogenic chemotherapy (Gralla et al. 2014). The study programme also included a phase 2 dose‑ranging study comparing 3 different doses of netupitant/palonosetron with palonosetron in people having highly emetogenic cisplatin‑based chemotherapy (Hesketh et al. 2014).

  • In Aapro et al. (2014), participants were randomised to receive either netupitant/palonosetron 300 mg/500 microgram or palonosetron 500 microgram (both given in combination with dexamethasone) given on the day of the first cycle of chemotherapy. The primary outcome was complete response (defined as no emesis and no rescue medication) during the delayed phase of cycle 1 (25 to 120 hours after chemotherapy). Statistically significantly more participants in the netupitant/palonosetron group achieved this outcome compared with the palonosetron group (76.9% [557/724] compared with 69.5% [504/725]; odds ratio [OR] 1.48, 95% confidence interval [CI] 1.16 to 1.87, p=0.001). Statistically significantly more participants in the netupitant/palonosetron group also had a complete response during the acute phase of cycle 1 (0 to 24 hours after chemotherapy) compared with the palonosetron group, although the difference was small (88.4% [640/724] compared with 85.0% [616/725]; OR 1.37, 95% CI 1.00 to 1.84, p=0.047). More participants in the netupitant/palonosetron group had no significant nausea (defined as a score of less than 25 mm on a visual analogue scale from 0 mm [no nausea] to 100 mm ['nausea as bad as it could be']) during the delayed phase of cycle 1 compared with the palonosetron group (76.9% compared with 71.3%, p=0.014). However for the acute phase there was no statistically significant difference between the 2 groups for this outcome (87.3% compared with 87.9%, p=0.74).

  • In Hesketh et al. (2014), statistically significantly more people achieved the primary outcome of complete response during the overall phase (0 to 120 hours after chemotherapy) of cycle 1 with netupitant/palonosetron 300 mg/500 microgram compared with palonosetron 500 microgram (89.6% [121/135] compared with 76.5% [104/136]; p=0.004).

  • In both Aapro et al. (2014) and Hesketh et al. (2014) netupitant/palonosetron was compared with palonosetron. There are no data from a published RCT with a predefined analysis comparing netupitant/palonosetron with other 5‑HT3 receptor antagonists and neurokinin‑1 receptor antagonists given in combination.

  • The EPAR for netupitant/palonosetron capsules states that a total of 1538 people received netupitant/palonosetron at the licensed dose during the clinical study programme, with 1169 people with cancer having at least 1 dose while participating in a phase 2 or 3 study and 317 people having 6 or more cycles of treatment. Overall, the EPAR concluded that netupitant/palonosetron was well tolerated with many adverse reactions likely to be associated with either the underlying condition or associated cytotoxic treatments. Similarly serious adverse events and deaths reflect the patient population and current treatment. In Aapro et al. (2014) and Gralla et al. (2014) the most common treatment-related adverse events were constipation, dyspepsia, eructation and headache.

  • As stated in the EPAR cases of severe constipation and complications due to constipation were seen during the clinical trial programme and information on this has been included in the SPC. In‑line with the other 5‑HT3 receptor antagonists the SPC also includes warnings and precautions on the risk of serotonin syndrome and QT prolongation. Netupitant/palonosetron is contraindicated in pregnancy (animal studies of netupitant have shown reproductive and teratogenic toxicity). Netupitant is a moderate inhibitor of CYP3A4, therefore the SPC includes information on potential interactions. See the SPC for further information on contraindications, warnings and precautions, potential interactions and adverse effects of netupitant/palonosetron.

Full text of evidence review.

Context

Netupitant/palonosetron capsules (Akynzeo) are the first combination preparation to contain both a 5‑HT3 receptor antagonist and a neurokinin‑1 receptor antagonist. Palonosetron is already available in oral and injectable formulations. Two other 5‑HT3 receptor antagonists are also available in the UK: ondansetron (available in oral, injectable and rectal formulations) and granisetron (available in oral, injectable and transdermal formulations). Two neurokinin‑1 receptor antagonists are available in the UK: aprepitant capsules and intravenous fosaprepitant (a pro‑drug of aprepitant) [see summaries of product characteristics].

Full text of context.

Estimated impact for the NHS

Guidelines such as the MASCC/ESMO antiemetic guidelines (2010) recommend regimens including both a 5‑HT3 receptor antagonist and a neurokinin‑1 receptor antagonist for the prevention of nausea and vomiting in people receiving highly emetogenic or anthracycline plus cyclophosphamide based chemotherapy regimens. Netupitant/palonosetron capsules are given as a single dose prior to each chemotherapy cycle, which may simplify the treatment regimen and be preferable to some people.

Netupitant/palonosetron costs £69.00 for each chemotherapy cycle. Costs for other 5‑HT3 receptor antagonist and neurokinin-1 receptor antagonist treatment regimens range from approximately £48 to £103 for each chemotherapy cycle. Example costs provided here do not include the cost of dexamethasone.

Full text of estimated impact for the NHS.

About this evidence summary

'Evidence summaries: new medicines' provide summaries of key evidence for selected new medicines, or for existing medicines with new indications or formulations, that are considered to be of significance to the NHS. The strengths and weaknesses of the relevant evidence are critically reviewed within this summary to provide useful information for those working on the managed entry of new medicines for the NHS, but this summary is not NICE guidance.