Regulatory Decision Summary for Akynzeo

The results of the two pivotal clinical studies filed in support of this submission demonstrated the superiority of the Akynzeo (300 mg netupitant / 0.5 mg palonosetron) over 0.5 mg palonosetron alone in the prevention of acute (0 to 24 hours) and delayed (24 to 120 hours) nausea and vomiting associated with highly emetogenic cancer chemotherapy. Briefly, statistical superiority of the netupitant and palonosetron combination was observed in the complete response rate (primary endpoint), defined as patients with no emetic episodes and no use of rescue medication. Cancer patients were chemotherapy naïve patients and received either highly emetogenic regimens, i.e., cisplatin regimen (Study 1) or a combination of anthracyclines and cyclophosphamide regimen (Study 2). It is noteworthy that previously, the anthracycline and cyclophosphamide regimen was considered moderately emetogenic.

While differences are expected between study 1 and 2, considering the difference in study design and patient populations in these trials, the data from study 2 supported a trend of decreased additional efficacy (over palonosetron alone) with decreasing emetogenicity of the chemotherapy regimen (it is recognized that an anthracyclines and cyclophosphamide regimen is not as emetogenic as a cisplatin-based one). Since almost all patients in Study 2 were females, known to be more prone to chemotherapy-induced nausea and vomiting, there remains some uncertainty regarding the superiority of Akynzeo over the use of palonosetron alone in male patients when exposed to these chemotherapies.

The efficacy of the palonosetron component of Akynzeo in the prevention of acute nausea and vomiting associated with moderate emetogenic chemotherapy has previously been established. There is, however, uncertainty in terms of establishing a clear benefit to the inclusion of netupitant, a neurokinin-1 receptor antagonist, in the prevention of delayed nausea with moderate emetogenic chemotherapy, particularly those in mid to lower end of the emetogenicity scale. In accordance with a number of Canadian practice guidelines, the indication for the prevention of acute nausea and vomiting associated with moderately emetogenic cancer therapy was limited to cancer patients whose nausea and vomiting were previously uncontrolled with the use of a 5-HT3 receptor antagonist (including palonosetron) alone.

Clinical studies also demonstrated that Akynzeo has an acceptable safety profile. The frequencies of patients reporting adverse reactions were similar across the netupitant and palonosetron combination groups and palonosetron alone groups. Many of the reported adverse reactions were likely associated with either the underlying condition or associated cytotoxic therapies. To further mitigate the risk to special populations, Akynzeo is contraindicated during pregnancy, and women of childbearing potential must use effective contraception therapy and up to one month after use. In addition, the Product Monograph includes serious warnings of possible drug interactions that may occur with other medicinal products that are substrates of CYP3A4 liver enzymes.

Besides the advantage of this fixed-dose combination over the use of a 5-HT3 receptor antagonist alone, decreasing the number of individual dose units to be taken by the patient may simplify therapy and improve patient compliance.

In conclusion, the benefit/risk profile of Akynzeo was considered acceptable with respect to the safety and efficacy data reviewed.