In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.
On October 10, 2014, oral fixed-combination netupitant and palonosetron (Akynzeo) was approved for use in prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of cancer chemotherapy including, but not limited to, highly emetogenic chemotherapy.1,2 Palonosetron prevents nausea and vomiting during the acute phase and netupitant prevents nausea and vomiting during both the acute and delayed phases after cancer chemotherapy.
Supporting Trials
Approval was based on results of two randomized trials in which the key efficacy endpoints were complete response (no emetic episode and no use of rescue medication) for the delayed phase at 25 to 120 hours, for the acute phase at 0 to 24 hours, and within 120 hours (overall phase) after the start of chemotherapy.
In the first trial,2,3 conducted in patients receiving a chemotherapy regimen including cisplatin (median dose of 75 mg/m2), 135 patients received a single dose of netupitant (300 mg)/palonosetron (0.5 mg) plus dexamethasone (12 mg), and 136 patients received a single dose of palonosetron (0.5 mg) plus dexamethasone (20 mg) prior to the start of chemotherapy. All patients received dexamethasone at 8 mg on days 2 to 4. Complete response was observed in 90.4% vs 80.1% in the delayed phase (P = .032), 98.5% vs 89.7% in the acute phase (P = .002), and 89.6% vs 76.5% in the complete phase (P = .003).
In the second trial,2,4 conducted in patients receiving an anthracycline and cyclophosphamide-based regimen, 724 patients received a single dose of netupitant (300 mg)/palonosetron (0.5 mg) plus dexamethasone (12 mg), and 725 received a single dose of palonosetron (0.5 mg) plus dexamethasone (20 mg). No antiemetic treatment was given on days 2 or 3. Complete response was observed in 76.9% vs 69.5% in the delayed phase (primary endpoint, P = .001), 88.4% vs 85.0% in the acute phase (P = .047), and 74.3% vs 66.6% in the complete phase
(P = .001).
How It Works
Palonosetron (available in single-agent form as Aloxi) is a 5-HT3 receptor antagonist that exhibits strong binding affinity for this receptor and little or no affinity for other receptors. 5-HT3 receptors are located on the nerve terminals of the vagus in the periphery and centrally in the chemoreceptor trigger zone of the area postrema.
Chemotherapeutic agents produce nausea and vomiting by stimulating the release of serotonin from the enterochromaffin cells of the small intestine. Serotonin then activates 5-HT3 receptors located on vagal afferents to initiate the vomiting reflex. Development of acute emesis depends on serotonin, and its 5-HT3 receptors have been shown to selectively stimulate the emetic response.
Netupitant is a selective antagonist of substance P/neurokinin 1 receptors. Delayed emesis is largely associated with substance P activation of tachykinin family neurokinin 1 receptors, distributed in the central and peripheral nervous systems. Netupitant inhibits substance P–mediated responses.
How It Is Given
A capsule of the new product contains 300 mg of netupitant and 0.5 mg of palonosetron. In patients receiving highly emetogenic chemotherapy, including cisplatin-based therapy, the recommended dosage in adults is one capsule given approximately 1 hour prior to the start of chemotherapy with dexamethasone at 12 mg given 30 minutes prior to chemotherapy on day 1 and dexamethasone given once daily on days 2 to 4.
In those receiving anthracycline- and cyclophosphamide-based chemotherapy or other chemotherapy not considered highly emetogenic, the recommended dosage in adults is one capsule approximately 1 hour prior to the start of chemotherapy with dexamethasone at 12 mg given 30 minutes prior to chemotherapy on day 1. Administration of dexamethasone on days 2 to 4 is not necessary.
The palonosetron/netupitant combination should be used with caution in patients receiving CYP3A4 substrates (eg, tacrolimus, imatinib, anastrozole, paclitaxel), since inhibition of CYP3A4 by netupitant can result in increased plasma concentrations of the concomitant drug that can last at least 4 days. Concomitant use with CYP3A4 inducers (eg, carbamazepine, phenobarbital, pioglitazone) should be avoided, since they decrease plasma concentrations of netupitant. Use of the combination should be avoided in patients with severe hepatic impairment and those with severe renal impairment or end-stage renal disease. The safety and efficacy of the combination have not been evaluated in patients aged < 18 years.
Safety Profile
The most common adverse events of any grade with palonosetron/netupitant vs palonosetron in the single cycle of the first trial were dyspepsia (4% vs 2%), fatigue (4% vs 2%), constipation (3% vs 1%), and erythema (3% vs 2%). The most common adverse events in the first cycle of the second trial were headache (9% vs 7%), asthenia (8% vs 7%), and fatigue (7% vs 5%), with similar adverse events occurring during subsequent treatment cycles.
Among all patients, liver function abnormalities consisting of aspartate transaminase (AST) or alanine transaminase (ALT) > 3 times upper limit of normal with total bilirubin > upper limit of normal occurred in 0.3% vs 0.6%, AST or ALT > 10 times upper limit of normal with total bilirubin > upper limit of normal occurred in 0% vs 0.2%, and AST or ALT > 3 times upper limit of normal with total bilirubin ≥ 2 times upper limit of normal occurred in 0.1% vs 0.1%.
Palonosetron/netupitant carries warnings/precautions for hypersensitivity reactions including anaphylaxis, which have been reported in patients receiving palonosetron with or without known hypersensitivity to other 5-HT3 receptor antagonists, and serotonin syndrome, which has been reported with 5-HT3 receptor antagonists alone but particularly with concomitant use of serotonergic drugs. ■
References
1. U.S. Food and Drug Administration: FDA approves Akynzeo for nausea and vomiting associated with cancer chemotherapy. Available at www.fda.gov.
2. AKYNZEO® (netupitant and palonosetron) capsules prescribing information. Eisai, October 2014. Available at www.akynzeo.com.
3. Hesketh PJ, Rossi G, Rizzi G, et al: Efficacy and safety of NEPA, an oral combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy. Ann Oncol 25:1340-1346, 2014.
4. Aapro M, Rugo H, Rossi G, et al: A randomized phase III study evaluating the efficacy and safety of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy. Ann Oncol 25:1328-1333, 2014.
