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Netupitant/Palonosetron (Akynzeo) Gets FDA Nod for Prevention of Chemo-Induced Nausea & Vomiting

First fixed combo targeting two critical pathways in CINV

The FDA has approved netupitant/palonosetron (Akynzeo, Helsinn Group/Eisai Inc.) for the 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.

The drug is the first approved fixed combination oral agent that targets two critical signaling pathways associated with chemotherapy-induced nausea and vomiting (CINV) by combining netupitant, an NK1 receptor antagonist, and palonosetron, a 5-HT3 receptor antagonist, in a single capsule for the prevention of CINV.

The approval of netupitant/palonosetron was based on the submission of phase II and phase III trial data from patients undergoing treatment with moderately and highly emetogenic chemotherapy regimens for a variety of tumor types. The most common adverse events included headache, asthenia, fatigue, dyspepsia, constipation and erythema.

CINV is one of the most common side effects of chemotherapy. Its management has been refined over the past several decades, but despite the existence of effective treatments and clear antiemetic guidelines, many patients still develop CINV, particularly during the delayed phase after chemotherapy.

Studies show that patients often receive antiemetic drug regimens that are inconsistent with CINV treatment guidelines, which call for multiple-pathway targeted antiemetic prophylaxis. The combination of an NK1 receptor antagonist, a 5-HT3 receptor antagonist, and dexamethasone meets guideline recommendations for optimal antiemetic therapy following highly emetogenic chemotherapy.

The efficacy of netupitant/palonosetron was established in a pivotal phase II, randomized, double-blind, dose-ranging study in 694 patients undergoing cisplatin-based chemotherapy for a variety of tumor types. The efficacy of the treatment was assessed in 135 chemotherapy-naive patients who received netupitant 300 mg/palonosetron 0.5 mg and in 136 patients who received oral palonosetron 0.5 mg.

For the key efficacy endpoints of a complete response (CR), defined as no emetic episode and no use of rescue medication; for the delayed phase (25- to 120-hour interval); the acute phase (0- to 24-hour interval), and the overall phase (0 to 120 hours) after the start of chemotherapy administration, netupitant/palonosetron showed significantly higher CRs compared with oral palonosetron in all phases (90.4% vs. 80.1% , respectively [P = 0.032]; 98.5% vs. 89.7% [P = 0.002]; and 89.6% vs. 76.5% [P = 0.003]).

The clinical efficacy profile of netupitant/palonosetron was further established in a multinational, randomized, double-blind, parallel-group, phase III study in 1,455 chemotherapy-naive patients receiving anthracycline and cyclophosphamide-based chemotherapy. The patients were randomly assigned to receive a single oral dose of either netupitant/palonosetron plus dexamethasone or palonosetron plus dexamethasone prior to chemotherapy.

The percentage of patients who met the primary endpoint of a CR in the delayed phase was significantly higher in the netupitant/palonosetron group compared with the oral palonosetron group (76.9% vs. 69.5%, respectively; P = 0.001), which was also seen in the overall (74.3% vs. 66.6%; P = 0.001) and acute (88.4% vs. 85.0%; P = 0.047) phases after chemotherapy.

In a separate study, 309 patients undergoing initial and repeat cycles of chemotherapy (including carboplatin, cisplatin, oxaliplatin, and doxorubicin regimens) received netupitant/palonosetron; efficacy was maintained throughout all cycles.

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