Superior Efficacy Shown for Novel Fixed-Dose Antiemetic Combination

A novel fixed-dose combination of netupitant and palonosetron, referred to as NEPA, was found to be highly effective in preventing chemotherapy-induced nausea and vomiting in 2 studies presented at the 2013 American Society of Clinical Oncology (ASCO) Annual Meeting.

“NEPA, a fixed-dose combination of netupitant, a new NK1 receptor antagonist, and palonosetron, a 5-HT3 receptor antagonist, targets dual antiemetic pathways and has been shown to uniquely work synergistically in vitro,” said principal investigator Matti S. Aapro, MD, of the Clinique de Genolier in Switzerland.¹

Netupitant is believed to work by blocking the action of substance P, an endogenous neurotransmitter (high concentrations of which are found in the vomiting center of the brain stem) that can stimulate the vomiting reflex. NEPA was developed to improve the convenience of administering guideline-based antiemetic prophylaxis, according to David Ettinger, MD, who reviewed the 2 studies at a poster discussion session.

The optimal dose of NEPA was initially determined in a study led by Paul Hesketh, MD, of the Lahey Hospital & Medical Center in Burlington, Massachusetts.² At ASCO, Aapro presented a late-breaking abstract examining the efficacy of NEPA at a fixed dose of 300 mg, which had proved most effective in the earlier study.

The dose-finding study was a randomized, double-blind comparison of 3 oral doses of NEPA (netupitant 100, 200, or 300 mg plus palonosetron 0.5 mg), compared with palonosetron 0.5 mg alone, in 694 previously untreated patients receiving cisplatin-based, highly emetogenic chemotherapy. The antiemetics were all given on day 1, and all patients received oral dexamethasone on days 1 to 4. An exploratory arm included aprepitant plus ondansetron and dexamethasone. The primary end point was complete response (ie, no emesis and no rescue medication).

“Each NEPA dose resulted in superior complete response rates compared with palonosetron,” Hesketh reported.

Complete responses were observed in 89.6% of patients receiving NEPA at the most effective dose of 300 mg, compared with 76.5% of the palonosetron group (P = .004). The percentage of patients protected from acute emesis was 98.5% with NEPA compared with 89.7% with palonosetron (P = .007). Delayed emesis protection was observed in 90.4% versus 80.1%, respectively (P = .018), and overall complete protection (no emesis, no significant nausea) in 83.0% versus 69.9% (P ≤.05).

Table

Late-Breaking Abstract: NEPA 300 mg in Patients Receiving Anthracyclines

Aapro presented findings from a multinational, randomized, double-blind study assessing the efficacy of a single oral dose of NEPA 300 mg versus palonosetron 0.5 mg in 1455 chemotherapy-naive patients receiving anthracycline-based (moderately emetogenic) chemotherapy; 98% were female and 97% had breast cancer.

In addition to NEPA or palonosetron, dexamethasone was given on day 1 in a dose of 12 mg to patients on the NEPA arm and 20 mg to those receiving palonosetron.

The primary end point of this study was complete response during the delayed phase (ie, 25 to 120 hours post chemotherapy).
“NEPA showed superior complete response rates as compared to palonosetron during the delayed, acute, and overall phases,” Aapro reported (Table). “NEPA was also superior to palonosetron during the delayed/overall phases for complete protection, no emesis, and no significant nausea.”

The most frequently reported study drug–related adverse events for NEPA included headache (3.3%) and constipation (2.1%), the majority being mild to moderate. Severe adverse events were rare (0.7%).

Ettinger, the Alex Grass Professor of Oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, said these were “good studies” that showed NEPA 300 mg to be more efficacious and more convenient than its comparators. He suggested that future studies compare NEPA plus dexamethasone with the guideline-recommended antiemetic regimen of aprepitant/palonosetron/dexamethasone.

References
1. Aapro MS, Rossi G, Rizzi G, et al. Phase III study of NEPA, a fixed-dose combination of netupitant (NETU) and palonosetron (PALO), versus PALO for prevention of chemotherapy-induced nausea and vomiting (CINV) following moderately emetogenic chemotherapy (MEC). J Clin Oncol. 2013;31(suppl):Abstract LBA9514. Presented at: 2013 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2013; Chicago, IL.
2. Hesketh PJ, Rossi G, Rizzi G, et al. Efficacy of NEPA, a novel combination of netupitant (NETU) and palonosetron (PALO), for prevention of chemotherapy-induced nausea and vomiting (CINV) following highly emetogenic chemotherapy (HEC). J Clin Oncol. 2013;31(suppl):Abstract 9512. Presented at: 2013 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2013; Chicago, IL.