ONE DOSE ANTIEMETIC REGIMEN

A single dose of a novel oral fixed-dose drug combination has been shown to reliably prevent nausea and vomiting in most cancer patients undergoing chemotherapy.

The product, dubbed NEPA, is a combination of the tachykinin NK₁ receptor antagonist netupitant 300 mg and the 5-hydroxytryptamine 3 receptor antagonist palonosetron 0.5 mg. These 2 drugs target what are believed to be critical signaling pathways associated with chemotherapy-induced nausea and vomiting (CINV).

NEPA, under development by Helsinn/Eisai, is currently awaiting approval. It has been under review by the US Food and Drug Administration since December 9, 2013 and by the European Medicines Agency since January 22, 2014.

Results from a series of clinical trials show that the efficacy of NEPA is equal to or better than current standard approaches. NEPA was effective over repeated cycles of use and with moderately emetogenic or highly emetogenic cancer drug combinations, and was associated with only mild adverse effects.

The results were published in the July 7 issue of the Annals of Oncology, and were presented in June at the Multinational Association of Supportive Care in Cancer (MASCC) annual meeting.

The randomized phase 3 study by Matti Aapro, MD, from the Institut Multidisciplinaire d'Oncologie in Genolier, Switzerland, and colleagues compared a single dose of NEPA with a single oral dose of palonosetron in 1455 chemotherapy-naïve patients with malignant solid tumors (97% breast cancer) receiving moderately emetogenic chemotherapy (anthracycline and cyclophosphamide). Patients in both groups also received dexamethasone. The primary end point was complete response (no emesis and no need for rescue medication) in the 25 to 120 hours after chemotherapy (the delayed phase).

During the delayed phase, complete response was better with NEPA than with palonosetron (76.9% vs 69.5%; P = .001). During the acute phase (0 to 24 hours after chemotherapy), NEPA was more effective overall.

More patients in the NEPA group than in the palonosetron group reported no significant nausea (74.6% vs 69.1%; P = .20).

"A single day 1 dose of NEPA along with dexamethasone only on day 1 seems suitable for prevention of CINV through the 5 days after chemotherapy." Dr. Aapro and colleagues conclude.

"As a combination agent targeting dual antiemetic pathways, a single dose of NEPA plus dexamethasone offers convenient guideline-based prophylaxis. This provides an opportunity to overcome barriers interfering with guideline adherence and in doing so offers promise for improving control of CINV for patients," they add.

Data from the multicycle extension study Dr. Aapro presented at the MASCC meeting showed that repeating NEPA continued to be effective for at least 4 cycles of moderately emetogenic chemotherapy.

The phase 3 study by Richard J. Gralla, MD, from the Albert Einstein College of Medicine in Bronx, New York, and colleagues compared NEPA plus dexamethasone with an oral 3-day regimen of aprepitant, palonosetron, plus dexamethasone for the prevention of CINV over repeated cycles of chemotherapy in 413 patients. The researchers report that 76% of patients were receiving moderately emetogenic chemotherapy and 24% were receiving highly emetogenic chemotherapy. Three-quarters of the patients completed at least 4 cycles of chemotherapy.

Complete response rates were better with NEPA than with the aprepitant regimen for cycle 4 (90% vs. 88%) and cycle 6 (91% vs 86%).

"Although the differences were small, the numerically better control in the NEPA group compared with aprepitant and palonosetron is important in the development of a new antiemetic agent, demonstrating that there is no suggestion of loss of efficacy in exchange for a regimen of potentially greater convenience," Dr. Gralla and colleagues write. "Further studies should be carried out to determine whether the highly convenient concept of NEPA will result in greater adherence, fostering improved emetic control."

In the phase 2 randomized dose-ranging study by Paul J. Hesketh, MD, from Lahey Hospital & Medical Center in Burlington, Massachusetts, and colleagues, which involved 694 patients receiving highly emetogenic cisplatin-based chemotherapy for solid tumors, NEPA combinations containing 100 mg, 200 mg, or 300 mg of netupitant each provided superior prevention of CINV than a single dose of palonosetron. The combination regimen with 300 mg of netupitant was the most effective and was selected for the phase 3 studies.

An analysis of efficacy data from several trials, which Dr. Hesketh presented at the MASCC meeting, demonstrated that NEPA was effective at preventing CINV regardless of what type of additional therapy was added to cisplatin; in contrast, the efficacy of aprepitant, ondansetron, and dexamethasone was reduced when anthracyclines and/or cyclophosphamide were added to cisplatin.

In an accompanying editorial, Paul L.R. Andrews, PhD, Emeritus Professor of Comparative Physiology at St. George's University of London in the United Kingdom, says that "the NEPA formulation appears to be an advance in terms of overall efficacy and simplicity of dosing regimen with the maintenance of efficacy over multiple cycles of chemotherapy being particularly encouraging."

His research is focused on the preclinical neuropharmacology of vomiting and nausea, particularly as an adverse effect of cancer chemotherapy.

"I am not a clinician, so I would prefer not to comment on the potential clinical positioning of NEPA," he told Medscape Medical News.

All studies were supported by Helsinn Healthcare SA. Several coauthors on each study have financial relationships with Helsinn Healthcare and/or Eisai, or with other pharmaceutical companies, as detailed in the publications. Dr. Andrews has disclosed no relevant financial relationships.

Ann Oncol. 2014;25:1258-1259, 1328-1333, 1333-1339, 1340-1346. Editorial, Aapro abstract, Gralla abstract, Hesketh abstract