No Evidence Of Increased Cyclophosphamide Toxicity Associated With The Antiemetic Agent NEPA, a Fixed-Dose Combination Of Netupitant and Palonosetron
Authors: Schwartzberg Lee , Oprean Cristina , Cardona-Huerta Servando , Rizzi Giada , Rossi Giorgia , Palmas Marco , Karthaus Meinolf , Aapro Matti 
Published: October 2019

Abstract

Background
Cyclophosphamide (CTX), a commonly used alkylating agent in the treatment of hematological malignancies and solid tumor diseases, is a prodrug metabolized to its active metabolite primarily via CYP2B6 with minor contribution of CYP3A4. CTX is also converted to neurotoxic and inactive metabolites mainly via CYP3A4. NEPA is a unique fixed-dose antiemetic combination of netupitant (NETU), a highly-selective NK1 receptor antagonist (RA) and palonosetron (PALO), a pharmacologically distinct 5-HT3 RA. Superiority of NEPA over PALO in preventing chemotherapy-induced nausea and vomiting was recently demonstrated in solid tumors. Although no significant drug-drug interactions between NETU, a moderate CYP3A4 inhibitor, and CTX are expected, NEPA has the potential to impact CTX metabolism and CTX-related toxicities.

Methods
This multinational, randomized, double-blind, parallel group study evaluated the efficacy and safety of a single oral dose of NEPA (NETU 300 mg + PALO 0.50 mg) versus a single oral 0.50 mg dose of PALO in chemotherapy-naïve patients receiving moderately emetogenic (anthracycline-CTX) chemotherapy for solid tumors during cycle 1 and during a multicycle extension, in the adjuvant, neoadjuvant or metastatic setting. All patients also received oral dexamethasone (DEX) on Day 1 (12 mg in the NEPA arm and 20 mg in the PALO arm). The primary efficacy endpoint was complete response (CR: no emesis, no rescue medication) in the delayed (25-120 hr) phase. Overall safety was assessed through reporting of adverse events.

Results
1450 and 1286 patients were included in the safety population for cycle 1 and the multicycle extension, respectively; 76% of all patients completed cycle 4. Treatment groups were comparable with the overall population being female (98%) and white (80%), with a mean age of 54 years. The median CTX total dose in both groups was 1000 mg.
Overall, the percentage of patients with at least one treatment-emergent adverse event (AE) was slightly higher for NEPA compared with PALO in cycle 1 but similar during the multicycle extension. The most commonly reported AEs were neutropenia, alopecia, and leukopenia, all known complications associated with CTX and anthracyclines. Frequencies of these AEs were comparable between treatment groups (36% vs 37%; 24% vs 23%; 22% vs 22%, respectively for NEPA vs PALO during the multicycle extension). All other AEs were reported by <11% of patients and the type, frequency, and severity of AEs were comparable between groups throughout the study. The proportion of patients experiencing serious AEs or those leading to discontinuation was low and similar in both groups.

Conclusion
There was no indication in this large study of increased adverse events in patients receiving NEPA compared with those who received PALO after single or repeated cycles of CTX and anthracycline chemotherapy. As a convenient, fixed-dose dual-pathway antiemetic drug combination, NEPA has potential utility in hematologic malignancies and solid tumors.

Disclosures:
Schwartzberg: Helsinn Healthcare, SA: Consultancy, Honoraria; Eisai Inc: Consultancy, Honoraria. Rizzi:Helsinn Healthcare, SA: Employment. Rossi:Helsinn Healthcare, SA: Employment. Palmas:Helsinn Healthcare, SA: Employment. Karthaus:Helsinn Healthcare, SA: Consultancy. Aapro:Helsinn Healthcare, SA: Consultancy, Honoraria, Research Funding.