A phase III trial of rolapitant plus granisetron/dexamethasone in patients treated with cisplatin-based chemotherapy revealed good tolerance and superiority in preventing chemotherapy-induced nausea and vomiting (CINV) in comparison with granisetron/dexamethasone alone. The results were presented during the Proffered Paper Session on Supportive and palliative care at ESMO Congress 2014 by Dr Martin Chasen from the Department of Palliative Rehabilitation, Elizabeth Bruyere Hospital Division of Palliative Care, Ottawa, Canada.
Rolapitant is a highly selective, competitive, long acting NK-1 receptor antagonist. Long half-time (approximately 180 hours) suggests that a single dose may be sufficient to prevent CINV during the entire 5-day (0–120 hours) at risk period. A dose of 200 mg achieved >90% NK-1 receptor occupancy in the brain and maintained that level for up to 5 days post a single dose. There is a reduced risk of drug interaction, it is not an inducer or inhibitor of CYP3A4.
Rolapitant demonstrated safety and efficacy of a single oral dose in large global randomised, controlled, double blind studies. It was studied in two phase III trials in patients receiving cisplatin-based highly emetogenic chemotherapy and in one phase III study in patients receiving moderately emetogenic anthracycline-based chemotherapy.
Key inclusion criteria for the study were patients ≥18 years of age, of either gender, and of any race, naive to cisplatin-therapy. Cisplatin-based chemotherapy was defined as a dose ≥60 mg/m2. Key exclusion criteria were patients scheduled to receive any other chemotherapeutic agent with an emetogenicity level of ≥4 (Hesketh Scale) from day 2 through day 6.
Events of emesis and use of rescue medication were recorded for 5 days.
In this multi-centre, randomised double-blind phase III study, 532 patients were randomised 1:1 to receive oral rolapitant plus granisetron/dexamethasone or placebo plus granisetron/dexamethasone prior to chemotherapy.
The primary endpoint was complete response (CR) defined as no emesis/no rescue medication in the delayed phase (>24-120 hours post-chemotherapy). Secondary endpoints included safety and tolerability; CR rates during acute (0-24 hours) and overall (0-120 hours) phases post-chemotherapy; incidence of no emesis in the acute, delayed, and overall phases of CINV; incidence of no significant nausea in the overall phase of CINV; and time to first emesis or use of rescue medication. Tertiary endpoints were effect of rolapitant on health-related quality of life (QoL) assessed by the Functional Living Index-Emesis Questionnaire (FLIE); complete protection defined as no emesis, no rescue medication, and maximum nausea VAS <25 mm (scale of 0 to 100 mm) for the Nausea and Vomiting Subject Diary Question 2; and incidence of no significant nausea in acute and delayed phases of CINV.
Demographics were well balanced between rolapitant and control groups with respect to gender, age, tumour type, and CINV risk factors.
The primary objective of this study was achieved with a higher CR rate in the delayed phase compared to placebo (72.7% vs 58.4%, p < 0.001). Statically significant results were also observed in key secondary endpoints of acute phase CR rate (83.7% vs 73.7%, p = 0.005), and overall CR rate (70.1% vs 56.5%, p =0.001).
Protection from CINV with rolapitant compared to control was observed early and persisted throughout the delayed phase. Treatment effect was initiated in the acute phase at approximately 12 hours following administration of chemotherapy. Time to first emesis or use of rescue medication was longer in rolapitant vs control group. By days 2–3, the rolapitant curve begins to plateau, indicating these patients are protected for up to 5 days post chemotherapy. In contrast, patients in the control group continued to experience late events of emesis and use of rescue medication.
A regional CR analysis was prospectively conducted in North America, Asia/South Africa, Europe, and Central/South America. The CR with rolapitant was observed consistently across geographic regions.
Slightly more patients reported no impact on daily QoL with rolapitant but it was not statistically significant (72.8% vs 67.8%, p = 0.231).
Treatment emergent adverse events were consistent across both arms (0.8% and 3.8%). Constipation and asthenia were most frequently reported treatment emergent adverse events. Majority of treatment emergent adverse events were considered by investigators to be related to chemotherapy or underlying cancer and not to rolapitant.
The authors concluded that the results of this study demonstrate the clinical benefit achieved over the entire CINV at risk period in the rolapitant group.
A new drug application was submitted to the FDA in early September 2014.
Dr Jorn Herrstedt, who discussed the study results, agreed on most of the conclusions from the study authors and added that they may have an impact on future antiemetic guidelines. However, in terms of conclusion that mean QoL (total and vomiting domain scores) improved significantly with rolapitant, he questioned if it is clinically relevant. He also said that rolapitant was well tolerated and overall incidences of treatment emergent adverse events were similar to those in the control group suggesting possibly less risk of drug-drug interactions.
The study was funded by Tesaro, Inc.
A. Poma: An employee of Tesaro.
M.L. Hedley: An employee of Tesaro.
R. Martell: An employee of Tesaro.
All other authors have declared no conflicts of interest
LBA47_PR - Phase 3 (P04832) trial results for rolapitant, a novel NK-1 receptor antagonist, in the prevention of chemotherapy-induced nausea and vomiting (CINV) in patients receiving cisplatin-based chemotherapy