Nausea and vomiting are common side effects of cancer chemotherapy, and can limit treatment if they become unsustainably severe. As a result, antiemetic drugs are commonly given to reduce these symptoms and improve quality of life in cancer patients undergoing chemotherapy.
These are commonly 5HT3 antagonists, such as ondansetron, palonosetron and granisetron, and more recently the neurokinin-1 receptor antagonist aprepitant has been approved. Another NK-1 antagonist drug, rolapitant, is being investigated by US-based biotech Tesaro.1
NK-1 is a G-protein coupled receptor found in the central nervous system, and is activated by the neuropeptide substance P. There is a particularly high concentration of the receptor in the brain’s vomiting centre, and thus when it is activated, the vomiting reflex is triggered. Blocking it should prevent this from occurring.
Its efficacy and safety in patients undergoing highly emetogenic chemotherapy was assessed in a Phase II double blind study in 454 patients receiving cisplatin.2 Subjects were given ondansetron and dexamethasone plus 10, 25, 100 or 200mg rolapitant or placebo. Those given the highest rolapitant dose had significantly lower rates of emesis or rescue medication throughout the five days after chemotherapy administration. Serious adverse events were similar across all treatment groups.
The results of Phase III trials have also been reported.3 In one, in patients being given highly emetogenic chemotherapy, 555 previously cisplatin-naïve subjects being treated with at least 60mg/m2 of the drug were randomised to receive granisetron plus dexamethasone along with either rolapitant or placebo.
A complete response of no emesis in the delayed phase 24–120 hours after chemotherapy was achieved in significantly more patients given rolapitant than given placebo – 70% compared with 62%. Complete response rates were also better in the acute phase and the overall phase of the two combined with rolapitant than placebo. Adverse event profiles were similar across all of the patients.
In another randomised, double blind Phase III trial, 1,369 chemotherapy-naïve patients undergoing moderately emetogenic chemotherapy were enrolled.4 They were being treated with cyclophosphamide, doxorubicin, epirubicin, lower dose carboplatin, irinotecan, ifosfamide, daunorubicin or cytarabine and were given granisetron, dexamethasone with either 200mg doses rolapitant or placebo.
Those given rolapitant once more had a higher (and comparable to the previous trial) complete response rate in the delayed phase – 71% versus 62%. It was also better in the acute and overall phases again. The drug was also well tolerated.
A safety analysis of these two Phase III trials combined showed that the adverse events rates were similar across all patient groups.5 The most commonly observed side-effects were fatigue, constipation and hair loss for those in the moderately emetogenic chemotherapy trial; in the highly emetogenic trial they were constipation, asthenia and neutropoenia.
Serious adverse event profiles were also similar with and without rolapitant in the regimen, and included febrile neutropoenia and neutropoenia, neutrophil count decrease, and thrombocytopoenia.
Its potential for the prevention of post-operative nausea and vomiting has also been evaluated.6 In a randomised, double blind, dose-ranging study with both placebo and active control groups, 619 adult women undergoing open abdominal surgery were given 5, 20, 70 or 200mg rolapitant, 4mg ondansetron, or placebo. Those given at least 20mg rolapitant were less likely to experience emesis compared with placebo during the first 24 hours after surgery, and significantly lower with the two higher doses.
While there were no significant differences between rolapitant and ondansetron 24 hours after surgery, at 72 and 120 hours the rolapitant group were less likely to have experienced emesis. Side-effects were similar in the placebo and rolapitant groups.
References
1. R.A. Duffy et al. Pharmacol. Biochem. Behav. 2012, 102, 95
2. L.E. Fein et al. J. Clin. Oncol. 2012, 30 (Suppl.), Abst. 9077
3. B.L. Rapoport et al. J. Clin. Oncol. 2014, 32 (Suppl.), Abst. 9638
4. I.D Schnadig et al. J. Clin. Oncol. 2014, 32 (Suppl.), Abst. 9633
5. L. Urban et al. J. Clin. Oncol. 2014, 32 (Suppl.), Abst. 9636
6. T.J. Gan et al. Anesth. Analg. 2011, 112, 804
