Rolapitant (1) – Varuby®

• Clinical trials
  • For the group of patients undergoing highly emetogenic antineoplastic chemotherapy, the pharmaceutical manufacturer cites the results of studies TS-P04832 and TS-P04833, as well as a patient population from study TS-P04834, to demonstrate the additional benefit. These are all randomised, double-blind and multicentre studies.
  • For the group of patients receiving moderately emetogenic antineoplastic chemotherapy, the pharmaceutical manufacturer relies on the results from a patient population of study TS-P04834 to demonstrate additional benefit. This is a randomised, controlled and double-blind study conducted at 175 centres in Europe, Asia, Central and South America, South Africa and the USA.

a) Patients receiving highly emetogenic antineoplastic chemotherapy

• An additional benefit of rolapitant over the appropriate comparator therapy is not proven.
• In summary, no relevant data are available for comparing rolapitant with the appropriate comparator therapy. No additional benefit can therefore be inferred for patients receiving highly emetogenic chemotherapy.

b) Patients receiving moderately emetogenic antineoplastic chemotherapy

• No proof of an additional benefit of rolapitant has been provided, either for patients not receiving carboplatin-containing chemotherapy (compared with the combination of granisetron and dexamethasone) or for patients receiving carboplatin-containing chemotherapy compared with the appropriate comparator therapy.
• Overall, based on the available data, no additional benefit of rolapitant can be inferred for patients receiving moderately emetogenic, non-carboplatin-containing chemotherapy.
• As no relevant data are available for these patients, no additional benefit can be inferred for this patient population either.
• Overall, the additional benefit of rolapitant is not proven for patients receiving moderately emetogenic chemotherapy.
• mortality
  • During the entire study duration, 2 patients (1.5 %) died in the rolapitant arm and 1 patient (1.0 %) in the control arm. There was no statistically significant difference between the treatment groups.
• morbidity
  • The primary endpoint of the study was the rate of complete response, which is a composite endpoint comprising vomiting and the use of rescue medication. As the use of emergency medication indirectly reflects the separately recorded patient-relevant endpoints of nausea and vomiting, it is not included in the analysis.
• Morbidity – Vomiting
  • In the analysis of the time to first vomiting over the entire study duration, no statistically significant difference was found between the treatment groups; however, the aforementioned uncertainties regarding the available data for treatment cycles 2–6 must be taken into account.
  • When considering only the first chemotherapy cycle, a significant difference in favour of rolapitant was observed for the endpoint ‘no vomiting’ over the entire treatment phase (comprising the first 120 hours of the cycle), with an absolute risk reduction of 14.5% (p=0.014); however, this difference is not apparent when the acute (0–24 hours of the cycle) and delayed (25–120 hours) phases are considered separately, making the result severe to interpret.
  • It should also be noted that, in the individual analysis of cycles 2 – 6, no statistically significant difference was found; consequently, the significance of the positive result in the first cycle would remain questionable even if these data could be taken into account without restriction for the assessment of additional benefit.
• Morbidity – Nausea
  • The endpoint of nausea is patient-relevant, and assessment using a visual analogue scale (VAS) is, in principle, appropriate. However, it is unclear on what basis the threshold value of 25 mm was chosen for the operationalisation of ‘major nausea’; no literature on its validation was provided. The assessment of the endpoint ‘no nausea’ is therefore used for this evaluation. The definition as a VAS score < 5 mm is considered adequate for this purpose.
  • No data are available for this endpoint over the entire study duration, although data are available for the individual cycles. There are no significant differences between the study arms in the acute, delayed or overall phases of the first cycle.
  • Even if the available data from cycles 2–6 could be taken into account without restriction, there would be no hint of additional benefit, as no significant difference is observed here either.
• quality of life
  • The FLIE (Functional Living Index – Emesis) questionnaire was used in the TS-P04834 study. The validity of the instrument in measuring health-related quality of life could not be demonstrated. Consequently, no relevant data are available for assessing additional benefit.
• Side effects
  • Data are available for the first cycle of chemotherapy for the endpoints of adverse events, serious adverse events, severe adverse events of CTCAE grade ≥ 3, and therapy discontinuation due to adverse events. No statistically significant difference between the treatment groups is apparent for any of the endpoints.
  • The supplementary analysis covering the entire study duration also shows no significant differences. Overall, there are no hints that rolapitant offers any additional benefit in terms of side effects.
• Overall assessment
  • As the reasons for discontinuation after the first chemotherapy cycle were not recorded in the TS-P04834 study, meaningful data are available only for the first cycle. However, for the assessment of additional benefit, it is relevant whether an antiemetic effect persists over several cycles, as chemotherapy is usually administered over several treatment cycles. Consideration of the first cycle alone is insufficient.
  • The relevance of a significant advantage of rolapitant in terms of the endpoint ‘no vomiting’ throughout the entire first cycle therefore remains questionable. No further significant differences between the study arms were observed. Furthermore, a supplementary analysis of the available data on the subsequent cycles does not provide any indications of any particular differences between the treatment groups.

Courtesy translation only, please refer to the German original.