Tivozanib (1) – Fotivda®

a) For first-line treatment of patients with a favourable or intermediate prognosis (MSKCC score 0–2)

• An additional benefit is not proven for tivozanib as first-line treatment in adult patients with advanced renal cell carcinoma with a favourable or intermediate prognosis (MSKCC score 0–2).
• The pharmaceutical manufacturer did not submit any direct comparative data for the assessment of the additional benefit of tivozanib for patients with a favourable or intermediate prognosis (MSKCC score 0–2).
• The adjusted indirect comparison of tivozanib versus sunitinib via the bridge comparator sorafenib that was submitted is not suitable for drawing conclusions regarding the additional benefit of tivozanib compared with the appropriate comparator therapy.
• Overall, there are no suitable data available to assess the additional benefit of tivozanib, and an additional benefit for this patient group is therefore not proven.

b) For first-line treatment of patients with an unfavourable prognosis (MSKCC score ≥ 3)

• Additional benefit is not proven for tivozanib as first-line treatment in adult patients with advanced renal cell carcinoma and an unfavourable prognosis (MSKCC score ≥ 3).
• The pharmaceutical manufacturer did not submit any data for the assessment of the additional benefit of tivozanib for patients with an unfavourable prognosis (MSKCC score ≥ 3).

c) in cases of disease progression following prior cytokine therapy, where treatment with VEGFR or mTOR pathway inhibitors has not yet been administered

• mortality
  • overall survival
  • Overall survival was assessed as a secondary endpoint in the TIVO-1 trial. No statistically significant difference was observed between the treatment groups.
  • In the mortality endpoint category, due to the marked differences in the number of patients who received subsequent therapy, only data with a high potential for bias are available.
  • An additional benefit of tivozanib over the appropriate comparator therapy is not proven for overall survival.
• morbidity
  • Progression-free survival (PFS)
  • PFS was assessed as the primary endpoint and was defined as the time from randomisation to the first disease progression or death from any cause.
  • For the PFS endpoint, a statistically significant difference in favour of tivozanib over sorafenib was observed in the relevant patient population of the TIVO-1 trial. In the tivozanib arm, the median PFS for the relevant patient population was 13 months, compared with 7.5 months in the control arm (hazard ratio (HR) 0.57; 95% confidence interval (CI) [0.34; 0.97]; p < 0.034). In the tivozanib arm, 24% of patients experienced a progression event. This compares with 37% in the sorafenib arm.
  • The PFS endpoint is a composite endpoint comprising endpoints from the categories of mortality and morbidity. The ‘mortality’ component of the endpoint was assessed via the ‘overall survival’ endpoint as a standalone endpoint. The ‘disease progression’ component of morbidity was not assessed on the basis of symptoms, but exclusively by means of imaging procedures (radiologically determined disease progression according to the RECIST criteria).
  • Taking the above aspects into account, there are differing views within the G-BA regarding the clinical relevance of the PFS endpoint. The overall conclusion regarding the extent of the additional benefit remains unaffected by this, as even if the present finding on PFS were taken into account in the overall assessment, the overall conclusion regarding the extent of the additional benefit would remain unchanged.
  • Symptoms (FKSI-DRS)
  • Disease-related symptoms were assessed using the FKSI-DRS (Functional Assessment of Cancer Therapy – Kidney Symptom Index – Disease-Related Symptoms) questionnaire, a subscale of the FKSI-15. This comprises 9 questions that focus on the specific symptoms experienced by patients with renal cell carcinoma.
  • No statistically significant difference was observed between the treatment groups. An additional benefit of tivozanib over sorafenib for one of the endpoints is therefore not proven.
  • Health status (EQ-5D VAS)
  • Health status was assessed using the visual analogue scale (VAS) of the EQ-5D questionnaire. On this scale, patients rate their health status on a scale from 0 (the worst conceivable health status) to 100 (the best conceivable health status). The time to the onset of a deterioration in disease symptoms of at least 7 mm and 10 mm is considered.
  • In neither of the two operationalisations was there a statistically significant difference between the treatment groups, meaning that the additional benefit of tivozanib over sorafenib is not proven for this endpoint.
  • In summary, no advantage of tivozanib treatment over sorafenib treatment can be identified with regard to disease symptoms and health status.
• quality of life
  • Health-related quality of life was assessed using the FACT-G questionnaire. The questionnaire consists of 27 questions, each rated on a scale of 0 to 5. For the FACT-G total score, the time to a deterioration of at least 5 points is taken into account.
  • No significant difference between the treatments was demonstrated, either for the FACT-G total score or for the four FACT-G subscales.
  • In summary, no advantage of tivozanib treatment over sorafenib treatment can be established with regard to health-related quality of life.
• Side effects
  • As adverse events occurred at least once in almost every patient in both treatment groups, the results for the endpoint ‘Adverse events (total)’ are presented only as supplementary information.
  • Serious adverse events (SAE)
  • There were no statistically significant differences between the tivozanib and sorafenib arms in the treatment groups for the endpoint ‘SAE’.
  • Severe AEs (CTCAE grade 3 or 4)
  • No statistically significant difference was observed between the treatment arms within the treatment groups.
  • Discontinuation due to AEs
  • No statistically significant difference was observed between the treatment arms within the treatment groups.
  • Specific AE
  • The pharmaceutical manufacturer has provided data only for a very small selection of preferred terms (PT) – for hypertension, fatigue, lipase, palmar-plantar erythrodysaesthesia syndrome and diarrhoea. Results for other system organ classes (SOCs) and PTs are missing for the subsequently submitted patient population. Due to this selective choice, the results on specific AEs are not taken into account for the benefit assessment.
  • An overall assessment of side effects reveals neither an advantage nor a disadvantage of tivozanib compared with sorafenib.
  • The sensitivity analyses presented by the pharmaceutical manufacturer for the relevant patient population of the TIVO-1 study do not allow for an assessment of specific side effects.
• Overall assessment
  • For the benefit assessment of tivozanib as a treatment for adult patients who have not yet been treated with VEGFR and mTOR signalling pathway inhibitors and in whom disease progression occurred following prior cytokine therapy for advanced renal cell carcinoma, the TIVO-1 trial provides results comparing tivozanib with sorafenib in terms of mortality (overall survival), morbidity, quality of life and side effects.
  • In summary, based on the data presented on overall mortality, symptoms, health status, quality of life and side effects, there are neither beneficial nor disadvantageous effects for tivozanib compared with sorafenib.

Courtesy translation only, please refer to the German original.