Cabozantinib (Cabometyx, 3) – Cabometyx®

a) Adult patients with untreated, advanced renal cell carcinoma at moderate risk (IMDC score 1–2)

• In summary, the additional benefit of cabozantinib is assessed as follows: the additional benefit is not proven.
• Consequently, the overall population is considered for which the additional benefit of cabozantinib over sunitinib in terms of overall survival is not proven.
• mortality
  • For the endpoint of overall survival, there was no statistically significant difference between the treatment arms (hazard ratio = 0.80 [0.53; 1.21], p-value = 0.170). The median survival time was 26.6 months for patients in the cabozantinib arm and 21.2 months for patients in the sunitinib arm.
  • For patients with a positive MET-IHC status, a statistically significant difference was observed in favour of cabozantinib (hazard ratio = 0.29 [0.15; 0.59], p-value < 0.001). By contrast, for patients with a negative or unknown MET-IHC status, there was no statistically significant difference between the study arms (hazard ratio = 1.42 [0.75; 2.69], p-value = 0.282; hazard ratio = 2.85 [0.98; 8.33], p-value = 0.055).
  • A separate assessment of the additional benefit based on this effect modification cannot be carried out with sufficient certainty due to methodological limitations in the CABOSUN study and the fact that this biomarker has not yet been established in clinical practice, particularly with regard to universally applicable cut-off values and operationalisations for determining expression levels, cannot be carried out with sufficient certainty.
• Morbidity – Progression-free survival (PFS)
  • PFS was the primary endpoint of the CABOSUN trial and was defined as the time from randomisation to disease progression or death from any cause.
  • At the final data cut-off on 15 September 2016, the median PFS was 8.6 months in the cabozantinib arm and 5.3 months in the sunitinib arm. There was a statistically significant difference between the study arms, with an absolute difference of 3.3 months (hazard ratio = 0.48 [0.31; 0.74], p-value = 0.0008).
  • 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 available results on PFS were taken into account, the overall conclusion regarding the extent of the additional benefit would remain unchanged.
• quality of life
  • In the CABOSUN study, no assessment of health-related quality of life was carried out.
• Side effects – severe adverse events (CTCAE grade ≥ 3)
  • For the endpoint of severe adverse events (AEs) with a CTCAE grade of ≥ 3, there is no statistically significant difference between the treatment arms in the overall population.
  • There is an effect modification by gender. For women, there is a statistically significant advantage in favour of cabozantinib, whereas for men there is no statistically significant difference between the treatment arms.
• Side effects – therapy discontinuation due to AEs
  • For the endpoint of discontinuation due to AEs, there was no statistically significant difference between the treatment arms.
  • The results are subject to uncertainty, as the data on therapy discontinuation due to AEs are based on the patient flow chart for the CABOSUN trial. In this context, only the primary reason for discontinuation given by patients was documented.
• Overall assessment
  • An additional benefit of treatment with cabozantinib is not proven for overall survival, as no statistically significant difference was observed between the treatment arms.
  • For the morbidity endpoint category, no patient-relevant endpoints were recorded in the CABOSUN study. Consequently, no information is available on disease-specific symptoms.
  • Furthermore, health-related quality of life was not assessed in the CABOSUN study. Data on patients’ quality of life are considered particularly important, especially in the context of palliative care as discussed here.
  • In the CABOSUN study, there are significant uncertainties in the assessment of adverse events (AEs), as, on the one hand, systematic recording of AEs was carried out exclusively for events with CTCAE grades 3 to 5 and, on the other hand, serious adverse events (SAEs) were not recorded in accordance with the standardised criteria of the ICH guideline.
  • In summary, based on the available study results on mortality and side effects, cabozantinib shows neither beneficial nor disadvantageous effects compared with sunitinib. Additional benefit is not proven for cabozantinib compared to sunitinib in the treatment of advanced renal cell carcinoma in untreated, adult patients at intermediate risk (IMDC score 1–2).

b) Adult patients with untreated, high-risk advanced renal cell carcinoma (IMDC score ≥ 3)

• In summary, the additional benefit of cabozantinib is assessed as follows: the additional benefit is not proven.
• For adult, previously untreated patients with high-risk advanced renal cell carcinoma (IMDC-5 score ≥ 3), there is no suitable evidence regarding the additional benefit of cabozantinib.
• In the CABSON trial, which was used for benefit assessment in adult patients with untreated, advanced renal cell carcinoma at intermediate risk (IMDC score 1–2) and which compared cabozantinib with sunitinib, 19 per cent of the enrolled patients had high-risk renal cell carcinoma (IMDC score ≥ 3).
• The question of the extent to which the study data on this patient group might be suitable for demonstrating the additional benefit of cabozantinib over sunitinib was not the subject of the present assessment procedure.

Courtesy translation only, please refer to the German original.