Cabozantinib (Cabometyx, 4) – Cabometyx®

• Clinical trials
  • This benefit assessment is based on the results of the third data cut-off from the CELESTIAL trial.
  • In this randomised, double-blind trial, cabozantinib plus best supportive care is compared with placebo plus best supportive care.

Adult patients with hepatocellular carcinoma for whom curative treatment is not the intention and for whom locoregional therapy is not an option, who have previously received sorafenib

• There is a hint of a minor additional benefit for cabozantinib as monotherapy for the treatment of hepatocellular carcinoma (HCC) in adults who have previously been treated with sorafenib.
• Consequently, a minor additional benefit is identified for cabozantinib compared with best supportive care in the treatment of adult patients with hepatocellular carcinoma who are not being treated with the intention of cure and for whom locoregional therapy is not an option, and who have previously received sorafenib.
• Due to significant uncertainties arising, amongst other things, from the lack of quality-of-life data and only limited data on morbidity, there is a hint of low certainty regarding the conclusion that indicates a minor additional benefit.
• mortality
  • With regard to overall survival, there is a statistically significant difference in favour of cabozantinib + BSC compared with placebo + BSC.
  • In patients receiving cabozantinib, the event occurred at a median of 2.1 months later (hazard ratio (HR): 0.78; [95% confidence interval (CI): 0.66; 0.93]; p-value = 0.006).
  • This is classified as a minor prolongation of survival.
  • Consequently, this endpoint yields an additional benefit, whose extent is considered to be minor.
• Morbidity – Progression-free survival (PFS)
  • In the CELESTIAL trial, PFS was defined as the time from randomisation to disease progression or death from any cause.
  • A statistically significant difference was observed in favour of cabozantinib (HR: 0.45; [95% CI: 0.38; 0.54]; p-value < 0.0001).
  • The median PFS was 4.9 months in patients in the cabozantinib arm and 1.9 months in patients in the placebo arm.
  • The PFS endpoint is a composite endpoint comprising endpoints from the mortality and morbidity categories.
  • The morbidity component was not assessed on the basis of symptoms, but exclusively by means of imaging procedures (in accordance with RECIST 1.1).
  • Taking the above aspects into account, there are differing views within the G-BA regarding the clinical relevance of the PFS endpoint for patients.
• Morbidity – EQ-5D VAS
  • Health status is assessed in this study using the EQ-5D visual analogue scale (VAS).
  • The results show a statistically significant disadvantage in the cabozantinib arm; however, the 95% confidence interval for the standardised mean difference does not lie entirely outside the irrelevance range of –0.2 to 0.2.
  • Overall, therefore, there are no relevant differences for this endpoint.
• quality of life
  • Data on quality of life are not collected in the CELESTIAL study.
  • It is therefore not possible to assess the additional benefit in terms of quality of life.
• Side effects – Total adverse events (AEs)
  • The results for the endpoint ‘Total adverse events’ are presented for supplementary information only.
  • Under this definition, almost every patient in both arms experienced an adverse event (cabozantinib arm 99 per cent, placebo arm 96 per cent).
• Side effects – Serious AEs
  • There is a statistically significant difference to the detriment of cabozantinib (HR: 1.31; [95% CI: 1.02; 1.69]; p = 0.035).
• Side effects – Severe side effects (CTCAE grade ≥ 3)
  • With regard to the endpoint of severe adverse events (CTCAE grade ≥ 3), there is a statistically significant disadvantage to the detriment of cabozantinib (HR: 2.60; [95% CI: 2.13; 3.18]; p < 0.001).
  • Patients in the treatment arm experienced this event, on a median basis, 3.1 months earlier.
• Side effects – discontinuation due to adverse events
  • The difference between the two treatment arms, to the detriment of cabozantinib, is statistically significant (HR: 1.64; [95% CI: 1.18; 2.28]; p = 0.003).
  • Most discontinuations due to adverse events were attributable to severe adverse events (CTCAE grade ≥ 3).
• Side effects – Specific adverse events
  • There are statistically significant disadvantages for cabozantinib with regard to the SOC ‘nervous system disorders’ (CTCAE grade ≥ 3), as well as the PTs (Preferred Term) ‘Decreased appetite’ (CTCAE grade ≥ 3), ‘Diarrhoea’ (CTCAE grade ≥ 3), ‘Fatigue’ (CTCAE grade ≥ 3), ‘hypertension’ (CTCAE grade ≥ 3), ‘palmar-plantar erythrodysaesthesia syndrome’ (CTCAE grade ≥ 3), ‘mucositis’ (AEs) and stomatitis (AEs).
• Overall assessment
  • The CELESTIAL study provides results on mortality, morbidity and side effects for the assessment of the additional benefit of cabozantinib in the treatment of patients with hepatocellular carcinoma who had previously been treated with sorafenib.
  • With regard to overall survival, there is an advantage of cabozantinib + BSC over placebo + BSC, whose extent is classified as minor.
  • For the endpoint of morbidity, data are available exclusively from the EQ-5D VAS. In the MMRM analyses, there is a statistically significant disadvantage to the detriment of cabozantinib. However, it cannot be concluded that this effect is clinically relevant. Overall, therefore, no disadvantage is identified.
  • Patients’ quality of life was not assessed in the study. It is therefore not possible to evaluate the additional benefit in terms of quality of life. Conclusions regarding quality of life and morbidity are considered particularly important in the present palliative, advanced-stage treatment setting.
  • For the endpoint category of side effects, only negative effects of cabozantinib + BSC compared with placebo + BSC are reported. These include an increase in serious and severe adverse events, as well as a higher rate of treatment discontinuation due to adverse events; these are assessed overall as a relevant disadvantage, which is why less benefit is identified in the ‘side effects’ category.
  • In its overall assessment, the G-BA concludes that, whilst there is a relevant disadvantage with regard to the ‘side effects’ endpoint, this does not entirely negate the advantage in terms of overall survival.

Courtesy translation only, please refer to the German original.