Vandetanib (2) – Caprelsa®

Aggressive and symptomatic medullary thyroid carcinoma (MTC) in patients with unresectable, locally advanced or metastatic disease

• mortality
  • The endpoint ‘overall survival’ was the only endpoint included in the benefit assessment in Study 58; it was analysed according to the intention-to-treat (ITT) principle over the entire period up to the data cut-off date for the primary analysis on 31 July 2009.
  • There was no statistically significant difference in overall survival between the vandetanib arm and the control arm. In the two treatment groups, a total of 21 (16.7 %) (vandetanib + BSC) and 10 (16.7 %) (placebo + BSC) patients, respectively, died in the relevant patient population.
  • An additional benefit of vandetanib over the appropriate comparator therapy is not proven for overall survival.
• Morbidity – Time to Worsening of Pain (TWP)
  • In Study 58, the endpoint ‘time to worsening of pain (Time to Worsening of Pain, TWP)’ was assessed as a composite endpoint, derived from the assessment of the most severe pain based on the validated BPI-SF (Brief Pain Inventory-Short Form) questionnaire and the patient’s report on the use of opioid analgesics.
  • For the endpoint ‘time to pain progression’, a statistical advantage was observed for vandetanib, with a prolongation of TWP compared with placebo (hazard ratio of 0.62, 95% confidence interval (CI): [0.39; 0.99], p-value: 0.045).
  • The median time to pain progression was approximately 11 months in the vandetanib group and approximately 3 months in the placebo group, corresponding to an improvement of around 8 months.
  • For the endpoint ‘time to pain progression’, the G-BA assesses the extent of the additional benefit of vandetanib as considerable, as it achieves a delay in the onset of a serious symptom of the disease compared with the appropriate comparator therapy, best supportive care.
• quality of life
  • In Study 58, data on quality of life were collected using the FACT-G (Functional Assessment of Cancer Therapy General Scale). This endpoint was assessed on a purely exploratory basis.
  • No usable data on quality of life were presented. Consequently, no valid conclusions can be drawn regarding the extent of the additional benefit for the endpoint ‘quality of life’.
• Side effects
  • The positive effects of vandetanib are offset by adverse events (AEs).
  • The overall rate of adverse events cannot be calculated for the time-adjusted analysis; when considering the non-time-adjusted results, high overall rates of side effects are evident (vandetanib arm: 100 per cent of patients, placebo arm: 94.9 per cent of patients). No statistically significant difference between the treatment groups could be demonstrated. For this endpoint, it is not proven that vandetanib + BSC causes either minor or major harm.
  • Comparison of the time-adjusted results in the vandetanib arm and the placebo arm revealed no statistically significant difference in serious adverse events (SAEs). When considering the non-time-adjusted results (RR), a statistically significant result was observed to the detriment of vandetanib + BSC. For this endpoint, the time-adjusted analysis does not prove that vandetanib + BSC causes minor or greater harm; however, when the relative risks are considered, vandetanib + BSC results in greater harm compared with placebo + BSC.
  • In the vandetanib arm, the time-adjusted analysis for the endpoint ‘severe adverse events (CTCAE grade ≥ 3)’ showed a statistically significant result to the detriment of vandetanib + BSC compared with the control arm. For this endpoint, when considering the non-time-adjusted analysis (RR), considerable differences in event rates are observed in favor of vandetanib + BSC (vandetanib arm: 61.1% vs. placebo arm: 23.7% of patients experiencing an event; RR and CI not calculated). For this endpoint, greater harm from vandetanib + BSC is not proven.
  • In the vandetanib arm, the time-adjusted analysis for the endpoint ‘therapy discontinuations due to AEs’ showed no statistically significant difference between the treatment groups compared with the control arm. For this endpoint, there was also no significant result when considering the non-time-adjusted analysis (RR). (Vandetanib arm: 11.9% vs. placebo arm: 1.7% of patients with an event, RR: 7.02 and 95% CI [0.95; 51.93]). For this endpoint, it is not proven that vandetanib + BSC causes greater or minor harm.
  • For the endpoint ‘skin rashes’, the time-adjusted analysis showed a statistically significant difference between the treatment groups to the detriment of vandetanib + BSC. For this endpoint, the unadjusted analysis (RR) also revealed considerably different event rates in favor of vandetanib + BSC (vandetanib arm: 49.2% vs. placebo arm: 13.6% of patients with an event; RR and CI not calculated). For this endpoint, greater harm from vandetanib + BSC is proven.
  • No time-adjusted analyses were available for the endpoint ‘diarrhoea’. For this endpoint, the non-time-adjusted analysis (RR) also showed significantly different event rates in the disadvantage of vandetanib + BSC (vandetanib arm: 52.4% vs. placebo arm: 22.0% of patients with an event; RR and CI not calculated). For the endpoint ‘diarrhoea’, the G-BA therefore considers there to be a disadvantage for vandetanib + BSC. However, the calculation of the incidence density ratio for the endpoint ‘diarrhoea (SAE)’ revealed no statistically significant difference between the treatment arms. For this endpoint, it is not proven that vandetanib + BSC causes greater or minor harm.
  • With regard to side effects, this therefore indicates greater harm from vandetanib, which justifies a downgrading of the extent of the additional benefit.

Courtesy translation only, please refer to the German original.