Cabozantinib (Cabometyx, 2) – Cabometyx®

• Clinical trials
  • The METEOR trial was a randomised, open-label, actively controlled, multicentre phase 3 trial in which cabozantinib was compared with everolimus.

a) Adult patients with advanced renal cell carcinoma (RCC) following prior targeted therapy against VEGF (vascular endothelial growth factor)

• For adult patients with advanced renal cell carcinoma following prior targeted therapy against VEGF, there is an indication of a minor additional benefit compared with the appropriate comparator therapy.
• In a balanced assessment, the G-BA classifies the extent of the additional benefit of cabozantinib as minor, based on the criteria in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in treating the disease.
• The certainty of the evidence is therefore classified as ‘indication’ on the basis of the available evidence.
• mortality
  • overall survival
  • Treatment with cabozantinib shows a statistically significant prolongation of overall survival compared with treatment with everolimus (hazard ratio (HR): 0.70, 95% CI [0.58; 0.85], p < 0.001). In the cabozantinib group, the median survival time was 21.4 months compared with 17.1 months in the everolimus group, which corresponds to a 4.3-month prolongation of survival.
• Morbidity – Progression-free survival
  • Progression-free survival (PFS), defined as the primary endpoint, was operationalised in this study as the time from randomisation to radiologically confirmed disease progression or death from any cause.
  • The median PFS differed statistically significantly between the treatment arms by an absolute value of +3.5 months, in favour of cabozantinib (7.4 versus 3.9 months; HR 0.52, 95% CI [0.43; 0.64], p < 0.001).
  • Taking the above aspects into account, there are differing views within the G-BA regarding the clinical relevance of the PFS endpoint to patients. This does not affect the overall conclusion regarding the extent of the additional benefit.
• Morbidity – Skeletal-related events
  • There are no statistically significant differences between the treatment groups, either for the combined endpoint or for the individual components.
• Morbidity – Symptoms (FKSI-DRS)
  • The time-to-event analyses show a statistically significant longer time to worsening of the symptoms assessed in the cabozantinib treatment group (5.6 vs. 2.8 months; HR 0.67, 95% CI [0.55; 0.83], p < 0.001).
• Morbidity – Health status (EQ-5D VAS)
  • These analyses show no statistically significant difference between the cabozantinib group and the everolimus group.
• quality of life
  • No valid data on health-related quality of life were collected in the METEOR study.
  • The FKSI-19 and its subscales cannot be used for this assessment, as the instrument – which has been expanded by four items compared with the FKSI-15 – has not been sufficiently validated.
• Side effects
  • Serious adverse events occurred in 47% of patients in the cabozantinib treatment arm and in 45% of patients in the everolimus treatment arm. No statistically significant difference was observed in the event time analyses.
  • Overall, patients were more frequently affected by severe adverse events (CTCAE grade ≥ 3) with cabozantinib than with everolimus (80% versus 68%). These events also occurred statistically significantly earlier with cabozantinib (2.2 months in the cabozantinib arm versus 3.6 months in the everolimus arm; HR 1.23, 95% CI [1.03; 1.47], p = 0.023).
  • With regard to the endpoint of therapy discontinuation due to adverse events, no significant difference was observed in terms of relative risk. In both the cabozantinib and everolimus arms, 27% of patients discontinued therapy due to an adverse event. With regard to the hazard ratio, there was a slight, statistically significant difference in favour of cabozantinib (HR 0.72, 95% CI [0.54; 0.98], p = 0.036).
  • Cabozantinib shows a significant disadvantage in terms of the incidence of diarrhoea, hypertension and palmar-plantar erythrodysaesthesia syndrome (diarrhoea: HR 3.85, 95% CI [3.02; 4.90], p < 0.001; hypertension: HR 5.29, 95% CI [3.46; 8.09], p < 0.001; palmar-plantar erythrodysaesthesia syndrome: HR 9.03, 95% CI [5.59; 14.58], p < 0.001).
  • Cabozantinib, on the other hand, shows advantages with regard to the incidence of the specific adverse events anaemia and pneumonitis (anaemia: HR 0.29, 95% CI [0.22; 0.40], p < 0.001; pneumonitis: HR 0.01 [0.00; 0.23], p < 0.01).
  • In summary, the endpoints relating to adverse events predominantly show disadvantages for cabozantinib compared with everolimus. This is attributable in particular to the disadvantages regarding severe adverse events (CTCAE grade ≥ 3), whilst there are both advantages and disadvantages with regard to specific adverse events.
• Overall assessment
  • For the benefit assessment of cabozantinib in the treatment of adult patients with advanced renal cell carcinoma following prior targeted therapy against VEGF, the METEOR study provides results on mortality (overall survival), morbidity and side effects compared with the appropriate comparator therapy, everolimus.
  • The results for the endpoint of overall survival show that treatment with cabozantinib, compared with everolimus, achieves a prolongation of overall survival, which is assessed as a relevant improvement of considerable extent.
  • Furthermore, treatment with cabozantinib has been shown to have positive effects on disease-specific symptoms, which increase under both therapies.
  • No valid data are available for the assessment of quality of life, although great importance is attached to findings on this endpoint, particularly in the context of palliative care as discussed here.
  • With regard to endpoints relating to side effects, cabozantinib shows significant disadvantages compared with everolimus, particularly due to an increase in severe adverse events (CTCAE Grade 3–4), whereas the data on specific adverse events reveal both advantages and disadvantages.
  • Overall, positive effects on overall survival and symptom relief are offset by predominantly negative effects in terms of side effects. The available data do not allow any conclusions to be drawn regarding effects on health-related quality of life.

Courtesy translation only, please refer to the German original.