Cabozantinib (Cabometyx, 1) – Cabometyx®

• Clinical trials
  • METEOR is a randomised, open-label, actively controlled, multicentre Phase 3 trial in which 658 patients were randomised in a 1:1 ratio to receive treatment with cabozantinib (330 patients) or everolimus (328 patients).

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

• Mortality – Overall survival
  • Three data cut-off dates are available for overall survival in the METEOR study: 22 May 2015, 31 December 2015 and 2 October 2016.
  • Treatment with cabozantinib demonstrated a statistically significant advantage in overall survival compared with everolimus across all three data cut-off dates.
  • As this data cut-off date represents the most mature data, the third data cut-off date (final analysis; 2 October 2016) is used for the present benefit assessment: This data set shows a statistically significant advantage from treatment with cabozantinib, with a median survival time of 21.4 months (cabozantinib) compared with 17.1 months (everolimus), representing an absolute difference of +4.3 months in the median (HR: 0.70, 95% CI [0.58; 0.85]; p < 0.001).
• Morbidity – Skeletal-related events
  • The endpoint ‘skeletal-related events’ is a composite endpoint comprising the following four individual components: bone radiotherapy (defined as palliative treatment of painful lesions or the treatment/prevention of fractures or spinal cord compression), pathological fractures (defined as symptomatic fractures), spinal cord compression (operationalised as neurological impairment or pain resulting from pressure exerted by metastases on the spinal cord) and surgical intervention on the bone (operationalised as surgical intervention to treat or prevent impending pathological fractures or spinal cord compression).
  • For the benefit assessment, therefore, only the reported result of the total score for skeletal-related events at the first data cut-off can be used, which shows no statistically significant difference between the two study arms.
• 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 the assessment because the instrument, which has been expanded by four items compared with the FKSI-15, has not been sufficiently validated.
• Side effects
  • No statistically significant differences were observed between the two treatment arms in terms of serious adverse events (SAEs) or discontinuations due to AEs.
  • Overall, more patients experienced severe adverse events (CTCAE grade ≥ 3) whilst on cabozantinib than whilst on everolimus (80% versus 68%), and these events also occurred statistically significantly earlier under 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).
  • Disadvantages associated with cabozantinib are evident in the side effects within the system organ class (SOC) ‘Gastrointestinal disorders’ and ‘Vascular disorders’ – these occurred more frequently with cabozantinib.
  • This difference is particularly pronounced among patients in the SOC ‘Vascular disorders’ (47% on cabozantinib versus 16% on everolimus).
  • Analyses of the time to first event also confirm a statistically significant earlier onset of both events with cabozantinib, with the hazard ratio for the SOC ‘vascular disorders’ being particularly high with cabozantinib (HR 3.23, 95% CI [2.36; 4.41], p < 0.001).
  • Disadvantages associated with cabozantinib are also evident in the side effects classified under the preferred terms (PT) ‘diarrhoea’ and ‘hypertension’ – these occurred significantly more frequently in patients on cabozantinib than on everolimus (75% versus 30% and 37% versus 8%).
  • The proportion of patients with severe AEs (CTCAE ≥ 3) was higher in the cabozantinib arm for both events (13% versus 8% and 15% versus 3.7%).
  • Analyses of the time to first event also showed that both events occurred statistically significantly earlier with cabozantinib, with a high hazard ratio (HR 3.85, 95% CI [3.02–4.90], p < 0.001 and HR 5.29, 95% CI [3.46; 8.09], p < 0.001).
  • A notable disadvantage of cabozantinib relates to the side effects associated with the PT ‘palmar-plantar erythrodysaesthesia syndrome’ (hereinafter: hand-foot syndrome): Hand-foot syndrome occurred in more patients treated with cabozantinib than with everolimus (44% versus 6%) and reached CTCAE grade ≥ 3 in more patients (8.5% versus 0.9%).
  • The time-to-event analyses also confirm that hand-foot syndrome occurred statistically significantly earlier with cabozantinib, with a markedly high hazard ratio (HR 9.03, 95% CI [5.59; 14.58], p < 0.001).
  • Advantages with cabozantinib are evident in side effects under the SOC ‘Blood and lymphatic system disorders’ and the PT ‘Anaemia’ – these occurred less frequently with cabozantinib compared with everolimus (27% versus 44% and 20% versus 40%).
  • Analyses of the time to first event support these advantages in that both events occurred statistically significantly later with cabozantinib (HR 0.38, 95% CI [0.29; 0.50], p < 0.001 and HR 0.29, 95% CI [0.22; 0.40], p < 0.001).
• Overall assessment
  • The METEOR study provides results on the additional benefit of Cabozantinib for the treatment of adult patients with advanced renal cell carcinoma after prior targeted therapy against VEGF, including mortality (overall survival), morbidity and side effects compared with the appropriate comparator therapy, everolimus.
  • The results for the overall survival endpoint show that cabozantinib, compared with everolimus, achieves a prolongation of overall survival, which is assessed as a relevant improvement.
  • The results on morbidity show no difference between cabozantinib and everolimus.
  • No valid data on quality of life were submitted for the benefit assessment, although great importance is attached to the findings on this endpoint, particularly in the context of palliative care as discussed here.
  • The endpoints relating to side effects show significant disadvantages for cabozantinib compared with everolimus, particularly with regard to severe adverse events (CTCAE Grade 3–4), gastrointestinal and vascular disorders, diarrhoea and hypertension, and are particularly pronounced in hand-foot syndrome.
  • Overall, the positive effects in terms of prolonged overall survival are offset by negative effects in terms of side effects.

Courtesy translation only, please refer to the German original.