Cabozantinib (1) – Cometriq®

• Clinical trials
  • This study is a randomised, double-blind, international, multicentre Phase III trial.
  • Adult patients with unresectable, locally advanced or metastatic medullary thyroid carcinoma were randomised in a 2:1 ratio to either an intervention group, which received cabozantinib, or a control group, which received a placebo.

adult patients with progressive, unresectable, locally advanced or metastatic medullary thyroid carcinoma

• mortality
  • In the study, ‘overall survival’ was assessed as a secondary endpoint.
  • In the overall study population, no statistically significant difference was observed either at the time of the interim analysis of overall survival as planned in the study protocol (data cut-off: 15 June 2011) or at the time of the second interim analysis conducted post-hoc (data cut-off: 15 June 2012) nor at the time of the final analysis of overall survival (data cut-off: 28 August 2014).
  • Relevant subgroup effects were observed with regard to the ECOG performance status (ECOG-PS) and the RET-M918T mutation status of the patients.
  • In the patient population with ECOG-PS 1 or 2, the median overall survival at the time of the second interim analysis was 77.7 weeks in the intervention arm versus 56.7 weeks in the control arm (HR 0.63, 95% CI [0.42; 0.95]; p = 0.0245; absolute difference: approx. 5.3 months) and, at the time of the final analysis, was 20 months in the intervention arm versus 12.2 months in the control arm (HR 0.68, 95% CI [0.46; 0.99]; p = 0.0437; absolute difference: 7.8 months).
  • In the patient population with a positive RET-M918T mutation status, the median overall survival at the time of the second interim analysis was 146.7 weeks in the intervention arm versus 81.6 weeks in the control arm (HR 0.57, 95% CI [0.34; 0.96]; p = 0.0306; absolute difference: approx. 16.3 months) and, at the time of the final analysis, was 44.3 months in the intervention arm versus 18.9 months in the control arm (HR 0.60, 95% CI [0.38; 0.94]; p = 0.0255; absolute difference: 25.4 months).
  • The validity and interpretability of the results in the patient populations are limited by a number of factors.
  • With regard to the subgroup stratification by ECOG-PS, it should be noted that no patients with ECOG-PS 3 or 4 were included in the XL184-301 study and therefore no data are available for these patient groups.
  • The subgroup analysis to investigate the presence of the specific RET-M918T mutation was not predefined in the study protocol.
  • A subgroup analysis planned in the study protocol based on overall RET mutation status (positive, negative, unknown) did not reveal any indication of an effect modification either at the time of the second interim analysis or at the time of the final analysis of overall survival (p-values of the interaction tests: 0.974 and 0.744, respectively).
  • Furthermore, as explained in more detail in the EPAR (p. 67 ff.), the reliability of the RET mutation status determinations carried out as part of the XL184-301 study is open to question.
• Morbidity – Progression-free survival (PFS)
  • Progression-free survival (PFS), defined as the time from randomisation to disease progression or death, was the primary endpoint of the study.
  • At the time of the final PFS analysis (data cut-off: 6 April 2011), the median progression-free survival in the overall population was 48.6 weeks in the intervention group versus 17.4 weeks in the control group, which represents a statistically significant result (HR 0.28 [0.19; 0.40]; p < 0.0001).
  • The PFS endpoint is a composite endpoint comprising endpoints from the categories of mortality and morbidity.
  • Mortality, symptoms and quality of life are considered separately; the combined PFS endpoint is therefore not used to assess the extent of the additional benefit.
• quality of life
  • Patients’ quality of life was assessed using questions 20–25 of the disease-specific patient questionnaire MDASY-THY.
  • Results were presented at 12 weeks and 24 weeks after randomisation.
  • A statistically significant difference to the detriment of cabozantinib was observed in response to the question regarding relationships with other people (week 12).
  • The same limitations regarding potential for bias and the validity of the data apply to the quality of life data as those already discussed in the section on symptoms.
  • Consequently, no valid conclusions can be drawn from the available data on quality of life either.
• Side effects
  • The desired effects of cabozantinib are offset by adverse events (AEs).
  • In the intervention group, there were statistically significantly higher rates of AEs compared with the control group (100% versus 94.5%), serious AEs (42.1% versus 22.9%) and AEs of CTCAE grade 3 or 4 (76.2% versus 37.6%).
  • However, there was no significant difference between the study arms in terms of therapy discontinuations due to AEs.
  • The most frequently observed AEs in the intervention arm (compared with the control arm), based on baseline proportions, were diarrhoea (63.1% versus 33.0%), hand-foot syndrome (50.0% versus 1.8%), weight loss (47.7% versus 10.1%), reduced appetite (45.8% versus 15.6%), nausea (43.0% versus 21.1%) and fatigue (40.7% versus 28.4%).
• Conclusion
  • The heterogeneous study results regarding the endpoint of overall survival – with statistically non-significant findings in the overall population and, in some cases, statistically significant advantages in individual patient populations (some of which were identified post hoc) – are offset by statistically significant disadvantages in terms of severe adverse events (SAEs).
  • Disadvantages were also observed, particularly with regard to gastrointestinal adverse events such as diarrhoea, weight loss and nausea, as well as reduced appetite, PPE syndrome (hand-foot syndrome) and fatigue.
  • Given the long-term course of the disease, characterised by slow progression and, in some cases, a good quality of life for patients, the timing of treatment initiation is of particular importance, especially as treatment with cabozantinib is associated not only with positive effects but also with significant side effects for patients.
  • The study results on cabozantinib show that patients with more advanced disease in particular – for example, those with an already impaired general condition (ECOG 1–2) – benefit from treatment with cabozantinib.
  • Taking into account the available results on mortality and side effects, and the lack of evaluable data on morbidity and quality of life, cabozantinib demonstrates a moderate—and not merely minor—improvement in treatment-related benefit that has not been achieved previously.

Courtesy translation only, please refer to the German original.