Cabozantinib (2) – Cometriq®

• Clinical trials
  • For the renewed benefit assessment of cabozantinib in the present therapeutic indication, the pharmaceutical manufacturer has submitted the results of the EXAM registration trial (final data cut-off date of 28 August 2014). This trial is a randomised, double-blind, international, multicentre Phase III trial.
  • The EXAM trial enrolled adults with unresectable, locally advanced or metastatic medullary thyroid carcinoma and were randomised in a 2:1 ratio to either an intervention group, which received cabozantinib, or a control group, which received a placebo.
  • The pharmaceutical manufacturer also presents data from the EXAMINER study in the dossier, with a data cut-off date of 15 July 2020. This is an ongoing multicentre, randomised-controlled, double-blind Phase IV trial.
  • This study is investigating the efficacy, safety and tolerability of cabozantinib at a daily dose of 60 mg compared with 140 mg in adults with progressive, metastatic medullary thyroid carcinoma, using a non-inferiority study design.

Adults with medullary thyroid carcinoma with progressive, unresectable, locally advanced or metastatic disease

• In its overall assessment, the G-BA classifies the extent of the additional benefit of cabozantinib for the treatment of medullary thyroid carcinoma in adults with progressive, unresectable, locally advanced or metastatic disease as non-quantifiable, because the scientific evidence does not permit quantification.
• The strength of the evidence is classified as ‘a hint’, particularly as no usable data on symptoms and health-related quality of life are available.
• mortality
  • In the EXAM trial, ‘overall survival’ was assessed as a secondary endpoint. In the overall population, no statistically significant difference was observed between the treatment groups for this endpoint.
  • Relevant subgroup effects were observed with regard to patients’ RET-M918T mutation status. Statistically significant differences in overall survival in favour of cabozantinib were observed in the patient population with a positive RET-M918T mutation status.
  • In contrast, in the patient population with a negative RET-M918T mutation status and those with an unknown RET-M918T mutation status, no statistically significant differences in overall survival were observed between the intervention and control arms.
  • The validity and interpretability of the results of the subgroup analysis are limited by a number of factors. The subgroup analysis investigating the presence of the specific RET-M918T mutation was not predefined in the study protocol. Furthermore, the reliability of the RET mutation status determination carried out as part of the EXAM study is open to question.
• Morbidity – Progression-free survival (PFS)
  • Progression-free survival (PFS) is the primary endpoint of the EXAM study. PFS was defined as the time from randomisation to the occurrence of disease progression or death.
  • There is a statistically significant difference between the treatment arms in favour of cabozantinib compared with placebo.
  • The PFS endpoint is a composite endpoint comprising endpoints from the ‘mortality’ and ‘morbidity’ categories. The ‘mortality’ component of the endpoint is already assessed as a standalone endpoint via the ‘overall survival’ endpoint. The ‘disease progression’ component of morbidity is assessed according to mRECIST criteria and is therefore not symptom-based but determined using imaging procedures.
  • It remains unclear from the available data whether the statistically significant prolongation of progression-free survival – radiologically determined disease progression according to the RECIST criteria – is associated with an improvement in symptoms or health-related quality of life.
  • The results for the PFS endpoint are therefore not used to assess the extent of the additional benefit.
• Health-related quality of life
  • In the EXAM study, quality of life was assessed using the MDASI-Thy quality-of-life scales. The required response rates were only achieved at baseline, meaning that no evaluable data are available.
  • With regard to health-related quality of life, additional benefit is not proven.
• Side effects
  • Adverse events occurred in almost all study participants.
  • For serious AEs (SAEs), severe AEs (CTCAE grade ≥ 3) and therapy discontinuations due to AEs, there was a statistically significant disadvantage for cabozantinib.
  • For the serious AEs ‘gastrointestinal disorders’ and ‘metabolic and nutritional disorders’, a statistically significant disadvantage was observed with respect to cabozantinib.
  • For severe adverse events with a CTCAE grade ≥ 3, a statistically significant disadvantage was observed for cabozantinib compared to other treatments for ‘gastrointestinal disorders’, ‘General disorders and administration site conditions’, ‘Metabolic and nutritional disorders’, ‘Nervous system disorders’ and ‘Vascular disorders’.
  • An overall analysis of the results regarding side effects reveals clear differences to the detriment of cabozantinib, particularly in the case of severe and serious adverse events.
• Overall assessment
  • For the assessment of the additional benefit of cabozantinib in the treatment of medullary thyroid carcinoma in adults with progressive, unresectable, locally advanced or metastatic disease, results on overall survival and side effects are available from the randomised, double-blind Phase IIIEXAM trial are available.
  • For the endpoint of overall survival, there is no statistically significant difference between the treatment groups in the overall population. In the patient population of patients with a positive RET-M918T mutation status, a statistically significant advantage was observed in favour of cabozantinib, whereas in the patient population of patients with a negative RET-M918Tmutation status, nor in the patient population with unknown RET-M918T mutation status. The validity and interpretability of the results of the patient population analysis are limited by a number of factors.
  • No evaluable data are available for the endpoint categories of morbidity and health-related quality of life.
  • With regard to side effects, there are overall marked differences to the detriment of cabozantinib, particularly in the case of serious and severe adverse events.
  • In the overall assessment of the available results, a statistically significant advantage in terms of overall survival in one patient population is offset by statistically significant disadvantages regarding side effects for the overall population. In the initial assessment of cabozantinib for this therapeutic indication, a minor additional benefit was identified, pending further findings from the data to be submitted after the deadline. However, the data submitted for the renewed benefit assessment after the deadline do not provide any new findings relevant to the benefit assessment.
  • In its overall assessment, the G-BA classifies the extent of the additional benefit of cabozantinib for the treatment of medullary thyroid carcinoma in adults with progressive, unresectable, locally advanced or metastatic disease as non-quantifiable, because the scientific evidence does not permit quantification.

Courtesy translation only, please refer to the German original.