Trametinib (3) – Mekinist®

• Clinical trials
  • For the benefit assessment of the active ingredient trametinib, the pharmaceutical manufacturer submitted the pivotal, randomised, double-blind, multicentre Phase III trial COMBI-AD (BRF115532).

Adult patients following complete resection of stage III BRAF V600 mutation-positive melanoma, for adjuvant treatment

• Overall, there is an indication of considerable additional benefit.
• Consequently, the certainty of the evidence for the observed additional benefit is classified as ‘indication’.
• mortality
  • overall survival
  • Treatment with trametinib in combination with dabrafenib results in a statistically significant advantage in overall survival compared with placebo (watchful waiting) (hazard ratio (HR): 0.52; 95% confidence interval (CI) [0.37; 0.73]; p-value: < 0.001).
  • At the time of data collection, 60 patients (13.7%) in the trametinib + dabrafenib arm and 93 patients (21.5%) in the placebo arm had died, meaning that the median survival time had not yet been reached in either treatment arm.
  • The combination therapy of trametinib and dabrafenib achieves a significant improvement in overall survival compared with the appropriate comparator therapy, which is a ‘watch-and-wait’ approach.
• Morbidity – Recurrences / Recurrence-free survival (RFS)
  • Patients in this therapeutic indication are treated with a curative approach as part of adjuvant treatment for melanoma following complete resection. Nevertheless, tumour cells may remain and cause a recurrence at a later stage. A recurrence means that the attempt at a cure through the curative therapeutic approach was unsuccessful. The occurrence of a recurrence is relevant to the patient.
  • Recurrences (event rate)
  • For the endpoint of recurrence, the first data cut-off point shows a statistically significant advantage for the combination therapy of trametinib with dabrafenib compared with placebo (relative risk (RR): 0.66; 95% CI [0.57; 0.76]; p-value: < 0.001). This result is confirmed by the second data cut-off.
  • Recurrence-free survival (RFS)
  • At the first data cut-off, trametinib in combination with dabrafenib showed a statistically significant prolongation of the time to recurrence or death compared with placebo (HR: 0.43; 95% CI [0.35; 0.53]; p-value: < 0.001). In the trametinib + dabrafenib arm, the median time to event has not yet been reached; in the placebo arm, it is 16.6 months. The results of the first data cut-off are confirmed by the second data cut-off.
  • Overall, for the endpoints of recurrence and RFS, there is a very clear, clinically relevant advantage of trametinib in combination with dabrafenib compared with the appropriate comparator therapy, which is watchful waiting.
• Morbidity – Health status (EQ-5D VAS)
  • Health status was assessed using the visual analogue scale (VAS) of the EQ-5D questionnaire.
  • The analyses show no statistically significant difference between the treatment arms.
  • The additional benefit of trametinib in combination with dabrafenib compared with the appropriate comparator therapy is not proven for the health status endpoint.
• quality of life
  • Health-related quality of life was not investigated in the COMBI-AD study. An additional benefit of trametinib in combination with dabrafenib is not proven for this endpoint category.
• Side effects
  • Total adverse events (AEs)
  • Adverse events occurred in almost all study participants. The results are presented here for supplementary information only.
  • Serious adverse events (SAEs), severe AEs (CTCAE ≥ 3), therapy discontinuation due to AEs
  • There were statistically significantly more SAEs, severe AEs (CTCAE ≥ 3) and therapy discontinuations due to AEs with treatment using trametinib in combination with dabrafenib compared with placebo (watchful waiting).
  • Specific AE
  • Specifically, serious eye diseases, serious fever and gastrointestinal disorders (CTCAE ≥ 3) occurred statistically significantly more frequently with treatment with trametinib in combination with dabrafenib than with placebo. There are therefore statistically significant adverse effects for these endpoints in favour of the placebo (watchful waiting) group compared with the combination therapy.
  • Overall, the results regarding side effects indicate relevant disadvantages for the combination therapy of trametinib and dabrafenib compared with the appropriate comparator therapy of watchful waiting. The combination therapy is characterised by a marked increase in serious adverse events, severe adverse events (CTCAE grade ≥ 3) and therapy discontinuations due to adverse events.
• Overall assessment
  • For the assessment of the additional benefit of trametinib in combination with dabrafenib for the adjuvant treatment of adult patients with stage III melanoma harbouring a BRAF V600 mutation following complete resection, results are available for the endpoint categories of mortality, morbidity and side effects.
  • Compared with the appropriate comparator therapy (watchful waiting), the combination therapy leads to a statistically significant, marked improvement in overall survival.
  • For the endpoints of recurrence and recurrence-free survival, trametinib in combination with dabrafenib also shows statistically significant, very marked advantages over watchful waiting. The prevention of recurrence represents an essential therapeutic goal in this curative treatment setting.
  • With regard to the patient-reported endpoint ‘health status’, neither an advantage nor a disadvantage can be identified for treatment with trametinib in combination with dabrafenib.
  • Data on health-related quality of life were not collected in the COMBI-AD study.
  • In terms of side effects, the combination therapy presents significant disadvantages due to a marked increase in serious adverse events, severe adverse events (CTCAE grade ≥ 3) and therapy discontinuations due to adverse events.
  • When the results for all patient-relevant endpoints are considered as a whole, the positive effects—which are particularly relevant in the current adjuvant treatment setting in terms of prolonging overall survival and preventing recurrence—are offset by significant disadvantages in terms of side effects. These disadvantages are weighed against the aim of curative treatment.
  • Consequently, trametinib in combination with dabrafenib is found to provide considerable additional benefit for the adjuvant treatment of adult patients with stage III melanoma harbouring a BRAF V600 mutation following complete resection.

Courtesy translation only, please refer to the German original.