Dabrafenib (4) – Tafinlar®

• Clinical trials
  • For the benefit assessment of the active ingredient dabrafenib, 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 a considerable additional benefit.
• Consequently, the certainty of the evidence for the identified additional benefit is classified as ‘indication’.
• Consequently, a considerable additional benefit is identified for dabrafenib in combination with trametinib for the adjuvant treatment of adult patients with stage III melanoma harbouring a BRAF V600 mutation following complete resection.
• mortality
  • overall survival
  • Treatment with dabrafenib in combination with trametinib 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 dabrafenib + trametinib 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 dabrafenib and trametinib 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)
  • The endpoints of recurrence and RFS comprise the following individual components:
  • - Local / regional recurrence
  • - Distant metastases
  • - Second primary melanoma
  • - Death (from any cause)
  • Recurrence (event rate)
  • For the endpoint of recurrence, the first data cut-off point showed a statistically significant advantage for the combination therapy of dabrafenib and trametinib compared with placebo (relative risk (RR): 0.66; 95% CI [0.57; 0.76]; p-value: < 0.001). This result is confirmed at the second data cut-off.
  • Recurrence-free survival (RFS)
  • At the first data cut-off, dabrafenib in combination with trametinib 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 dabrafenib + trametinib 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 dabrafenib in combination with trametinib 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.
  • An additional benefit of dabrafenib in combination with trametinib 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 dabrafenib in combination with trametinib is therefore not proven for this endpoint category.
• Side effects
  • Serious adverse events (SAEs), severe adverse events (CTCAE ≥ 3), therapy discontinuation due to AEs
  • There were statistically significantly more SAE, severe AEs (CTCAE ≥ 3) and therapy discontinuations due to AEs during treatment with dabrafenib in combination with trametinib 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 dabrafenib in combination with trametinib than with placebo. Thus, for these endpoints, there are statistically significant effects to the detriment of the combination therapy compared with placebo (watchful waiting).
  • Overall, the results regarding side effects indicate relevant disadvantages for the combination therapy of dabrafenib and trametinib 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 dabrafenib in combination with trametinib 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, there are also statistically significant, very marked advantages of dabrafenib in combination with trametinib compared with 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 dabrafenib in combination with trametinib.
  • 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 goal of curative treatment.

Courtesy translation only, please refer to the German original.