Dabrafenib (1) – Tafinlar®

Patients with BRAF V600 mutation-positive unresectable or metastatic melanoma

• For patients with BRAF V600 mutation-positive unresectable or metastatic melanoma, an additional benefit over the appropriate comparator therapy is not proven.
• mortality
  • The results on overall survival are distorted in particular by the early crossover in the BREAK-3 trial.
  • The effect of dabrafenib on overall survival cannot be assessed due to the bias caused by the crossover.
  • The sensitivity analyses submitted by the pharmaceutical manufacturer for the indirect comparison, which adjust for crossover using statistical procedures, are based on assumptions whose fulfilment cannot be verified using the available data; they are therefore not taken into account for the benefit assessment.
  • Consequently, there is no conclusive evidence available for the endpoint ‘overall survival’ to assess the additional benefit of dabrafenib compared with the appropriate comparator therapy.
• Morbidity – Symptoms of the disease
  • In the BREAK-3 study, disease symptoms were assessed using different instruments (EORTC QLQ C30 symptom scales) to those used in the BRIM 3 study (pain, assessed using a visual analogue scale).
  • No indirect comparison regarding disease symptoms was provided by the pharmaceutical manufacturer.
  • Consequently, there is no evidence available to assess the additional benefit with regard to disease symptoms.
• Morbidity – Progression-free survival
  • The endpoint ‘progression-free survival’ was assessed in both studies as a composite endpoint comprising endpoints from the categories of mortality and morbidity.
  • The individual components were not presented separately.
  • The systematic assessment of disease progression was not based on patient-relevant symptoms but was carried out using imaging procedures.
  • Asymptomatic findings detected by imaging procedures are not, per se, clinically relevant to patients.
  • Furthermore, the uncertainties regarding the comparability of the study populations, as outlined above for the indirect comparison, also apply to the ‘progression-free survival’ endpoint.
  • For these reasons, the endpoint ‘progression-free survival’ cannot be used to demonstrate additional benefit.
• quality of life
  • Health-related quality of life was assessed in the BREAK-3 study using different instruments (EORTC QLQ C30, EQ-5D) to those used in the BRIM 3 study (FACT-M).
  • No indirect comparison regarding health-related quality of life was provided by the pharmaceutical manufacturer.
  • Consequently, there is no evidence available to assess the additional benefit for the health-related quality of life endpoint.
• Side effects
  • The study arms in the submitted BREAK-3 and BRIM 3 studies differ significantly in terms of treatment duration.
  • The median duration of treatment in the BREAK-3 study was 4.9 months in the dabrafenib arm and 2.8 months in the dacarbazine arm, in the BRIM 3 study, 3.1 months in the vemurafenib arm and 0.76 months in the dacarbazine arm.
  • For both studies, it must be assumed that the results for the endpoint ‘adverse events’ are biased against the placebo.
  • As the bias cannot be assessed for the individual studies, the extent of the additional benefit cannot be evaluated for the indirect comparison between dabrafenib and vemurafenib.
  • There is therefore no conclusive evidence available for the endpoint ‘side effects’ to assess the additional benefit of dabrafenib compared with the appropriate comparator therapy.
• Conclusion
  • Taking the available results on mortality, morbidity and side effects into account as a whole, there is no conclusive evidence to assess the additional benefit of dabrafenib compared with the appropriate comparator therapy.
  • On the basis of the evidence presented, an additional benefit is therefore not proven.

Courtesy translation only, please refer to the German original.