Dabrafenib (2) – Tafinlar®

• Clinical trials
  • To assess the additional benefit of the combination of dabrafenib and trametinib, the pharmaceutical manufacturer submitted data from the randomised, open-label, multicentre, actively controlled COMBI-v (MEK116513), in which the dabrafenib-trametinib combination was directly compared with the appropriate comparator therapy, vemurafenib.

Adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation

• For adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation, there is an indication of considerable additional benefit compared with the appropriate comparator therapy.
• The G-BA classifies the extent of the additional benefit of the combination of dabrafenib and trametinib as considerable, based on the criteria set out in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in the treatment of the disease.
• Having weighed up the aspects discussed, the certainty of the findings in the present assessment is classified as an indication.
• mortality
  • overall survival
  • For treatment with the dabrafenib-trametinib combination, the first data cut-off point showed a statistically significant prolongation of overall survival compared with vemurafenib for the overall population (hazard ratio (HR): 0.69, 95% confidence interval (CI) [0.53; 0.89]; p = 0.005), although the median survival time in the intervention arm had not yet been reached (95% CI [18.3; n.a.]).
  • A statistically significant prolongation of overall survival in the dabrafenib-trametinib arm compared with the control arm was also observed for the overall population at the second data cut-off (HR: 0.66, 95% CI [0.53; 0.81]; p < 0.001), with a median survival time of 25.6 months in the dabrafenib-trametinib arm compared with 18.0 months in the vemurafenib arm (absolute difference: +7.6 months).
  • These results for the overall population are interpreted as a moderate prolongation of survival, indicating, at the endpoint level, a considerable additional benefit of the dabrafenib-trametinib combination compared with vemurafenib.
  • The subgroup analysis for the endpoint of overall survival provided proof of an effect modification by the characteristic ‘gender’ in both data cuts. Accordingly, women showed better outcomes than men in both data sets: the hazard ratio for the patient population of female patients in the first data set was 0.46 (95% CI [0.30; 0.71]; p < 0.001) and 0.48 (95% CI [0.35; 0.67]; p < 0.001) in the second data set.
  • For the patient population of male patients, however, the subgroup analysis revealed no statistically significant difference between the intervention and vemurafenib arms; the hazard ratio was 0.87 (95% CI [0.62; 1.22]; p = 0.420) and 0.82 (95% CI [0.62; 1.09]; p = 0.168) in the second data cut-off.
  • Taking these aspects into account and in view of remaining uncertainties – in particular regarding further possible gender-associated factors that are not necessarily causally linked to biological sex – as well as an imbalance in the gender distribution between the two study arms despite randomisation, the additional benefit for this endpoint was assessed on the basis of the overall population, despite the observed effect modification by the characteristic of sex.
• Morbidity – Progression-free survival
  • The median progression-free survival (PFS) for the overall population was 11.4 months for the dabrafenib-trametinib combination, compared with 7.3 months in the vermurafenib arm. The difference is statistically significant (HR 0.56, 95% CI [0.46; 0.69], p < 0.001).
  • Subgroup analysis also provided proof of a significant sex-specific interaction in terms of PFS (p < 0.001): The median progression-free survival for the dabrafenib-trametinib combination was 15.6 months in female patients (HR: 0.44, 95% CI [0.32; 0.61]) and 9.5 months in male patients (HR: 0.65, 95% CI [0.50; 0.85]).
  • The PFS endpoint is a composite endpoint comprising endpoints from the categories of mortality and morbidity. The ‘mortality’ component of the endpoint was assessed in the study via the ‘overall survival’ endpoint as a standalone endpoint. The ‘disease progression’ component of morbidity was not assessed on the basis of symptoms, but exclusively using imaging (radiological via MRI or CT, as well as photographic) procedures. Taking the above aspects into account, there are differing views within the G-BA regarding the clinical relevance of the PFS endpoint to patients. This does not affect the overall conclusion regarding the extent of the additional benefit.
• Quality of life – EORTC-QLQ-C30
  • For all six functional scales examined, a statistically significant advantage was observed in favour of the dabrafenib-trametinib combination compared with the appropriate comparator therapy: global health status (HR 0.64, 95% CI [0.51; 0.79]; p < 0.001), physical functioning (HR 0.66, 95% CI [0.53; 0.83]; p < 0.001), role functioning (HR 0.69, 95% CI [0.56; 0.85]; p < 0.001), emotional functioning (HR 0.70, 95% CI [0.54; 0.91]; p < 0.001), cognitive functioning (HR 0.77, 95% CI [0.62; 0.96]; p < 0.001) and social functioning (HR 0.59, 95% CI [0.47; 0.73]; p < 0.001).
• Side effects – severe adverse events (SAEs), discontinuation due to adverse events (AEs)
  • No statistically significant difference was observed between the treatment groups for the endpoints of SAE and discontinuation due to AEs (SAE: HR 1.03, 95% CI [0.80; 1.32], p < 0.819; discontinuation due to AEs: HR 1.01, 95% CI [0.66; 1.55], p < 0.957). There is no additional benefit of the dabrafenib-trametinib combination compared with the appropriate comparator therapy, vemurafenib.
• Overall assessment
  • Taking the available results on mortality, morbidity, quality of life and side effects, in accordance with Section 5(7) in conjunction with Section 2(3) of the AM-NutzenV, the combination of dabrafenib and trametinib demonstrates a significant improvement in treatment-related benefit compared with the appropriate comparator therapy that has not previously been achieved, which is based in particular on a moderate prolongation of survival as well as a significant improvement in disease-related symptoms, alongside positive effects on health-related quality of life and a significant reduction in side effects.

Courtesy translation only, please refer to the German original.