Trametinib (1) – Mekinist®

• Clinical trials
  • No direct comparative studies are available to assess the additional benefit of trametinib as monotherapy compared with the appropriate comparator therapy, vemurafenib; the pharmaceutical manufacturer has submitted an indirect comparison of the two active ingredients (trametinib: METRIC; Vemurafenib: BRIM 3).

a) Trametinib monotherapy in 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, an additional benefit over the appropriate comparator therapy is not proven.
• However, due to methodological shortcomings, the indirect comparison cannot be used for the benefit assessment.
• In the randomised, controlled trials used for the indirect comparison (trametinib: METRIC; vemurafenib: BRIM 3), the same comparator therapy was not used for all patients included in the respective control arm relevant to the assessment (METRIC: dacarbazine or paclitaxel; BRIM 3: dacarbazine), meaning that there was no uniform, common bridge comparator.
• Consequently, there are no usable data available for assessing the additional benefit of trametinib monotherapy compared with the appropriate comparator therapy.

b) Trametinib in combination with dabrafenib in adult patients with unresectable or metastatic melanoma harbouring 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.
• Taking into account 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, trametinib in combination with dabrafenib 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.
• The G-BA classifies the extent of the additional benefit of the combination of trametinib and dabrafenib 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.
• As the results of only one study form the basis of the benefit assessment, the present assessment can at most provide indications of additional benefit.
• Mortality – Overall survival
  • For treatment with the dabrafenib-trametinib combination, a statistically significant prolongation of overall survival compared with vemurafenib was observed for the overall population at the first data cut-off (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.e.]).
  • 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 overall survival endpoint provided proof of an effect modification by the characteristic ‘gender’ in both data cut-offs.
  • Accordingly, women showed better outcomes than men in both data cuts: the hazard ratio for the patient population of female patients in the first data cut 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.
• 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 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.
• 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: overall 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 – SAE, discontinuation due to AE
  • No statistically significant difference was observed between the treatment groups for the endpoints 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).
• Overall assessment
  • When side effects are considered as a whole, the dabrafenib–trametinib combination shows predominantly positive effects compared with vemurafenib, particularly in terms of a significant reduction in severe adverse events (AEs of CTCAE grade ≥ 3).
  • Furthermore, the dabrafenib-trametinib combination was associated with significantly fewer adverse events classified as ‘benign, malignant and unspecified neoplasms (including cysts and polyps)’ (MedDRA System Organ Class [SOC]) and which are of particular relevance in vemurafenib therapy with regard to the occurrence of secondary malignancies.
  • Taking into account the severity of the side effects and their clinical relevance, the positive effects clearly outweigh the negative ones when viewed as a whole. In its overall assessment of the side effects, the G-BA concludes that the dabrafenib-trametinib combination offers considerable additional benefit compared with vemurafenib.
  • When considering the morbidity endpoints as a whole, and in light of the results regarding symptoms and health status (EQ-5D visual analogue scale), the dabrafenib-trametinib combination provides a considerable additional benefit compared with vemurafenib for the entire patient population.
  • In the overall analysis of health-related quality of life endpoints, there is a considerable additional benefit of the dabrafenib-trametinib combination compared with vemurafenib for the entire patient population.

Courtesy translation only, please refer to the German original.