Binimetinib (1) – Mektovi®

• Clinical trials
  • The COLUMBUS trial is a randomised, open-label, active-controlled, multicentre, three-arm Phase III trial.
  • The coBRIM trial is a randomised, double-blind, active-controlled, multicentre, two-arm Phase III trial.

a) Adult, treatment-naïve patients with unresectable or metastatic melanoma harbouring a BRAF V600 mutation

• For untreated patients with unresectable or metastatic melanoma harbouring a BRAF V600 mutation, additional benefit is not proven.
• Overall, therefore, an additional benefit is not proven for patient population a).
• mortality
  • For the endpoint of overall survival, there is no statistically significant difference between binimetinib in combination with encorafenib and vemurafenib in combination with cobimetinib (hazard ratio: 0.87 [0.60; 1.24], p-value = n/a). An additional benefit of binimetinib in combination with encorafenib compared with vemurafenib in combination with cobimetinib is therefore not proven for overall survival.
• morbidity
  • No statistically significant difference was observed for the progression-free survival (PFS) endpoint (hazard ratio: 0.81 [0.57; 1.13], p-value = n/a).
  • The data presented on patient-reported endpoints in the categories of morbidity and health-related quality of life are considered unusable due to differences in data collection strategies between the COLUMBUS and coBRIM studies.
  • Due to the differing data collection strategies in the COLUMBUS and coBRIM studies and their unclear implications, the data on disease symptoms are, on the whole, considered unusable in the context of an indirect comparison.
  • The limitations of the data relating to the assessment of disease symptoms, which stem from differing measurement strategies in the COLUMBUS and coBRIM studies, apply equally to the assessment of health status.
• quality of life
  • The limitations of the data mentioned in connection with the assessment of disease symptoms, due to differing measurement strategies in the COLUMBUS and coBRIM studies, apply equally to the assessment of health-related quality of life.
  • Consequently, the results on health-related quality of life are considered unusable, in line with the explanations given in the ‘Symptoms’ section.
• Side effects
  • Differences are evident between the bridging arms of the COLUMBUS and coBRIM studies with regard to endpoints in the ‘Side effects’ category.
  • In the COLUMBUS study, higher rates of events were observed in the vemurafenib arm for all endpoints relating to side effects than in the bridging arm of the coBRIM study.
  • These differences may be due to a different approach to the follow-up of AEs and to continued treatment with vemurafenib following progression in the COLUMBUS study.
  • In the COLUMBUS study, AEs were monitored for up to 30 days after discontinuation of study medication, regardless of whether follow-up therapy was initiated during that period. In the coBRIM study, AEs were monitored for up to 28 days after discontinuation of study medication or until the start of follow-up therapy.
  • Contrary to the guidelines in the SmPC for vemurafenib, in the COLUMBUS trial 17.8% of patients continued to be treated with vemurafenib even after progression, as determined by an independent, blinded committee, continued to be treated with vemurafenib, whilst in the coBRIM trial, treatment was continued in accordance with the SmPC until progression.
  • Due to the open-label design of the COLUMBUS trial, in contrast to the coBRIM trial, there are uncertainties regarding the results for the endpoint ‘discontinuation due to AEs’.
  • Information on specific AEs is incomplete. For the coBRIM study, time-adjusted analyses are available only for a selection of AEs.
  • In summary, it must be noted that there are significant uncertainties regarding side effects, meaning that an assessment of adverse events is not possible on the basis of the indirect comparison presented.
• Overall assessment / Conclusion
  • For the assessment of the additional benefit of binimetinib in combination with encorafenib for the treatment of adult patients with unresectable or metastatic melanoma harbouring a BRAF V600 mutation, results are available on mortality, morbidity, quality of life and side effects compared with vemurafenib in combination with cobimetinib.
  • This assessment is based on an adjusted indirect comparison of the Phase III trials COLUMBUS (binimetinib in combination with encorafenib versus vemurafenib) and coBRIM (vemurafenib in combination with cobimetinib versus vemurafenib in combination with placebo) via the bridge comparator vemurafenib.
  • Based on the indirect comparison, only the results regarding mortality are sufficiently meaningful.
  • For the endpoint of overall survival, there is no statistically significant difference between binimetinib in combination with encorafenib and vemurafenib in combination with cobimetinib.
  • The data presented on patient-reported endpoints in the categories of morbidity and health-related quality of life are considered unusable due to differences in data collection strategies between the COLUMBUS and coBRIM studies.
  • There are significant uncertainties regarding side effects. This is partly due to differences in study conduct regarding continued treatment with vemurafenib following progression, and partly due to the high proportion of potentially informative censorings with regard to the endpoints of SAE and severe AEs (CTCAE grade ≥ 3).
  • Furthermore, there is uncertainty regarding the endpoint of discontinuation due to AEs, owing to the open-label design of the COLUMBUS study, in contrast to the coBRIM study.
  • Further uncertainties arise from the incomplete data on specific side effects.
  • In the overall assessment of side effects, it is therefore not possible to evaluate adverse events on the basis of an indirect comparison.

b) Adult, previously treated patients with unresectable or metastatic melanoma harbouring a BRAF V600 mutation

• An additional benefit is not proven for previously treated patients with unresectable or metastatic melanoma harbouring a BRAF V600 mutation.
• No relevant data were presented for the assessment of the additional benefit of binimetinib in combination with encorafenib compared with the appropriate comparator therapy in pre-treated patients with unresectable or metastatic melanoma harbouring a BRAF V600 mutation.
• Consequently, additional benefit is not proven for previously treated patients with unresectable or metastatic melanoma carrying a BRAF V600 mutation.

Courtesy translation only, please refer to the German original.