Research in context
Evidence before this study
We searched PubMed for clinical studies published in English before June 12, 2017 (no start date restriction), of combined BRAF and MEK inhibition for the treatment of patients with BRAFV600E-mutant non-small-cell lung cancer (NSCLC). We used the search terms “dabrafenib AND trametinib”, “vemurafenib AND cobimetinib”, and “encorafenib AND binimetinib”, all with “non-small cell lung cancer”. Of nine publications identified, only one was a primary analysis of a prospective clinical trial, representing the previously reported analysis of dabrafenib plus trametinib in the previously treated patient cohort of the phase 2 BRF113928 study. Although dabrafenib plus trametinib demonstrated robust clinical activity with a manageable safety profile in previously treated patients with BRAFV600E-mutant NSCLC, the clinical effect of this regimen on treatment-naive patients has not yet been characterised.
Added value of this study
We found that combination dabrafenib plus trametinib had substantial and durable antitumour activity in patients with previously untreated BRAFV600E-mutant metastatic NSCLC. The safety profile was tolerable, with no unexpected safety issues observed with dabrafenib plus trametinib in this setting.
Implications of all the available evidence
To our knowledge, this trial is the first to assess combination BRAF and MEK inhibition in patients with previously untreated BRAFV600E-mutant NSCLC. Notably, the overall response and median progression-free survival observed with combination dabrafenib plus trametinib were similar when compared indirectly with those of previously treated patients in cohort B of this study. Although cross-trial comparisons should be undertaken with caution, the antitumour activity observed in the current study seems to be similar to that observed for other targeted therapies, including EGFR tyrosine kinase inhibitors and ALK inhibitors in selected patient populations. Additionally, owing to the rarity of this patient population and the loss of clinical equipoise that precludes randomisation versus chemotherapy given the data for the combination in previously treated patients, a randomised trial in patients with BRAFV600E-mutant NSCLC would be infeasible. As such, the results of this study provide evidence to support a change in the management of patients with BRAFV600E-mutant NSCLC, a population in which additional therapeutic options are still needed.