Rechallenge with dabrafenib plus trametinib possesses antitumor activity in patients with advanced BRAF V600-mutant melanoma who had previously progressed on BRAF inhibitor therapy, a study published in The Lancet Oncology has shown.1
Patients with BRAF V600 mutation-positive melanoma derive benefit from the combination of dabrafenib and trametinib, a BRAF inhibitor and MEK inhibitor, respectively; however, most patients develop resistance to these agents and ultimately disease progression.
Preclinical studies and case studies have suggested that acquired resistance to BRAF inhibition can be reversed. Therefore, researchers sought to evaluate the antitumor activity of rechallenge with dabrafenib and trametinib in a phase 2 clinical trial (ClinicalTrials.gov Identifier: NCT02296996).
For the open-label, single-arm study, investigators enrolled 25 adult patients with advanced BRAF V600-mutant melanoma who had experienced disease progression on BRAF inhibitors with or without MEK inhibitors and were off-treatment for at least 12 weeks. All participants received oral dabrafenib twice daily plus trametinib once daily.
Results showed that 32% (95% CI, 15-54) of patients achieved a partial response, including 6 patients who had progressed on previous treatment with dabrafenib plus trametinib and 2 patients who had progressed on prior BRAF inhibitor monotherapy. In addition, 40% (95% CI, 21-61) of patients exhibited stable disease.
Two patients reported grade 3 adverse events, including 1 case of panniculitis and pyrexia, each. There were no unexpected or grade 4 or 5 treatment-related adverse events, but 1 patient experienced an Addison crisis triggered by grade 2 pyrexia symptoms. No patients died due to combination dabrafenib and trametinib rechallenge.
The findings suggest that rechallenge with dabrafenib and trametinib represents a potential new treatment option for patients with BRAF V600 mutation-positive melanoma.
1. Schreuer M, Jansen Y, Planken S, et al. Combination of dabrafenib plus trametinib for BRAF and MEK inhibitor pretreated patients with advanced BRAFV600-mutant melanoma: an open-label, single arm, dual-centre, phase 2 clinical trial. Lancet Oncol. 2017 March 3. doi: 10.1016/S1470-2045(17)30171-7 [Epub ahead of print]