In a Belgian two-center phase II trial reported in The Lancet Oncology, Schreuer et al found that rechallenge with the BRAF inhibitor dabrafenib (Tafinlar) and the MEK inhibitor trametinib (Mekinist) showed activity in patients with BRAF V600–mutant melanoma whose disease had progressed on BRAF inhibitor treatment. Some data suggest that acquired resistance to BRAF inhibition may be reversible.
In the study, 25 patients who had previously received a MEK inhibitor and a BRAF inhibitor and whose disease had progressed on BRAF inhibitor treatment were enrolled between April 2014 and February 2016 and treated with dabrafenib at 150 mg orally twice daily plus trametinib at 2 mg orally once daily. Patients had to have been off BRAF inhibitor treatment for ≥ 12 weeks. All patients had received immune checkpoint inhibitor treatment after their first BRAF inhibitor treatment (with or without MEK inhibitor treatment). The primary endpoint was the proportion of patients with investigator-assessed overall response.
Responses and Toxicity
Partial response was observed in eight patients (32%, 95% confidence interval [CI] = 15%–54%); of these patients, 6 had had disease progression on previous dabrafenib plus trametinib treatment and 2, on previous BRAF inhibitor monotherapy. Stable disease was observed in an additional 10 patients (40%, 95% CI = 21%–61%).
No unexpected or grade ≥ 4 adverse events were observed. Grade 3 adverse events consisted of panniculitis in one patient (4%) and pyrexia in one patient (4%). A serious adverse event occurred in one patient, who had Addison crisis triggered by grade 2 pyrexia symptoms, which resolved after discontinuation of dabrafenib and trametinib.
The investigators concluded: “Rechallenge with dabrafenib plus trametinib showed anti-tumour activity in patients who had previously progressed on BRAF inhibitors and as such, rechallenge represents a potential new treatment option for these patients.”
The study was funded by Vlaamse Liga Tegen Kanker and Novartis.
Bart Neyns, MD, of the Universitair Ziekenhuis Brussel, is the corresponding author of The Lancet Oncology article
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