Dabrafenib Plus Trametinib Significantly Improves PFS in BRAF V600E-Positive Advanced Thyroid Cancer
Key Insights
Dabrafenib plus trametinib extended median progression-free survival to 12.8 months versus 3.7 months with placebo in previously treated BRAF V600E-positive differentiated thyroid cancer (search) (HR: 0.38; p<0.0001).
The overall response rate reached 57% with the combination therapy compared to just 4% with placebo, including a 6% complete response rate.
Safety findings were consistent with the known profile of the regimen, with pyrexia (48%) and anemia (45%) as the most common adverse events.
Dabrafenib plus trametinib demonstrated statistically and clinically significant improvements in progression-free survival and overall response rate compared with placebo in previously treated patients with locally advanced or metastatic, radioactive iodine-refractory, BRAF V600E-positive differentiated thyroid cancer (search), according to findings from a global phase III randomized trial published in The Lancet Oncology.
The double-blind, placebo-controlled trial enrolled 153 patients from 42 sites across 11 countries between December 2021 and May 2024. Participants had locally advanced or metastatic radioactive iodine-refractory BRAF V600E-positive differentiated thyroid cancer (search) and had progressed after one or two prior VEGFR-targeted therapies. Patients were randomly assigned in a 2:1 ratio to receive either dabrafenib 150 mg twice daily plus trametinib 2 mg once daily or matched placebo.
Efficacy Outcomes
After a median follow-up of 17.4 months, median progression-free survival reached 12.8 months in the dabrafenib plus trametinib group compared with 3.7 months in the placebo group (hazard ratio: 0.38; 95% CI: 0.25–0.57; p<0.0001). The progression-free survival benefit was generally consistent across most predefined subgroups.
The overall response rate was substantially higher with the combination therapy at 57% versus 4% for placebo (p<0.0001). Complete responses were observed in 6% of patients receiving dabrafenib plus trametinib compared with 2% in the placebo group, while partial responses occurred in 51% versus 2%, respectively. The disease control rate was 88% with the combination versus 63% with placebo.
Overall survival did not reach statistical significance at the planned interim analysis. Median overall survival was not reached in the dabrafenib plus trametinib group and was 25.9 months in the placebo group (HR: 0.66; 95% CI: 0.36–1.19; p=0.083). The authors noted that the analysis was limited by the low number of events and by crossover after centrally confirmed disease progression; by the data cutoff, 30 of 31 patients in the placebo group with disease progression had crossed over to open-label dabrafenib plus trametinib. The median duration of response had not been reached at the time of analysis.
Safety Profile
Safety findings were consistent with the known profile of dabrafenib plus trametinib, with no new safety signals reported. Adverse events of any grade occurred in 98% of patients receiving the combination and 90% of those receiving placebo. Pyrexia was the most commonly reported adverse event, affecting 48% of treated participants, followed by anemia at 45%.
Serious adverse events of any grade were reported in 43% of patients receiving dabrafenib plus trametinib and 25% of those receiving placebo. Pneumonia was the most frequent grade 3 or higher adverse event, occurring in 8% versus 2% of patients. Serous retinopathy was reported in 7% of patients in the combination group and in no patients in the placebo group. Adverse events leading to treatment discontinuation occurred in 8% of patients receiving dabrafenib plus trametinib and 6% of those receiving placebo. One treatment-related death due to cerebrovascular accident occurred in the combination therapy group.
Clinical Implications
The mean patient age was 62.6 years; 52% were female, and 86% were Asian. All patients had papillary thyroid cancer confirmed by pathology, and most had received one prior VEGFR-targeted therapy. Randomization was stratified by the number of prior VEGFR-targeted therapies and prior lenvatinib treatment.
"Dabrafenib plus trametinib showed statistically and clinically significant improvements in progression-free survival and overall response rate with no new safety signals," the investigators concluded. "Hence, dabrafenib plus trametinib should be considered a new standard of care for the treatment of patients with previously-treated, locally advanced or metastatic, radioactive iodine-refractory BRAF V600E (search)-positive, differentiated thyroid cancer."
Ming Gao, MD, of the Department of Thyroid and Breast Surgery, Tianjin Union Medical Center, The First Affiliated Hospital of Nankai University, Tianjin, China, served as the corresponding author for the study.