In a global phase III trial reported in The Lancet Oncology by Gao et al, dabrafenib plus trametinib significantly improved 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.
Study Details
The trial focused on patients with limited later-line treatment options: those whose disease had progressed after one or two prior VEGFR-targeted therapies and who had an ECOG performance status of 0 to 2.
Investigators enrolled 153 patients from 42 sites in 11 countries. Patients were randomly assigned 2:1 to receive dabrafenib plus trametinib or matching placebos. Dabrafenib was given at 150 mg twice daily, and trametinib was given at 2 mg once daily. Randomization was stratified by the number of prior VEGFR-targeted therapies and prior lenvatinib treatment.
The primary endpoint was progression-free survival by blinded independent review committee assessment according to RECIST version 1.1. Key secondary endpoints included overall response rate, overall survival, duration of response, and safety.
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.
Key Findings
At a median follow-up of 17.4 months, dabrafenib plus trametinib extended median progression-free survival to 12.8 months, compared with 3.7 months with placebo (hazard ratio [HR] = 0.38, P < .0001). The progression-free survival benefit was generally consistent across most predefined subgroups.
Responses were also more frequent with the combination. The overall response rate was 57% with dabrafenib plus trametinib vs 4% with placebo (P < .0001), including complete responses in 6% vs 2% of patients and partial responses in 51% vs 2%. The disease control rate was 88% vs 63%.
Overall survival did not significantly differ at the planned interim analysis. Median overall survival was not reached with dabrafenib plus trametinib and was 25.9 months with placebo (HR = 0.66, P = .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 was not reached in either group.
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 patients receiving placebo. The most common adverse events with dabrafenib plus trametinib were pyrexia, reported in 48% of patients, and anemia, reported in 45%.
Serious adverse events occurred in 43% of patients receiving dabrafenib plus trametinib and 25% of those receiving placebo. Pneumonia was the most common grade 3 or worse adverse event, occurring in 8% vs 2% of patients. Adverse events led to treatment discontinuation in 8% and 6%, respectively. Serous retinopathy was reported in 7% of patients in the dabrafenib plus trametinib group and in no patients in the placebo group.
“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–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, is the corresponding author for The Lancet Oncology article.
DISCLOSURE: The study was funded by Novartis Pharmaceuticals. For full disclosures of the study authors, visit thelancet.com.
