Efficacy and safety of dabrafenib plus trametinib in adults with differentiated thyroid cancer: a randomised, double-blind, placebo-controlled, phase 3 trial
Mené sur 153 patients atteints d'un cancer différencié de la thyroïde avec mutation BRAFV600E et réfractaire à l'iode radioactif (âge médian : 62,6 ans ; durée médiane de suivi : 17,4 mois), cet essai international de phase III évalue l'efficacité, du point de vue de la survie sans progression, et la toxicité d'un traitement combinant dabrafénib et tramétinib
Background: In preliminary studies, dabrafenib plus trametinib showed clinically beneficial results in patients with radioactive iodine-refractory BRAFV600E-positive differentiated thyroid cancer. However, the combination has not been studied in a phase 3 trial yet. To address this, we studied the efficacy and safety of dabrafenib plus trametinib in patients with radioactive iodine-refractory BRAFV600E-positive differentiated thyroid cancer.
Methods: In this phase 3, global, randomised, double-blind, placebo-controlled trial, previously treated patients aged ≥18 years with locally advanced or metastatic, radioactive iodine-refractory BRAFV600E-positive differentiated thyroid cancer and Eastern Cooperative Oncology Group performance status 0–2 were enrolled from 42 sites in 11 countries. Participants were randomly assigned (2:1) to receive either dabrafenib (150 mg orally; twice daily) plus trametinib (2 mg orally; once daily) or matching placebos. Randomisation was computer generated and was stratified by the number of previous vascular endothelial growth factor receptor-targeted therapies and previous lenvatinib treatment with block sizes of six per stratum combination. Patients, investigators, and funders were masked to treatment assignment. The primary endpoint was progression-free survival, defined as time from randomisation or start of the treatment to first progression or death, assessed by the blinded independent review committee per Response Evaluation Criteria in Solid Tumors version 1.1 in all randomly assigned patients. The secondary outcomes were overall survival, overall response rate, duration of response, and safety. This trial is registered with ClinicalTrials.gov, NCT04940052, and is ongoing.
Findings: From Dec 10, 2021, to May 09, 2024, 153 patients with differentiated thyroid cancer were assigned to receive either dabrafenib plus trametinib (n=101) or placebo (n=52). 73 (48%) participants were male and 80 (52%) participants were female, mean age was 62·6 years (SD 10·2), 18 (12%) participants were White, 131 (86%) were Asian, three (2%) were Black or African American, and one (1%) was from multiple races. With a median follow-up of 17·4 months (IQR 10·5–25·2), progression-free survival was significantly longer in patients in the dabrafenib plus trametinib group compared with those in the placebo group (median 12·8 months [95% CI 10·2–21·2] vs 3·7 months [2·3–7·5]; stratified hazard ratio [HR] 0·38, 95% CI 0·25–0·57; p<0·0001). Dabrafenib plus trametinib treatment resulted in a significantly higher overall response rate (58 [57%] of 101) compared with placebo (two [4%] of 52; stratified difference 53% [95% CI 42–64, p<0·0001]). An interim analysis of overall survival did not achieve significance for dabrafenib plus trametinib over placebo (stratified HR 0·66, 95% CI 0·36–1·19; p=0·083]. The median duration of response was not reached. The most common grade 3 or worse adverse event was pneumonia, which occurred in eight (8%) of 101 patients in the dabrafenib plus trametinib group and one (2%) of 52 patients in the placebo group. Any-grade serious adverse events occurred in 43 (43%) patients in the dabrafenib plus trametinib group and 13 (25%) patients in the placebo group. One (1%) on-treatment death occurred in the dabrafenib plus trametinib group due to cerebrovascular accident, which was assessed by the investigator as related to the study drug. The most common adverse event in the dabrafenib plus trametinib group was pyrexia (n=48; 48%). Adverse events leading to discontinuation occurred in eight (8%) patients in the dabrafenib plus trametinib group and three (6%) patients in the placebo group. Grade 5 adverse events of pneumonia (n=2; 2%), bradycardia (n=1; 1%), cerebrovascular accident (n=1; 1%), septic shock (n=1; 1%), and squamous cell carcinoma (n=1; 1%) occurred in the dabrafenib plus trametinib group and events of pericardial effusion and multiple organ dysfunction syndrome occurred in one patient each (2%) the placebo group. Serous retinopathy adverse events were seen in seven (7%) patients in the dabrafenib plus trametinib group and none in the placebo group.
Interpretation: In previously-treated patients with locally advanced or metastatic, radioactive iodine-refractory BRAFV600E-positive differentiated thyroid cancer, dabrafenib plus trametinib showed significant benefits for progression-free survival and overall response rate, with no new safety signals. These findings support the second-line use of dabrafenib plus trametinib in patients with radioactive iodine-refractory BRAFV600E-positive differentiated thyroid cancer.
The Lancet Oncology , résumé, 2026