Dabrafenib Combo Confers PFS Benefit in RAI-Refractory BRAF V600-Mutant DTC

In a phase 3 study (NCT04940052), the combination of dabrafenib (Taflinar) plus trametinib (Mekinist) (D+T) delivered significant benefits in progression-free survival (PFS) and overall response rate (ORR) vs placebo in patients with radioactive iodine (RAI)-refractory BRAF V600-mutated differentiated thyroid cancer (DTC), further validating the therapeutic use of this treatment for this indication.¹

Primary analysis data were presented by Lori J. Wirth, department of Medicine at Massachusetts General Hospital, at the 2025 European Society for Medical Oncology (ESMO) Congress. Notably, in the overall population, D+T significantly prolonged PFS compared with the placebo (12.8 months vs 3.7 months; P <.001), amounting to a hazard ratio (HR) of 0.38 (95% CI, 0.25–0.57). This benefit was consistent across all demographic and clinical subgroups.

Regarding secondary end points, the combination also demonstrated a higher confirmed ORR compared with the placebo (57.4% vs 3.8%), with a stratified difference of 53.4% (95% CI, 42.3%–64.5%, P <.001); this benefit was also consistent across all prespecified subgroups.

Further, the median overall survival (OS) in the placebo arm was 25.9 months; while median OS for the D+T arm was not mature at the time of the presentation, the data thus far appears to favor the combination with a HR of 0.66, although Wirth noted that the 95% confidence interval crosses 1 (0.36–1.19).

What were the study’s design and patient characteristics?

In this global, multicenter, randomized, double-blind phase 3 study, 153 adult patients with locally advanced or metastatic DTC were randomized 2:1 to receive either D+T combination therapy (n=101) or placebo (n=52), with a median follow-up time of 17.4 months.² Patients in the placebo were also eligible to crossover to D+T following centrally confirmed disease progression. Those in the D+T arm received 150 mg of dabrafenib twice a day and 2 mg of trametinib once daily.

The primary end point of the study was PFS per blinded independent central review (BICR) assessment. Secondary end points included ORR, OS, and safety and tolerability.

Patient inclusion criteria included being positive for a BRAF V600E mutation, refractory to RAI, and having 1 or 2 prior vascular endothelial growth factor receptor (VEGFR) targeted treatments. Randomization stratification factors included whether the patient had received prior lenvatinib (Lenvima) and number of prior VEGFR targeted therapies.

Baseline characteristics of patients were generally well balanced between arms. Of note, 85.6% (n=131) of the overall patient population were Asian, comprising 89.1% (n=90) of the D+T arm and 78.8% (n=41) of the placebo arm.

What were the safety findings?

In terms of safety, the safety profile was consistent with the established safety profile of D+T, with no unexpected safety signals reported. The most commonly occurring adverse events (AEs) in the D+T arm included pyrexia (47.5%) and anemia (44.6%); pyrexia was also the most common treatment-related serious AE (3%). There were also numerous laboratory AEs observed in those who received D+T, including anemia, hypoglycemia, and decreases in neutrophil and white blood cell counts, but Wirth remarked that most events were grades 1 or 2. About 8% of patients who received D+T had treatment-related AEs that led to discontinuation.

“These [efficacy and safety] results do support the use of [D+T] in patients with previously treated, locally advanced and/or metastatic RAI-refractory BRAF-mutated DTC,” concluded Wirth during the presentation.¹

DISCLOSURES: Wirth declared a consulting role with Eisai, Inc, Coherus BioSciences, AbbVie Inc, Bicara Therapeutics, Fore Biotherapeutics, Leo Pharma, Pyxis, Tubulis, Merck, and Novartis.

REFERENCES:

1. Wirth, LJ. Efficacy and safety of dabrafenib plus trametinib (D+T) in patients with radioactive iodine (RAI)-refractory BRAF V600-mutant differentiated thyroid cancer (DTC). Presented at: ESMO 2025 Congress; October 17–21, 2025; Berlin, Germany. Abstract 2987O.

2. Study of Efficacy and Safety of Dabrafenib Plus Trametinib in Previously Treated Patients With Locally Advanced or Metastatic, Radio-active Iodine Refractory BRAFV600E Mutation-positive Differentiated Thyroid Cancer. ClinicalTrials.gov. Updated September 24, 2025. Accessed October 21, 2025. https://clinicaltrials.gov/study/NCT04940052