First-Line Lenvatinib Versus Dabrafenib Plus Trametinib (D+T) in BRAF-Mutated Differentiated Thyroid Cancer (DTC): Insights From Real-World Data

Background
BRAF mutations are present in approximately 40%–60% of patients with DTC. Lenvatinib is the NCCN Category 1 preferred first-line (1L) systemic therapy for progressive radioiodine-refractory (RAI-R) DTC—including BRAF-mutated disease. For patients with BRAF V600E–positive, RAI-R DTC, BRAF-targeted therapy is recommended for those unsuitable for lenvatinib or as a 2L agent for patients after disease progression or intolerance to one or more prior multikinase inhibitors. This analysis compares real-world effectiveness of 1L treatment with lenvatinib versus D+T in patients with BRAF-mutated tumors.

Methods
Patients with DTC who initiated lenvatinib monotherapy (n = 319; Dec 2014–Jul 2025) or D+T (n = 131; June 2016–Sept 2025) were identified from the Tempus multimodal real- world database. Among them, 88 patients were treated with lenvatinib and 54 patients were treated with D+T as 1L therapy for DTC harboring BRAF V600E and/or K601E mutations. Retrospective analyses in this patient cohort (n = 142) were performed to compare real-world progression-free survival (rwPFS) and overall survival (exploratory; rwOS) between patients treated with 1L lenvatinib and those treated with 1L D+T in BRAF-mutated DTC.

Results
Of the 142 patients in the study cohort who were treated with lenvatinib or D+T, the median age was 66 years (interquartile range: 57–74); 45% of patients were female and 55% were male. The majority (75%) of patients were White, 5.7% were Asian, 3.4% were African American, and 16% had their race categorized as “Other.” Papillary, follicular, and Hürthle histology accounted for 92%, 0.7%, and 1.4% of patients, respectively, while the remaining 6% had uncommon or unspecified histology. Demographics and clinical characteristics were balanced between patients treated with 1L lenvatinib or D+T. At median follow-up of 33.6 months, median rwPFS indexed from treatment initiation dates was 17.0 months (95% confidence interval [CI], 12.2–27.8) in patients treated with lenvatinib and 6.2 months (95% CI, 4.9–8.7) in patients treated with D+T (hazard ratio [HR] for lenvatinib vs D+T, 0.44 [95% CI, 0.28–0.69]. Median rwOS was 70.7 months (95% CI, 51.8 – 90.8) in patients treated with lenvatinib, and 37.8 months (95% CI, 16.4–66.4) in patients treated with D+T (HR for lenvatinib vs D+T, 0.34 [95% CI, 0.18–0.62]). Sensitivity analyses showed that rwPFS and rwOS benefits associated with lenvatinib were maintained irrespective of age, sex, or race.

Conclusions
In this retrospective study of real-world data, 1L therapy with lenvatinib demonstrated longer rwPFS and rwOS compared with 1L D+T in patients with DTC harboring BRAF mutations. While recognizing the inherent limitations of real-world data, this study has implications regarding the sequencing of agents used to treat patients with BRAF-mutated RAI- R DTC.