BRAFV600E mutation is associated with better prognoses in radioactive iodine refractory thyroid cancer patients treated with multi-kinase inhibitors: a retrospective analysis of registered clinical trials.

Background: The antiangiogenic multi-kinase inhibitors (MKIs) apatinib, donafenib, and anlotinib have demonstrated satisfactory efficacy in radioactive iodine refractory differentiated thyroid cancer (RAIR-DTC) in their phase II/III trials. However, the potential impact factors on the efficacy of these MKIs remain unclear.

Methods: RAIR-DTC patients enrolled in clinical trials of apatinib, donafenib, and anlotinib in our center were retrospectively reviewed. The Kaplan-Meier method was used to examine the relationship between clinicopathological variables and progression-free survival (PFS) and overall survival (OS), followed by a multivariate Cox analysis on PFS.

Results: A total of 71 progressive RAIR-DTC patients were reviewed, of which 26.7% were treated by anlotinib, 45.1% by apatinib, and 28.2% by donafenib. The median follow-up time was 44.1 months, the median PFS was 21.1 months, and the estimated median OS was 47.7 months. PFS and OS showed no significant differences in patients treated with apatinib, donafenib, or anlotinib. In the univariate analyses, patients with BRAF^V600E mutation showed longer PFS (HR 0.345, 95% CI 0.187-0.636, p < 0.001) and OS (HR 0.382, 95% CI 0.166-0.878, p = 0.019) compared with patients with wild-type BRAF. Patients with follicular thyroid cancer and bone metastases had shorter PFS, and patients with worse Eastern Cooperative Oncology Group performance status, bone metastases, and a larger tumor burden had shorter OS. In the multivariate Cox analysis, BRAF^V600E mutation was the only independent predictor of longer PFS (HR 0.296, 95% CI 0.138-0.638, p = 0.002). The overall response rate and disease control rate didn't differ between BRAF^V600E mutation status. Subgroup analysis of PFS in papillary thyroid cancer patients stratified by BRAF^V600E mutation status showed that BRAF^V600E mutation was associated with longer PFS in all clinicopathological subgroups (hazard ratio < 1).

Conclusion: RAIR-DTC patients with BRAF^V600E mutation treated with apatinib, donafenib, or anlotinib achieved better prognoses compared with patients with wild-type BRAF, indicating that the genetic background may play a role in predicting the efficacy of MKIs therapies.

Trial registration: This retrospective cohort included patients in our center from clinical trials of apatinib (NCT02731352, NCT03048877), donafenib (NCT02870569, NCT03602495), and anlotinib (NCT05007093).