Anlotinib Plus Sintilimab for BRAF V600E Negative Unresectable or Metastatic Anaplastic Thyroid Carcinoma: A Single-Center,Single-Arm,Phase 2 Trial

Abstract

Background:

Anaplastic thyroid carcinoma (ATC) is a rare and highly aggressive malignancy. Dabrafenib plus trametinib has shown efficacy in BRAF^V600E-mutant ATC, but effective therapies remain limited for patients without this mutation. This study aimed to evaluate the efficacy and safety of anlotinib plus sintilimab in BRAF^V600E-negative ATC.

Methods:

In this phase 2 trial, patients with BRAF^V600E-negative unresectable or metastatic ATC received anlotinib (12 mg orally once daily on days 1–14 of a 21-day cycle) plus sintilimab (200 mg intravenously on day 1). The primary endpoint was investigator-assessed objective response rate (ORR). This study is registered at www.chictr.org.cn, ChiCTR2200067045.

Results:

From December 27, 2022, to June 11, 2025, 21 patients were enrolled. One (4.8%) patient achieved complete response, and nine (42.9%) patients achieved partial response. The ORR and disease control rate were 47.6% (10/21) and 85.7% (18/21), respectively. After median follow-up of 9.97 months (confidence interval [CI] 6.10 to NA), 61.9% (13/21) of patients had discontinued treatment, mainly due to disease progression (7/21, 33.3%), adverse events (AEs) (2/21, 9.5%), and other reasons (4/21, 19.0%). Median progression-free survival (PFS) was 9.63 months (CI 4.03 to NA), with eight (38.1%) patients were still on treatment. Subgroup analysis showed longer PFS in patients with neutrophil–lymphocyte ratio <3.06 (18.43 vs. 3.67 months; p = 0.010) and <5 (14.23 vs. 2.67 months; p = 0.002). Median overall survival was not reached (CI 13.90 to NA), 15 (71.4%) patients remained alive. AEs occurred in 66.7% (14/21) of patients, including grade 3 AEs in 19.0% (4/21). The most common were aspartate aminotransferase (AST) increased (6/21, 28.6%) and alanine aminotransferase (ALT) increased (5/21, 23.8%). Grade 3 immune-related AEs occurred in three patients, including AST/ALT increased, diarrhea, hypertension, and hypertriglyceridemia.

Conclusions:

Anlotinib plus sintilimab showed favorable efficacy and manageable safety in BRAF^V600E-negative unresectable or metastatic ATC, supporting further investigation.