Checkpoint Inhibition in Addition to Dabrafenib/Trametinib for BRAF V600E Mutated Anaplastic Thyroid Carcinoma.

BACKGROUND: The dabrafenib plus trametinib combination (DT) has revolutionized treatment of BRAFV600E-mutated anaplastic thyroid carcinoma (BRAFm-ATC). However, patients eventually develop resistance and progress. Single-agent anti-PD-1 inhibitor spartalizumab has shown a median overall survival (mOS) of 5.9 months. Combination of immunotherapy with BRAF/MEK inhibitors seems to improve outcomes compared to BRAF/MEK inhibitors alone, although no direct comparison is available. BRAF-targeted therapy prior to surgery (neoadjuvant approach) has also shown improvement in survival. We studied the efficacy and safety of DT plus pembrolizumab (DTP) compared to current standard of care DT alone as an initial treatment, as well as in the neoadjuvant setting.

METHODS: Retrospective single-center study of patients with BRAFm-ATC treated with first-line BRAF-directed therapy between 1/2014 and 3/2023. Three groups were evaluated: DT, DTP (pembrolizumab added upfront or at progression), and neoadjuvant (DT before surgery, and pembrolizumab added before or after surgery). Primary endpoint was mOS between DT and DTP. Secondary endpoints included median progression-free survival (mPFS) and response rate with DT vs DTP as initial treatments, and exploratory endpoint was mOS in neoadjuvant group.

RESULTS: 71 patients were included in the primary analysis: n=23 in DT, n=48 in DTP. Baseline demographics were similar between groups, including presence of metastatic disease at start of treatment (p=0.427) and prior treatments with surgery (p=0.864) and radiation (p=0.678). mOS was significantly longer with DTP (17.0 months [95%CI,11.9-22.1]) compared to DT alone (9.0 months [95%CI,4.5-13.5]), p=0.037. mPFS was also significantly improved with DTP as the initial treatment (11.0 months [95%CI,7.0-15.0]) compared to DT alone (4.0 months [95%CI,0.7-7.3]), p=0.049. Twenty-three patients were in the exploratory neoadjuvant group, where mOS was the longest (63.0 months [95%CI,15.5-110.5]). No grade 5 adverse events (AEs) occurred in all three cohorts, and 32.4% had immune-related AEs, most frequently hepatitis and colitis.

CONCLUSIONS: Our results show that in BRAFm-ATC, addition of pembrolizumab to dabrafenib/trametinib may significantly prolong survival. Surgical resection of the primary tumor after initial BRAF-targeted therapy in selected patients may provide further survival benefit. However, conclusions are limited by the retrospective nature of the study. Additional prospective data are needed to confirm this observation.