PMID- 38226606 OWN - NLM STAT- MEDLINE DCOM- 20240318 LR - 20240318 IS - 1557-9077 (Electronic) IS - 1050-7256 (Linking) VI - 34 IP - 3 DP - 2024 Mar TI - Checkpoint Inhibition in Addition to Dabrafenib/Trametinib for BRAF(V600E)-Mutated Anaplastic Thyroid Carcinoma. PG - 336-346 LID - 10.1089/thy.2023.0573 [doi] AB - Background: The dabrafenib plus trametinib combination (DT) has revolutionized the treatment of BRAF(V600E)-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 (BRAF/MEKi) seems to improve outcomes compared with BRAF/MEKi alone, although no direct comparison is available. BRAF-targeted therapy before surgery (neoadjuvant approach) has also shown improvement in survival. We studied the efficacy and safety of DT plus pembrolizumab (DTP) compared with 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 January 2014 and March 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). The primary endpoint was mOS between DT and DTP. Secondary endpoints included median progression-free survival (mPFS) and response rate with DT versus DTP as initial treatments, and the exploratory endpoint was mOS in the neoadjuvant group. Results: Seventy-one patients were included in the primary analysis: n = 23 in DT and n = 48 in DTP. Baseline demographics were similar between groups, including the 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 [confidence interval CI, 11.9-22.1]) compared with DT alone (9.0 months [CI, 4.5-13.5]), p = 0.037. mPFS was also significantly improved with DTP as the initial treatment (11.0 months [CI, 7.0-15.0]) compared with DT alone (4.0 months [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 [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. FAU - Hamidi, Sarah AU - Hamidi S AUID- ORCID: 0000-0002-1528-9885 AD - Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. FAU - Iyer, Priyanka C AU - Iyer PC AD - Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. FAU - Dadu, Ramona AU - Dadu R AD - Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. FAU - Gule-Monroe, Maria K AU - Gule-Monroe MK AD - Department of Neuroradiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. FAU - Maniakas, Anastasios AU - Maniakas A AUID- ORCID: 0000-0002-4354-2841 AD - Department of Head & Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. FAU - Zafereo, Mark E AU - Zafereo ME AUID- ORCID: 0000-0001-7918-9739 AD - Department of Head & Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. FAU - Wang, Jennifer R AU - Wang JR AUID- ORCID: 0000-0002-0807-3832 AD - Department of Head & Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. FAU - Busaidy, Naifa L AU - Busaidy NL AD - Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. FAU - Cabanillas, Maria E AU - Cabanillas ME AD - Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. LA - eng PT - Journal Article DEP - 20240213 PL - United States TA - Thyroid JT - Thyroid : official journal of the American Thyroid Association JID - 9104317 RN - QGP4HA4G1B (dabrafenib) RN - 33E86K87QN (trametinib) RN - EC 2.7.11.1 (Proto-Oncogene Proteins B-raf) RN - 0 (Oximes) RN - 0 (Protein Kinase Inhibitors) RN - EC 2.7.11.1 (BRAF protein, human) RN - 0 (Imidazoles) RN - 0 (Pyridones) RN - 0 (Pyrimidinones) SB - IM MH - Humans MH - *Thyroid Carcinoma, Anaplastic/drug therapy/genetics MH - Retrospective Studies MH - Proto-Oncogene Proteins B-raf/genetics MH - Prospective Studies MH - Antineoplastic Combined Chemotherapy Protocols MH - Oximes MH - Protein Kinase Inhibitors/therapeutic use MH - *Thyroid Neoplasms/drug therapy/genetics MH - Mutation MH - *Imidazoles MH - *Pyridones MH - *Pyrimidinones OTO - NOTNLM OT - BRAFV600E OT - anaplastic thyroid carcinoma OT - dabrafenib OT - immunotherapy OT - neoadjuvant OT - trametinib EDAT- 2024/01/16 13:41 MHDA- 2024/03/18 06:43 CRDT- 2024/01/16 08:26 PHST- 2024/03/18 06:43 [medline] PHST- 2024/01/16 13:41 [pubmed] PHST- 2024/01/16 08:26 [entrez] AID - 10.1089/thy.2023.0573 [doi] PST - ppublish SO - Thyroid. 2024 Mar;34(3):336-346. doi: 10.1089/thy.2023.0573. Epub 2024 Feb 13.