Limited treatment options exist for "inoperable" thyroid cancers. Neoadjuvant (NEO) use of systemic tyrosine kinase inhibitors (TKI) has been anecdotally reported. We aimed to evaluate whether NEO-TKI therapy facilitates surgical resection.

Single-institution experience of patients receiving TKI for papillary (PTC), follicular (FTC) and anaplastic thyroid carcinomas (ATC) during 2018-2023 was reviewed. Our center has a well-established multidisciplinary pathway with protocol-driven management of advanced thyroid cancers. TKI regimens included dabrafenib/trametinib, lenvatinib/pembrolizumab or lenvatinib alone.

10/42 patients (median age 56 years) received NEO-TKI with intent to improve resectability of primary (n=5, 2 FTC/3 PTC) or recurrent tumors (n=5, 1 ATC/4 PTC). All had locoregionally advanced disease: cT size 9±2.6 cm with lymphadenopathy (n=9) and vital structure involvement (n=8). All were "inoperable" or resectable with unacceptable morbidities. Genomic analysis detected BRAF V600E mutation in 1/1 ATC and 6/7 PTC, and NRAS/TERT or HRAS/TERT in both FTC. NEO-TKI yielded clinical results quickly, including mass reduction and cessation of hemoptysis from tracheal invasion. Seven patients received intended surgery with R0 resection and without major surgical complications. Patients tolerated NEO-TKI well with minimal toxicity. Two years post-operatively, all patients are alive without new locoregional recurrence.

NEO-TKI seems extremely effective in downstaging surgically "inoperable" thyroid cancers to achieve R0 resection while avoiding unnecessary morbidities. Multidisciplinary approach with early genomic profiling to guide personalized NEO-TKI is essential. Prospective studies using NEO-TKI are urgently needed as this series suggests neoadjuvant therapy may have a significant role in future surgical resection strategies for thyroid cancers.