Background: Anaplastic thyroid cancer (ATC) is a rare and lethal tumor of thyroid epithelium, with disease-specific mortality approaching 100%. ATC accounts for > 50% of the 1200 annual deaths attributable to thyroid cancer. In the pre-molecular era, treatment options were largely ineffective, reflected in a median overall survival of 3-4 months following diagnosis. Outcomes have improved in BRAF V600E-mutated ATC with the FDA approval of dabrafenib and trametinib (Subbiah et al. JCO, 2018). However, a significant need exists for patients with BRAF wild-type tumors and patients with BRAF-mutated tumors who progress following treatment with BRAF-directed therapies. Abemaciclib is a CDK4/6 inhibitor currently FDA-approved in combination with endocrine therapy for hormone-positive breast cancer. Genomic analyses of ATC have indicated the presence of an intact Rb (Retinoblastoma) expression as well as the existence of CDKN2A (the gene encoding human p16) mutations in up to 32% of patients with ATC (Khan et al., Head Neck, 2019). Moreover, Lee et al. in 2008 reported undetectable p16 levels in 24 out of 27 (89%) patients with ATC. Low p16 levels would be expected to result in accelerated S phase entry, leading to uncontrolled ATC growth. Finally, studies in mouse xenograft models have demonstrated that ribociclib (a CDK4/6 inhibitor) slows proliferation and induces apoptosis of ATC cells (Lee et al., Cancer Letters, 2018). These molecular alterations and pre-clinical data provide a mechanistic rationale by which to evaluate CDK4/6 inhibitors in ATC and, to date, no CDK4/6 inhibitors have been evaluated in thyroid cancer. Methods: This multicenter, single-arm Phase 2 study will evaluate the safety and efficacy of treatment with abemaciclib in patients with histologically confirmed unresectable or metastatic ATC, using an optimal Simon two-stage design. Patients with BRAF V600E+ ATC must have progressed on or have an intolerance to dabrafenib and trametinib. The study intervention is abemaciclib 200 mg orally twice daily. The primary endpoint is overall response rate at eight weeks from the start of treatment. Secondary endpoints include progression-free survival and overall survival. Currently, 6 patients have been enrolled. Planned genomic analysis will be conducted to identify potential predictive biomarkers. Clinical trial information: NCT04552769.