*2.1. Patient Characteristics*

Twenty-two patients (11 female) with advanced radioiodine refractory DTC fulfilled the inclusion criteria. The mean age at primary presentation was 53.1 ± 13.1 years and 60.8 ± 13.7 years at Lenvatinib treatment start. For most of the patients (*n* = 12), the histological subtype was FTC, followed by 7 PDTC and 3 PTC patients. Ten patients initially presented with stage IV, 9 patients with stage III and 3 patients with stage II DTC according to the seventh edition of the American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging system. A total of 4 out of 12 patients with FTC showed vascular invasion. Histopathological data of study patients are presented in Tables S1 and S3 in the supplements. Seven patients already showed distant metastases at primary presentation (5/7 patients with pulmonary metastases). At Lenvatinib treatment start, the majority of the patients (*n* = 20) showed advanced metastatic disease and in 14 patients, more than one site was affected. Metastatic sites were most frequently the

lung (*n* = 19), followed by lymph nodes (*n* = 12), bone (*n* = 5), pleura (*n* = 2), liver (*n* = 2), subcutaneous metastases (n = 1), brain (*n* = 1) and kidney (*n* = 1). Local recurrence occurred in 6/22 patients (2/6 without distant metastases). Mean Thyroglobulin (Tg)-level at treatment start was 3950 ± 7062 ng/mL.

Prior to start of Lenvatinib treatment, all patients had total thyroidectomy with or without lymphadenectomy. Surgery had been followed by RIT for remnant ablation. Additionally, 15/22 patients received more than two courses of RIT (range 2–11), 12/22 patients had undergone further surgery/metastasectomy, 13/22 had received external beam radiotherapy, 9/22 patients had been treated with TKIs other than Lenvatinib (Sorafenib *n* = 7, Pazopanib *n* = 3, Cabozantinib *n* = 2), 2/22 had received chemotherapy and one patient had undergone redifferentiation therapy with Dabrafenib. Single-patient characteristics are presented in Table S1 in the supplemental information.

In 14/22 patients, treatment was initiated at full dose (daily dose of 24 mg per day) and 8/22 patients received reduced dosage (20 mg per day *n* = 1, 18 mg per day *n* = 3, 14 mg per day *n* = 3, 10 mg per day *n* = 1). The mean Lenvatinib dose during treatment was 17.7 ± 4.2 mg/die. Dose interruptions and incremental reductions in the dose because of toxic effects were seen in 16/22 patients. The most frequent adverse effects were hypertension (*n* = 14), fatigue (*n* = 12), decreased appetite (*n* = 12), diarrhea (*n* = 11) and nausea (*n* = 6).
