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Introduction: Lenvatinib has become the most commonly prescribed first-line (1L) agent for the treatment of radioactive iodine-refractory differentiated thyroid cancer (RAI-r DTC) since its approval in 2015. With no real-world studies describing clinical outcomes of 1L lenvatinib and subsequent therapy, the current study aimed to assess treatment sequencing and related clinical outcomes in patients treated with 1L lenvatinib in the USA METHODS: We conducted a multisite, retrospective chart review of US patients with a diagnosis of RAI-r DTC who had initiated 1L therapy with lenvatinib from January 1, 2016 through May 31, 2017 with follow-up through October 17, 2018. Physicians completed electronic case report forms for two patient cohorts: patients still receiving 1L lenvatinib (cohort 1) and those who had initiated second-line (2L) therapy prior to data cutoff (cohort 2). Real-world objective response rate (ORR) was assessed for both cohorts. Progression-free survival (PFS) and overall survival (OS) were assessed for cohort 2., Results: A total of 252 patients met the study criteria with 71 in cohort 1 and 181 in cohort 2. Patients were predominantly female, had papillary DTC, and had lung metastases. The ORR was 64.8% for cohort 1 and 53.6% for cohort 2. In cohort 2, median PFS from 1L lenvatinib initiation was 14.0 months (95% CI 12.7-15.0). Second-line treatments included sorafenib (49.7%), cabozantinib (19.3%), and other targeted/chemotherapy/immuno-oncology agents. The ORR in 2L therapy was 15.5%. For cohort 2, the 12-, 18-, and 24-month OS from initiation of 1L lenvatinib was 92.8%, 81.5%, and 66.9%, respectively., Conclusions: In this first real-world examination of clinical effectiveness of 1L lenvatinib and subsequent therapy among patients in the US, the results demonstrated that treatment with 1L lenvatinib followed by another 2L therapy may deliver a clinical benefit, thus allowing a number of potential 2L options following 1L lenvatinib for patients with RAI-r DTC.