Real-World Efficacy and Safety of Lenvatinib and Sorafenib in Thyroid Cancer: A Retrospective, Propensity-Score-Matched Study

Background: Lenvatinib and sorafenib are multitargeted tyrosine kinase inhibitors (mTKIs) approved for the treatment of radioiodine-refractory thyroid cancer (TC). In the absence of direct comparative clinical trials, we leveraged real-world TriNetX data to compare their effectiveness and tolerability in progressive TC. TriNetX is a federated international electronic medical record research network that aggregates anonymized data from multiple health care organizations. Methods: This retrospective cohort study included adult patients with TC initiating lenvatinib or sorafenib. Patients with other malignancies treated with these agents or exposure to the alternative mTKI were excluded. Propensity score matching was performed to balance demographic characteristics, tumor burden, and comorbidities. The primary outcome was overall survival (OS) at 1 and 3 years. Secondary outcomes included all-cause hospitalization, emergency care utilization, and selected treatment-emergent adverse events. Exploratory subgroup analyses were performed across demographic, disease-related, and comorbidity strata. Results: With matched cohorts of 214 patients in each arm, lenvatinib was associated with significantly improved OS compared with sorafenib at both 1 year (78.5% vs. 64.5%; hazard ratio HR with confidence interval CI 0.538 0.373–0.775) and 3 years (62.1% vs. 45.8%; HR with CI 0.590 [0.444–0.784). All-cause hospitalization and emergency care admission rates were comparable. Hematological adverse events occurred more frequently with sorafenib, while renal and cardiovascular events trended higher with lenvatinib. Survival benefits with lenvatinib were consistent across subgroups and appeared especially pronounced in patients with high tumor burden. Conclusions: Lenvatinib was associated with improved OS compared with sorafenib in patients with TC, with broadly comparable safety profiles. These findings, based on retrospective real-world data, support the use of lenvatinib as a preferred first-line mTKI in line with current treatment paradigms.