Combination Targeted Therapy with Lenvatinib and Pembrolizumab in Progressive, Radioiodine-Refractory Differentiated Thyroid Cancers.

ABSTRACT

PURPOSE: Lenvatinib, a potent multi-kinase inhibitor, improves progression-free survival (PFS) in patients with radioiodine (RAI)-refractory differentiated thyroid cancer (DTC); however, most patients experience disease progression, warranting further therapy. We evaluated the efficacy and safety of combination lenvatinib plus pembrolizumab (LP) in these patients. PATIENTS AND METHODS: We enrolled patients with progressive, RAI-refractory DTC that were either naïve to multi-kinase inhibitors (cohort 1) or who had progressed on lenvatinib (cohort 2). Patients received oral lenvatinib daily (cohort 1, 20 mg; cohort 2, dose at progression ) and intravenous pembrolizumab (200 mg) every 21 days. RESULTS: 30 and 27 patients were enrolled in cohort 1 and 2, respectively. Adverse events were consistent with those observed in other cancers. In cohort 1, the confirmed overall response rate (ORR) was 65.5%. There were no complete responses (CR, primary endpoint). The 12 and 18-month PFS were 72.0% and 58.0%, respectively, and median PFS was 26.8 months. In cohort 2, the confirmed ORR was 16% (primary endpoint), and median PFS was 10.0 months (95% CI; 7.0-17.9 months). Tumor histology, driver mutations, and immune-related biomarkers, including PD-L1 expression, thyroid-specific antibody levels, and CD8+ T cell tumor infiltrate, did not correlate with response to therapy. Increased baseline peripheral blood monocytes and neutrophil to lymphocyte ratio were associated with a worse PFS in cohort 1. CONCLUSIONS: Combination lenvatinib plus pembrolizumab may enhance the durability of lenvatinib monotherapy in lenvatinib-naïve patients. Furthermore, the addition of pembrolizumab may be a viable salvage therapy for patients who have progressed on lenvatinib.