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.

中文翻译：

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Lenvatinib 和 Pembrolizumab 联合靶向治疗进展性放射性碘难治性分化型甲状腺癌


目的：乐伐替尼是一种有效的多激酶抑制剂，可改善放射性碘（RAI）难治性分化型甲状腺癌（DTC）患者的无进展生存期（PFS）；然而，大多数患者会出现疾病进展，需要进一步治疗。我们评估了乐伐替尼联合派姆单抗（LP）在这些患者中的疗效和安全性。患者和方法：我们招募了患有进行性 RAI 难治性 DTC 的患者，这些患者要么未曾接受过多激酶抑制剂（第 1 组），要么在接受仑伐替尼治疗后出现进展（第 2 组）。患者每天接受口服乐伐替尼（队列 1，20 毫克；队列 2，进展时剂量），每 21 天静脉注射派姆单抗（200 毫克）。结果：第 1 组和第 2 组分别有 30 名和 27 名患者入组。不良事件与其他癌症中观察到的一致。在队列 1 中，确认的总体缓解率 (ORR) 为 65.5%。没有完全缓解（CR，主要终点）。 12 个月和 18 个月的 PFS 分别为 72.0% 和 58.0%，中位 PFS 为 26.8 个月。在队列 2 中，确认的 ORR 为 16%（主要终点），中位 PFS 为 10.0 个月（95% CI；7.0-17.9 个月）。肿瘤组织学、驱动突变和免疫相关生物标志物，包括 PD-L1 表达、甲状腺特异性抗体水平和 CD8+ T 细胞肿瘤浸润，与治疗反应无​​关。基线外周血单核细胞和中性粒细胞与淋巴细胞比率的增加与队列 1 中较差的 PFS 相关。 结论：乐伐替尼加派姆单抗联合治疗可能会增强未接受过乐伐替尼患者的乐伐替尼单药治疗的持久性。此外，对于使用仑伐替尼病情进展的患者来说，添加派姆单抗可能是一种可行的挽救疗法。