目标：本研究旨在评估程序性死亡-1（PD-1）抑制剂联合酪氨酸激酶抑制剂（TKI）治疗与TKI单药治疗作为转移性非明显细胞肾癌（nccRCC）患者第二线方案的疗效和安全性。方法：回顾性分析了2011年10月至2020年9月间失败一线TKI治疗的67例转移性nccRCC患者的临床病理资料，其中22例接受TKI单药治疗，45例接受TKI加PD-1抑制剂作为第二线治疗。根据实体肿瘤疗效评价标准1.0/1.1（RECIST 1.0/1.1）评估疗效，使用Kaplan-Meier方法绘制生存曲线，采用Log rank检验分析两组患者生存差异。观察两组治疗后的治疗相关不良事件（AEs）。结果：总体客观缓解率（ORR）为37.3%（25/67），疾病控制率（DCR）为56.7%（38/67）。总体第二线进展无进展生存期（PFS）为7.7个月，总生存期（OS）为25.2个月。联合治疗组患者的ORR和DCR分别为48.9%（22/45）和71.1%（32/45），明显优于TKI单药组[13.6%（3/22）和27.3%（6/22），P=0.007和P=0.001]。联合治疗组二线治疗的中位PFS为9.2个月，显著高于TKI单药组（5.2个月，P=0.001），但两组中位OS在统计学上无显著差异（28.2个月对20.8个月，P=0.068）。常见的治疗相关不良事件包括高血压、腹泻、乏力、口腔炎、手足综合征和甲状腺功能减退症。联合治疗组甲状腺功能减退症的发生率[40.0%（18/45）]高于TKI单药组[22.7%（5/22），P=0.044]；两组其他治疗相关不良事件的发生率在统计学上没有显著差异（均P>0.05）。结论：免疫靶向联合治疗比TKI单药治疗更为有效，并且在一线TKI治疗失败的转移性nccRCC患者中具有良好的耐受性。

Objective: This study aimed to evaluate the efficacy and safety of programmed death-1 (PD-1) inhibitor combined tyrosine kinase inhibitor (TKI) therapy versus TKI monotherapy as the second-line regimen for patients with metastatic non-clear cell renal carcinoma (nccRCC) who failed first-line TKI therapy. Methods: The clinicopathological data of 67 patients with metastatic nccRCC who failed first-line TKI therapy between October 2011 and September 2020 were retrospectively analyzed, including 22 patients who received TKI monotherapy and 45 patients who received TKI plus PD-1 inhibitor as the second-line therapy. The efficacy was assessed according to Response Evaluation Criteria in Solid Tumors version 1.0/1.1 (RECIST 1.0/1.1), the Kaplan-Meier method was used to plot the survival curves, and the Log rank test was used to analyze the differences in the survival between the two groups. Treatment-related adverse events (AEs) after treatment were observed in both groups. Results: The overall objective response rate (ORR) and disease control rate (DCR) were 37.3% (25/67) and 56.7% (38/67), respectively. The overall second-line progression-free survival (PFS) was 7.7 months and Overall Survival (OS) was 25.2 months. The ORR and DCR of patients in the combination therapy group were 48.9% (22/45) and 71.1% (32/45), respectively, which were significantly improved compared with the TKI monotherapy group [13.6% (3/22) and 27.3% (6/22), respectively] (P=0.007 and P=0.001, respectively). The median PFS of 9.2 months for second-line treatment was longer in patients in the combination therapy group than in the TKI monotherapy group (5.2 months, P=0.001), but the median OS was not statistically different between the two groups (28.2 months vs 20.8 months, P=0.068). Common treatment-related AEs included hypertension, diarrhea, fatigue, stomatitis, hand-foot syndrome, and hypothyroidism. The incidence of hypothyroidism was higher in the combination therapy group [40.0% (18/45)] than in the TKI monotherapy group [22.7% (5/22), P=0.044]; the incidence of other treatment-related AEs between the two groups were not statistically significant (all P>0.05). Conclusion: Immune-targeted combination therapy was more effective than TKI monotherapy alone and was well tolerated in the treatment of metastatic nccRCC patients who failed first-line TKIs.