Mori Kanami, Numakura Kazuyuki, Matsushita Yuto, Kojima Takahiro, Osawa Takahiro, Sazuka Tomokazu, Hatakeyama Shingo, Goto Keisuke, Yamana Kazutoshi, Kandori Shuya, Kimura Takahiro, Nishiyama Naotaka, Bando Yukari, Fujita Kazutoshi, Ueda Kosuke, Tanaka Hajime, Tomida Ryotaro, Kurahashi Toshifumi, Kitamura Hiroshi, Miyake Hideaki, Habuchi Tomonori
Department of Urology, Akita University Graduate School of Medicine, Akita, Japan.
Department of Urology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Cancer Sci. 2025 Feb;116(2):444-452. doi: 10.1111/cas.16326. Epub 2024 Nov 17.
Nivolumab plus ipilimumab (NIVO+IPI) has a long-term response rate of 30% for patients with metastatic renal cell carcinoma (mRCC). However, 20% of patients develop primary resistant disease (PRD) to NIVO+IPI and show poor survival outcomes. In this study, we aimed to evaluate the effect of PRD as a second-line treatment in patients with mRCC. The data used in this multi-institutional, retrospective cohort were collected between August 2015 and January 2023. In total, 189 patients with mRCC were treated with NIVO+IPI and then with a vascular endothelial growth factor receptor-tyrosine kinase inhibitor. Associations between PRD and progression-free survival of second-line treatment (PFS), progression-free survival 2 (PFS2), and overall survival (OS) were analyzed. The median age at NIVO+IPI initiation was 67 years in the male-dominant population (n = 140, 74.1%), and most patients had clear cell histology (n = 140, 74.1%). PRD was recorded in 42 (22.2%) of 189 patients during NIVO+IPI therapy. Patients who experienced PRD showed poor PFS (hazard ratio [HR], 1.788; 95% confidence interval [CI], 1.176-2.718; p = 0.007), PFS2 (HR, 4.127; 95% CI, 2.649-6.431; p < 0.001), and OS (HR, 3.330; 95% CI, 2.040-5.437; p < 0.001). Before starting second-line therapy, patients with PRD tended to have a poor performance status compared with non-PRD patients and a higher IMDC risk. Second-line drug therapy was not associated with treatment outcomes in patients with PRD. PRD in patients with mRCC receiving NIVO+IPI as first-line treatment was associated with poor clinical course, even with second-line therapy.
纳武利尤单抗联合伊匹木单抗（NIVO+IPI）治疗转移性肾细胞癌（mRCC）患者的长期缓解率为30%。然而，20%的患者对NIVO+IPI产生原发性耐药疾病（PRD），生存结局较差。在本研究中，我们旨在评估PRD作为mRCC患者二线治疗的效果。本多机构回顾性队列研究使用的数据收集于2015年8月至2023年1月之间。共有189例mRCC患者接受了NIVO+IPI治疗，随后接受了血管内皮生长因子受体酪氨酸激酶抑制剂治疗。分析了PRD与二线治疗无进展生存期（PFS）、无进展生存期2（PFS2）和总生存期（OS）之间的关联。在以男性为主的人群（n = 140，74.1%）中，开始使用NIVO+IPI时的中位年龄为67岁，大多数患者为透明细胞组织学类型（n = 140，74.1%）。在189例接受NIVO+IPI治疗的患者中，有42例（22.2%）记录了PRD。发生PRD的患者PFS较差（风险比[HR]，1.788；95%置信区间[CI]，1.176-2.718；p = 0.007），PFS2较差（HR，4.127；95%CI，2.649-6.431；p < 0.001），OS较差（HR，3.330；95%CI，2.040-5.437；p < 0.001）。在开始二线治疗前，与非PRD患者相比，PRD患者的体能状态往往较差，且国际转移性肾细胞癌数据库联盟（IMDC）风险较高。二线药物治疗与PRD患者的治疗结局无关。接受NIVO+IPI作为一线治疗的mRCC患者中的PRD与不良临床病程相关，即使进行二线治疗也是如此。
