Cancer Prognostics and Health Outcomes Unit, University of Montreal Health Center, Montreal, QC, Canada; Urology Unit, ASST Spedali Civili of Brescia, Department of Medical and Surgical Specialties, Radiological Science and Public Health, University of Brescia, Brescia, Italy.
Cancer Prognostics and Health Outcomes Unit, University of Montreal Health Center, Montreal, QC, Canada; Division of Experimental Oncology, Unit of Urology, Urological Research Institute, IRCCS San Raffaele Scientific Institute, and Vita-Salute San Raffaele University, Milan, Italy.
Clin Genitourin Cancer. 2020 Aug;18(4):314-321.e1. doi: 10.1016/j.clgc.2019.11.010. Epub 2019 Dec 5.
Tyrosine kinase inhibitor-based adjuvant therapy showed no survival benefits for patients with high-risk nonmetastatic renal cell carcinoma (nmRCC). Five randomized immune-oncology checkpoint inhibitor trials are ongoing. We assessed the effect of stage, grade, and histologic type on cancer-specific mortality (CSM) in candidates for 1 of the 4 North American ongoing immune-oncology checkpoint inhibitor trials of high-risk nmRCC.
From the Surveillance, Epidemiology, and End Results database (2001-2015), we identified patients who had undergone surgery for nmRCC and had met the inclusion criteria for the PROSPER RCC (nivolumab in treating patients with localized kidney cancer undergoing nephrectomy), CheckMate 914 (a study comparing the combination of nivolumab and ipilimumab versus placebo in participants with localized renal cell carcinoma), KEYNOTE-564 [safety and efficacy study of pembrolizumab (MK-3475) as monotherapy in the adjuvant treatment of renal cell carcinoma post nephrectomy], or IMmotion010 [a study of atezolizumab as adjuvant therapy in participants with renal cell carcinoma (RCC) at high risk of developing metastasis following nephrectomy] trials. Kaplan-Meier and multivariable Cox regression models were used to assess the 10-year CSM rates in the overall cohort according to stage, grade, and histologic characteristics, and in 4 generated random samples according to the eligible patients for each of the 4 trials.
Of 116,750 patients who had undergone surgery for nmRCC, 18,559 (15.9%) had fulfilled the inclusion criteria for 1 of the 4 trials. The greatest proportion of higher stage and grade combinations and sarcomatoid histologic features would have qualified for IMmotion010, followed by KEYNOTE-564, CheckMate 914, and PROSPER RCC. Multivariable Cox regression models demonstrated the most unfavorable prognosis for stage N1 grade 3/4 (hazard ratio [HR], 11.5; P < .001), stage T4N0 grade 3/4 (HR, 9.8; P < .001), and sarcomatoid histologic features (HR, 5.5; P < .001). Among the 4 random samples, the difference in the qualifying criteria resulted in the greatest versus progressively lower CSM rates in the IMmotion010, KEYNOTE-564, CheckMate 914, and PROSPER RCC trials, respectively (P < .001).
Our findings indicate that participation in adjuvant immunotherapy trials should be predominantly encouraged for patients with high-grade stage T3, T4, and N1 and patients with any stage with sarcomatoid pathologic features.
酪氨酸激酶抑制剂辅助治疗并未为高危非转移性肾细胞癌（nmRCC）患者带来生存获益。目前正在进行五项随机免疫肿瘤检查点抑制剂试验。我们评估了分期、分级和组织学类型对 4 项北美正在进行的高危 nmRCC 免疫肿瘤检查点抑制剂试验中符合条件的患者的癌症特异性死亡率（CSM）的影响。
从监测、流行病学和最终结果数据库（2001-2015 年）中，我们确定了接受 nmRCC 手术且符合 PROSPER RCC（nivolumab 治疗接受肾切除术的局限性肾癌患者）、CheckMate 914（比较 nivolumab 和 ipilimumab 联合与安慰剂在局限性肾细胞癌患者中的疗效）、KEYNOTE-564[ pembrolizumab（MK-3475）单药作为肾细胞癌术后辅助治疗的安全性和疗效研究]或 IMmotion010[ atezolizumab 作为肾细胞癌（RCC）辅助治疗的研究，该研究在接受肾切除术的患者中进行，这些患者有发展为转移的高风险]试验纳入标准的患者。使用 Kaplan-Meier 和多变量 Cox 回归模型根据分期、分级和组织学特征评估总体队列中的 10 年 CSM 率，并根据 4 项试验中每项试验的合格患者生成 4 个随机样本进行评估。
在接受 nmRCC 手术的 116750 名患者中，有 18559 名（15.9%）符合 4 项试验中的 1 项的纳入标准。具有较高分期和分级组合以及肉瘤样组织学特征的患者最有可能符合 IMmotion010 标准，其次是 KEYNOTE-564、CheckMate 914 和 PROSPER RCC。多变量 Cox 回归模型显示 N1 级 3/4 期（风险比[HR]，11.5；P<0.001）、T4N0 级 3/4 期（HR，9.8；P<0.001）和肉瘤样组织学特征（HR，5.5；P<0.001）的预后最差。在 4 个随机样本中，在 IMmotion010、KEYNOTE-564、CheckMate 914 和 PROSPER RCC 试验中，合格标准的差异导致 CSM 率的差异最大，且逐渐降低（P<0.001）。
我们的研究结果表明，对于高级别 T3、T4 和 N1 期和任何具有肉瘤样病理特征的患者，应主要鼓励参加辅助免疫治疗试验。
