Department of Urology, University Hospital Frankfurt, Goethe University Frankfurt am Main, Frankfurt am Main, Hessen, Germany; Cancer Prognostics and Health Outcomes Unit, Division of Urology, University of Montréal Health Center, Montréal, Québec, Canada.
Cancer Prognostics and Health Outcomes Unit, Division of Urology, University of Montréal Health Center, Montréal, Québec, Canada; Department of Maternal-Child and Urological Sciences, Sapienza Rome University, Policlinico Umberto I Hospital, Rome, Italy.
Semin Oncol. 2022 Oct;49(5):394-399. doi: 10.1053/j.seminoncol.2022.10.001. Epub 2022 Oct 23.
Multiple systemic immune-oncology (IO) combination therapies have demonstrated overall survival (OS) benefits in metastatic renal clear cell carcinoma (mRCC). However, the magnitude of benefits over time has not been compared in a structured fashion. To assess OS and progression free survival (PFS) efficacy as reflected by hazard ratios [HR]) according to the duration of follow-up over time for each of four IO combination therapies. A systematic PubMed (MEDLINE) literature review was performed (January, 1, 2016 to February, 20, 2022). Only phase III randomized clinical trials with proven OS benefit relative to sunitinib were included. These search criteria yielded four eligible RCTs: CheckMate 214 (nivolumab plus ipilimumab), Keynote 426 (pembrolizumab plus axitinib), CheckMate 9ER (nivolumab plus cabozantinib), CLEAR (lenvatinib plus pembrolizumab). OS and PFS HRs were tabulated for all four studies including all reported timepoints. Median follow-up ranged from 25-68 months for CheckMate 214 (5 timepoints), 13-43 months for Keynote 426 (3 timepoints), 18-33 months for CheckMate 9ER (3 timepoints) and 27-34 months for CLEAR (2 timepoints). Respective OS and PFS HRs were 0.68-0.72 and 0.98-0.86, 0.53-0.73 and 0.69-0.68, 0.60-0.70 and 0.51-0.56, 0.66-0.72 and 0.39-0.47 for CheckMate 214, Keynote 426, CheckMate 9ER and CLEAR. Regarding OS HRs virtually no change was recorded over time for CheckMate 214, but a decrease in magnitude occurred in the three IO-TKI remaining studies. Regarding PFS HRs, no benefit was recorded for CheckMate 214. Statistically significant benefit was recorded in the remaining IO-TKI studies. However, it also decreased with longer follow-up. It remains to be seen, whether further 'slippage' of efficacy will persist as the data matures further for all IO-TKI combinations.
多种全身性免疫肿瘤（IO）联合疗法已证明在转移性肾透明细胞癌（mRCC）中具有总生存（OS）获益。然而，随着时间的推移，其获益幅度尚未以结构化的方式进行比较。评估四种 IO 联合疗法中每一种根据随访时间长短的 OS 和无进展生存期（PFS）疗效（反映为危险比[HR]）。进行了系统的 PubMed（MEDLINE）文献复习（2022 年 2 月 20 日）。仅纳入与舒尼替尼相比具有 OS 获益的 III 期随机临床试验。这些搜索标准产生了四项合格的 RCT：CheckMate 214（纳武利尤单抗加伊匹单抗）、Keynote 426（帕博利珠单抗加阿昔替尼）、CheckMate 9ER（纳武利尤单抗加卡博替尼）、CLEAR（仑伐替尼加帕博利珠单抗）。汇总了所有四项研究的 OS 和 PFS HR，包括所有报告的时间点。CheckMate 214 的中位随访时间为 25-68 个月（5 个时间点），Keynote 426 为 13-43 个月（3 个时间点），CheckMate 9ER 为 18-33 个月（3 个时间点），CLEAR 为 27-34 个月（2 个时间点）。相应的 OS 和 PFS HR 分别为 0.68-0.72 和 0.98-0.86、0.53-0.73 和 0.69-0.68、0.60-0.70 和 0.51-0.56、0.66-0.72 和 0.39-0.47，用于 CheckMate 214、Keynote 426、CheckMate 9ER 和 CLEAR。关于 OS HR，CheckMate 214 的记录几乎没有随时间变化，但在其余三项 IO-TKI 研究中观察到幅度下降。关于 PFS HR，CheckMate 214 没有获益。在其余的 IO-TKI 研究中记录了统计学显著获益。然而，随着随访时间的延长，获益也随之下降。随着所有 IO-TKI 联合的数据进一步成熟，是否会出现进一步的“疗效下滑”仍有待观察。
