Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, WA.
Department of Epidemiology, University of Washington, Seattle, WA.
Clin Genitourin Cancer. 2022 Dec;20(6):558-567. doi: 10.1016/j.clgc.2022.08.006. Epub 2022 Aug 19.
Early progression on first-line (1L) platinum-based therapy or between therapy lines may be a surrogate of more aggressive disease and poor outcomes in advanced urothelial carcinoma (aUC), but its prognostic role regarding immune checkpoint inhibitor (ICI) response and survival is unclear. We hypothesized that shorter time until start of second-line (2L) ICI would be associated with worse outcomes in aUC.
We performed a retrospective multi-institution cohort study in patients with aUC treated with 1L platinum-based chemotherapy, who received 2L ICI. Patients receiving switch maintenance ICI were excluded. We defined time to 2L ICI therapy as the time between the start of 1L platinum-based chemotherapy to the start of 2L ICI and categorized patients a priori into 1 of 3 groups: less than 3 months versus 3-6 months versus more than 6 months. We calculated overall response rate (ORR) with 2L ICI, progression-free survival (PFS) and overall survival (OS) from the start of 2L ICI. ORR was compared among the 3 groups using multivariable logistic regression, and PFS, OS using cox regression. Multivariable models were adjusted for known prognostic factors.
We included 215, 215, and 219 patients in the ORR, PFS, and OS analyses, respectively, after exclusions. ORR difference did not reach statistical significance between patients with less than 3 months versus 3-6 months versus more than 6 months to 2L ICI. However, PFS (HR 1.64; 95% CI 1.02-2.63) and OS (HR 1.77; 95% CI 1.10-2.84) was shorter among those with time to 2L ICI less than 3 months compared to those who initiated 2L ICI more than 6 months.
Among patients with aUC treated with 2L ICI, time to 2L ICI less than 3 months was associated with lower, but not significantly different ORR, but shorter PFS and OS compared to 2L ICI more than 6 months. This highlights potential cross resistance mechanisms between ICI and platinum-based chemotherapy.
一线（1L）铂类治疗或治疗线之间的早期进展可能是晚期尿路上皮癌（aUC）侵袭性更强的疾病和不良结局的替代指标，但关于免疫检查点抑制剂（ICI）反应和生存的预后作用尚不清楚。我们假设，二线（2L）ICI 开始时间越短，aUC 的结局越差。
我们对接受 1L 铂类化疗治疗的 aUC 患者进行了回顾性多机构队列研究，这些患者接受了 2L ICI 治疗。排除接受转换维持 ICI 的患者。我们将 2L ICI 治疗时间定义为从 1L 铂类化疗开始到 2L ICI 开始之间的时间，并预先将患者分为以下 3 组之一：<3 个月、3-6 个月和>6 个月。我们计算了 2L ICI 开始后的总体缓解率（ORR）、无进展生存期（PFS）和总生存期（OS）。使用多变量逻辑回归比较 3 组之间的 ORR，使用 cox 回归比较 PFS、OS。多变量模型调整了已知的预后因素。
排除后，我们分别在 ORR、PFS 和 OS 分析中纳入了 215、215 和 219 名患者。<3 个月与 3-6 个月与>6 个月患者接受 2L ICI 之间的 ORR 差异无统计学意义。然而，与接受 2L ICI 时间超过 6 个月的患者相比，接受 2L ICI 时间<3 个月的患者 PFS（HR 1.64；95%CI 1.02-2.63）和 OS（HR 1.77；95%CI 1.10-2.84）较短。
在接受 2L ICI 治疗的 aUC 患者中，2L ICI 时间<3 个月与较低但无统计学意义的 ORR 相关，但与 2L ICI 时间>6 个月相比，PFS 和 OS 更短。这突显了 ICI 和铂类化疗之间潜在的交叉耐药机制。
