Foundation Medicine, Cambridge, MA.
Rush University Medical Center, Chicago, IL.
JCO Precis Oncol. 2022 Aug;6:e2200121. doi: 10.1200/PO.22.00121.
In real-world settings, patients with metastatic urothelial carcinoma (mUC) are often more frail than clinical trials, underscoring an unmet need to identify patients who might be spared first-line chemotherapy. We sought to determine whether tumor mutational burden (TMB) identifies patients with comparable or superior clinical benefit of first-line single-agent immune checkpoint inhibitors (ICPI) in real-world patients deemed cisplatin-unfit.
Patients with mUC treated in first-line advanced setting (N = 401) received ICPI (n = 245) or carboplatin regiment without ICPI (n = 156) at physician's discretion in standard-of-care settings across approximately 280 US academic or community-based cancer clinics between March 2014 and July 2021. Deidentified data were captured into a real-world clinicogenomic database. All patients underwent testing using Foundation Medicine assays. Progression-free survival (PFS), time to next treatment (TTNT), and overall survival (OS) comparing ICPI versus chemotherapy were adjusted for known treatment assignment imbalances using propensity scores.
TMB ≥ 10 was detected in 122 of 401 (30.4%) patients. Among patients receiving ICPI, those with TMB ≥ 10 had more favorable PFS (HR, 0.59; 95% CI, 0.41 to 0.85), TTNT (HR, 0.59; 95% CI, 0.43 to 0.83), and OS (HR, 0.47; 95% CI, 0.32 to 0.68). Comparing ICPI versus carboplatin, adjusting for imbalances, patients with TMB ≥ 10 had more favorable PFS (HR, 0.51; 95% CI, 0.32 to 0.82), TTNT (HR, 0.56; 95% CI, 0.35 to 0.91), and OS (HR, 0.56; 95% CI, 0.29 to 1.08) on ICPI versus chemotherapy, but not TMB < 10. Comparisons unadjusted for imbalances had similar associations.
In real-world settings, mUC patients with TMB ≥ 10 have more favorable outcomes on first-line single-agent ICPI than carboplatin, adding clinical validity to TMB assessed by an existing US Food and Drug Administration-approved platform.
在真实世界环境中，转移性尿路上皮癌（mUC）患者通常比临床试验中的患者更为虚弱，这突显了一种未满足的需求，即需要确定哪些患者可能无需接受一线化疗。我们旨在确定肿瘤突变负担（TMB）是否能识别出在真实世界中被认为不适合顺铂治疗的患者中，一线单药免疫检查点抑制剂（ICPI）具有相当或更好的临床获益的患者。
在 2014 年 3 月至 2021 年 7 月期间，大约 280 家美国学术或社区癌症诊所的标准护理环境中，根据医生的判断，401 例 mUC 患者（n = 401）在一线晚期环境中接受了 ICPI（n = 245）或卡铂联合非 ICPI（n = 156）治疗。在大约 280 家美国学术或社区癌症诊所的标准护理环境中，根据医生的判断，401 例 mUC 患者（n = 401）接受了一线晚期环境中的 ICPI（n = 245）或卡铂联合非 ICPI（n = 156）治疗。在大约 280 家美国学术或社区癌症诊所的标准护理环境中，根据医生的判断，401 例 mUC 患者（n = 401）接受了一线晚期环境中的 ICPI（n = 245）或卡铂联合非 ICPI（n = 156）治疗。从大约 280 家美国学术或社区癌症诊所的标准护理环境中，根据医生的判断，401 例 mUC 患者（n = 401）接受了一线晚期环境中的 ICPI（n = 245）或卡铂联合非 ICPI（n = 156）治疗。无标识符数据被捕获到一个真实世界的临床基因组数据库中。所有患者均接受 Foundation Medicine 检测。使用倾向评分调整已知治疗分配不平衡，比较 ICPI 与化疗的无进展生存期（PFS）、下一次治疗时间（TTNT）和总生存期（OS）。
在 401 例患者中，有 122 例（30.4%）检测到 TMB≥10。在接受 ICPI 治疗的患者中，TMB≥10 的患者具有更有利的 PFS（HR，0.59；95%CI，0.41 至 0.85）、TTNT（HR，0.59；95%CI，0.43 至 0.83）和 OS（HR，0.47；95%CI，0.32 至 0.68）。与卡铂相比，在调整了不平衡因素后，TMB≥10 的患者在接受 ICPI 治疗时具有更有利的 PFS（HR，0.51；95%CI，0.32 至 0.82）、TTNT（HR，0.56；95%CI，0.35 至 0.91）和 OS（HR，0.56；95%CI，0.29 至 1.08），而 TMB<10 的患者则没有。未调整不平衡因素的比较也具有相似的相关性。
在真实世界环境中，与卡铂相比，TMB≥10 的 mUC 患者在一线单药 ICPI 治疗中具有更有利的结局，这为现有美国食品和药物管理局批准的平台评估的 TMB 提供了临床有效性。
