肿瘤突变负荷作为一线免疫检查点抑制剂与卡铂在顺铂不适用于尿路上皮癌患者中的获益预测因子。
Tumor Mutational Burden as a Predictor of First-Line Immune Checkpoint Inhibitor Versus Carboplatin Benefit in Cisplatin-Unfit Patients With Urothelial Carcinoma.
机构信息
Foundation Medicine, Cambridge, MA.
Rush University Medical Center, Chicago, IL.
出版信息
JCO Precis Oncol. 2022 Aug;6:e2200121. doi: 10.1200/PO.22.00121.
PURPOSE
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.
METHODS
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.
RESULTS
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.
CONCLUSIONS
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.
目的
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。
方法
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）。
结果
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。
结论
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。
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