Foundation Medicine, Cambridge, Massachusetts.
Upstate Medical University, Syracuse, New York.
Cancer Res Commun. 2022 Sep 21;2(9):1037-1048. doi: 10.1158/2767-9764.CRC-22-0161. eCollection 2022 Sep.
Patients with advanced gastroesophageal cancer (mEG) and tumor mutational burden ≥10 mut/Mb (TMB ≥ 10) have more favorable outcomes on immune checkpoint inhibitor (ICPI) monotherapy compared with chemotherapy in subgroup analyses of randomized controlled trials. We sought to evaluate the robustness of these associations in real-world settings where patients and practices are more diverse. A total of 362 2 L and 692 1 L patients, respectively received ICPI ( = 99, 33) or chemotherapy ( = 263, 659) across approximately 280 U.S. academic or community-based cancer clinics March 2014-July 2021. Deidentified data were captured into a real-world clinico-genomic database. All patients underwent Foundation Medicine testing. Time to next treatment (TTNT) and overall survival (OS) comparing ICPI versus chemotherapy were adjusted for treatment assignment imbalances using propensity scores. 2L: TMB ≥ 10 had more favorable TTNT [median 24 vs. 4.1 months; HR: 0.19; 95% confidence interval (CI): 0.09-0.44; = 0.0001] and OS (median 43.1 vs. 6.2 months; HR: 0.24; 95% CI: 0.011-0.54; = 0.0005), TMB < 10 did not ( > 0.05). 1L: TMB ≥ 10 had more favorable TTNT (not reached vs. median 4.1 months; HR: 0.13; 95% CI: 0.03-0.48; = 0.0024) and OS (not reached vs. median 17.1 months; HR: 0.30; 95% CI: 0.08-1.14; = 0.078), TMB < 10 had less favorable TTNT (median 2.8 vs. 6.5 months; HR: 2.36; 95% CI: 1.25-4.45; = 0.008) and OS (median 4.5 vs. 13.1 months; HR: 1.82, 95% CI: 0.87-3.81; = 0.11). TMB ≥ 10 robustly identifies patients with mEG with more favorable outcomes on 2 L ICPI monotherapy versus chemotherapy. 1 L data are more limited, but effects are consistent with 2L.
Using real-world data, we sought to evaluate robustness of these clinical associations using the same assay platform and biomarker cut-off point used in both clinical trials and pan-tumor CDx approvals for later treatment lines. TMB ≥ 10 robustly identified patients with mEG with more favorable outcomes on ICPI monotherapy versus chemotherapy and suggests this subset of patients could be targeted for further trial development.
在随机对照试验的亚组分析中，与化疗相比，晚期胃食管癌症（mEG）且肿瘤突变负担≥10 突变/Mb（TMB≥10）的患者接受免疫检查点抑制剂（ICPI）单药治疗的结局更有利。我们试图在患者和治疗方案更为多样化的真实世界环境中评估这些关联的稳健性。
2014 年 3 月至 2021 年 7 月，在美国约 280 家学术或社区癌症诊所中，分别有 362 名 2 线和 692 名 1 线患者接受了 ICPI（n=99，33）或化疗（n=263，659）。从真实世界临床基因组数据库中提取了经过去标识处理的数据。所有患者均接受了 Foundation Medicine 检测。使用倾向性评分调整治疗分配不平衡对 ICPI 与化疗相比的下一次治疗时间（TTNT）和总生存期（OS）进行调整。2 线：TMB≥10 患者的 TTNT 更有利[中位 24 与 4.1 个月；HR：0.19；95%置信区间（CI）：0.09-0.44；P=0.0001]和 OS[中位 43.1 与 6.2 个月；HR：0.24；95%CI：0.011-0.54；P=0.0005]，TMB<10 则不然（P>0.05）。1 线：TMB≥10 患者的 TTNT 更有利（未达到与中位 4.1 个月；HR：0.13；95%CI：0.03-0.48；P=0.0024）和 OS（未达到与中位 17.1 个月；HR：0.30；95%CI：0.08-1.14；P=0.078），TMB<10 患者的 TTNT 和 OS 更差（中位 2.8 与 6.5 个月；HR：2.36；95%CI：1.25-4.45；P=0.008）和（中位 4.5 与 13.1 个月；HR：1.82，95%CI：0.87-3.81；P=0.11）。TMB≥10 可明确识别出 2 线 ICPI 单药治疗更有利的 mEG 患者。1 线数据更为有限，但结果与 2 线一致。
使用真实世界数据，我们试图使用相同的检测平台和生物标志物截断值来评估这些临床关联的稳健性，这些检测平台和生物标志物截断值在临床试验和泛肿瘤 CDx 批准中均用于后续治疗线。TMB≥10 可明确识别出 2 线 ICPI 单药治疗更有利的 mEG 患者，这表明这部分患者可以作为进一步临床试验的目标。
