Center for Drug Evaluation and Research; Oncology Center of Excellence, U.S. Food and Drug Administration, White Oak.
Center for Drug Evaluation and Research.
Ann Oncol. 2019 May 1;30(5):830-838. doi: 10.1093/annonc/mdz060.
Pragmatic end points, such as time-to-treatment discontinuation (TTD), defined as the date of starting a medication to the date of treatment discontinuation or death has been proposed as a potential efficacy end point for real-world evidence (RWE) trials, where imaging evaluation is less structured and standardized.
We studied 18 randomized clinical trials of patients with metastatic non-small-cell lung cancer (mNSCLC), initiated after 2007 and submitted to U.S. Food and Drug Administration. TTD was calculated as date of randomization to date of discontinuation or death and compared to progression-free survival (PFS) and overall survival (OS) across all patients, as well as in treatment-defined subgroups [EGFR mutation-positive treated with tyrosine kinase inhibitor (TKI), EGFR wild-type treated with TKI, ALK-positive treated with TKI, immune checkpoint inhibitor (ICI), chemotherapy doublet with maintenance, chemotherapy monotherapy].
Overall across 8947 patients, TTD was more closely associated with PFS (r = 0.87, 95% CI 0.86-0.87) than with OS (0.68, 95% CI 0.67-0.69). Early TTD (PFS-TTD ≥ 3 months) occurred in 7.7% of patients overall, and was more common with chemo monotherapy (15.0%) while late TTD (TTD-PFS ≥ 3 months) occurred in 6.0% of patients overall, and was more common in EGFR-positive and ALK-positive patients (12.4% and 22.9%). In oncogene-targeted subgroups (EGFR positive and ALK positive), median TTDs (13.4 and 14.1 months) exceeded median PFS (11.4 and 11.3 months).
At the patient level, TTD is associated with PFS across therapeutic classes. Median TTD exceeds median PFS for biomarker-selected patients receiving oncogene-targeted therapies. TTD should be prospectively studied further as an end point for pragmatic randomized RWE trials only for continuously administered therapies.
实用终点，例如治疗终止时间（TTD），定义为开始用药日期到治疗终止或死亡日期，已被提议作为真实世界证据（RWE）试验的潜在疗效终点，在这些试验中，影像学评估的结构和标准化程度较低。
我们研究了 18 项 2007 年后启动并提交给美国食品和药物管理局的转移性非小细胞肺癌（mNSCLC）患者的随机临床试验。TTD 计算为随机分组日期至停药或死亡日期，并与所有患者的无进展生存期（PFS）和总生存期（OS）进行比较，以及在治疗定义的亚组中进行比较[表皮生长因子受体（EGFR）突变阳性患者接受酪氨酸激酶抑制剂（TKI）治疗、EGFR 野生型患者接受 TKI 治疗、ALK 阳性患者接受 TKI 治疗、免疫检查点抑制剂（ICI）治疗、含维持化疗的化疗双联治疗、化疗单药治疗]。
在 8947 名患者中，TTD 与 PFS 的相关性（r=0.87，95%CI 0.86-0.87）比 OS（0.68，95%CI 0.67-0.69）更密切。总体上，7.7%的患者出现早期 TTD（PFS-TTD≥3 个月），化疗单药治疗更为常见（15.0%），6.0%的患者出现晚期 TTD（TTD-PFS≥3 个月），EGFR 阳性和 ALK 阳性患者更为常见（12.4%和 22.9%）。在靶向肿瘤基因治疗亚组（EGFR 阳性和 ALK 阳性）中，中位 TTD（13.4 和 14.1 个月）超过中位 PFS（11.4 和 11.3 个月）。
在患者水平上，TTD 与治疗类别中的 PFS 相关。接受靶向肿瘤基因治疗的生物标志物选择患者的中位 TTD 超过中位 PFS。仅对于持续给药的治疗，TTD 应作为前瞻性研究的实用随机 RWE 试验终点进一步研究。
