Broadstreet HEOR, 201-343 Railway St, Vancouver, BC, Canada.
Bristol Myers Squibb Pharmaceuticals Ltd, Sanderson Rd, Denham, Uxbridge, England, UK.
Lung Cancer. 2022 Aug;170:122-132. doi: 10.1016/j.lungcan.2022.06.009. Epub 2022 Jun 15.
The study objective was to estimate the relationship between objective response and survival-based endpoints by drug class, in first-line advanced non-small cell lung cancer (aNSCLC).
A systematic literature review identified randomized controlled trials (RCTs) of first-line aNSCLC therapies reporting overall survival (OS), progression-free survival (PFS), and/or objective response rate (ORR). Trial-level and arm-level linear regression models were fit, accounting for inclusion of immunotherapy (IO)-based or chemotherapy-only RCT arms. Weighted least squares-based R were calculated along with 95% confidence intervals (CIs). For the main trial-level analysis of OS vs. ORR, the surrogate threshold effect was estimated. Exploratory analyses involved further stratification by: IO monotherapy vs. chemotherapy, dual-IO therapy vs. chemotherapy, and IO + chemotherapy vs. chemotherapy.
From 17,040 records, 57 RCTs were included. In the main analysis, trial-level associations between OS and ORR were statistically significant in both the IO-based and chemotherapy-only strata, with R estimates of 0.54 (95% CI: 0.26-0.81) and 0.34 (0.05-0.63), respectively. OS gains associated with a given ORR benefit were statistically significantly larger within IO vs. chemotherapy comparisons compared to chemotherapy vs. chemotherapy comparisons (p < 0.001). Exploratory analysis suggested a trend by IO type: for a given change in ORR, 'pure' IO (IO monotherapy and dual-IO) vs. chemotherapy RCTs tended to have a larger OS benefit than IO + chemotherapy vs. chemotherapy RCTs. For ORR vs. PFS, trial-level correlations were strong in the IO-based vs. chemotherapy (R = 0.84; 0.72-0.95), and chemotherapy vs. chemotherapy strata (R = 0.69; 0.49-0.88). For OS vs. PFS, correlations were moderate in both strata (R = 0.49; 0.20-0.78 and R = 0.49; 0.23-0.76).
The larger OS benefit per unit of ORR benefit in IO-based RCTs compared to chemotherapy-only RCTs provides an important addition to the established knowledge regarding the durability and depth of response in IO-based treatments.
本研究旨在评估不同药物类别在一线治疗晚期非小细胞肺癌（aNSCLC）中，客观缓解率（ORR）与生存终点之间的关系。
系统文献回顾确定了报告总生存期（OS）、无进展生存期（PFS）和/或客观缓解率（ORR）的一线 aNSCLC 治疗的随机对照试验（RCT）。对试验水平和手臂水平进行线性回归模型拟合，同时考虑免疫治疗（IO）或化疗的 RCT 臂。计算加权最小二乘（R）及其 95%置信区间（CI）。对于 OS 与 ORR 的主要试验水平分析，估计了替代终点效应。进一步按 IO 单药治疗与化疗、双 IO 治疗与化疗、IO+化疗与化疗进行分层的探索性分析。
从 17040 条记录中，纳入了 57 项 RCT。在主要分析中，IO 为基础和单纯化疗组中，OS 与 ORR 之间的试验水平关联具有统计学意义，R 估计值分别为 0.54（95%CI：0.26-0.81）和 0.34（0.05-0.63）。与化疗组相比，IO 组中与给定 ORR 获益相关的 OS 获益更大（p<0.001）。探索性分析表明，按 IO 类型存在趋势：对于给定的 ORR 变化，与化疗相比，“纯”IO（IO 单药治疗和双 IO）与化疗的 RCT 倾向于具有更大的 OS 获益。对于 ORR 与 PFS，在 IO 为基础与化疗（R=0.84；0.72-0.95）和化疗与化疗（R=0.69；0.49-0.88）组中，试验水平相关性较强。对于 OS 与 PFS，在两个组中相关性适中（R=0.49；0.20-0.78 和 R=0.49；0.23-0.76）。
与单纯化疗相比，基于 IO 的 RCT 中每单位 ORR 获益的 OS 获益更大，这为 IO 治疗的持久性和反应深度方面的已有知识提供了重要补充。
