Magnitude of the Benefit of Progression-Free Survival as a Potential Surrogate Marker in Phase 3 Trials Assessing Targeted Agents in Molecularly Selected Patients with Advanced Non-Small Cell Lung Cancer: Systematic Review

BackgroundIn evaluation of the clinical benefit of a new targeted agent in a phase 3 trial enrolling molecularly selected patients with advanced non-small cell lung cancer (NSCLC), overall survival (OS) as an endpoint seems to be of limited use because of a high level of treatment crossover for ethical reasons. A more efficient and useful indicator for assessing efficacy is needed.Methods and FindingsWe identified 18 phase 3 trials in the literature investigating EGFR-tyrosine kinase inhibitor (TKIs) or ALK-TKIs, now approved for use to treat NSCLC, compared with standard cytotoxic chemotherapy (eight trials were performed in molecularly selected patients and ten using an “all-comer” design). Receiver operating characteristic analysis was used to identify the best threshold by which to divide the groups. Although trials enrolling molecularly selected patients and all-comer trials had similar OS-hazard ratios (OS-HRs) (0.99 vs. 1.04), the former exhibited greater progression-free survival-hazard ratios (PFS-HR) (mean, 0.40 vs. 1.01; PPConclusionThe notably enhanced PFS benefit was quite specific to trials with molecularly selected patients. A PFS-HR cutoff of ∼0.6 may help detect clinical benefit of molecular targeted agents in which OS is of limited use, although desired threshold might differ in an individual trial.背景：在一项纳入经分子筛选的晚期非小细胞肺癌（non-small cell lung cancer, NSCLC）患者的3期临床试验中，评估新型靶向药物的临床获益时，由于伦理原因导致较高的治疗交叉率，作为终点指标的总生存期（overall survival, OS）的应用价值有限，因此亟需一种更高效、更实用的疗效评估指标。 方法与结果：我们在文献中检索到18项3期临床试验，对比了目前获批用于治疗非小细胞肺癌的表皮生长因子受体-酪氨酸激酶抑制剂（EGFR-tyrosine kinase inhibitor, EGFR-TKIs）或间变性淋巴瘤激酶-酪氨酸激酶抑制剂（ALK-tyrosine kinase inhibitor, ALK-TKIs）与标准细胞毒性化疗的疗效。其中8项试验纳入经分子筛选的患者，10项采用“全入组（all-comer）”设计。本研究采用受试者工作特征（Receiver Operating Characteristic, ROC）分析以确定划分分组的最佳阈值。尽管纳入经分子筛选患者的试验与全入组试验的总生存期风险比（OS-HRs）相近（0.99 vs. 1.04），但前者的无进展生存期风险比（PFS-HR）优势更为显著（均值分别为0.40 vs. 1.01）。 结论：无进展生存期获益的显著增强仅在纳入经分子筛选患者的试验中具有特异性。当总生存期的应用价值有限时，无进展生存期风险比约0.6的截断值可辅助检测分子靶向药物的临床获益，不过具体阈值可能因单个试验而异。