Delayed Separation of Kaplan–Meier Curves is Commonly Observed in Studies of Advanced/Metastatic Solid Tumors Treated with Anti-PD-(L)1 Therapy: Systematic Review and Meta-Analysis
Do‐Youn Oh, Nana Rokutanda, Magdalena Żotkiewicz, Philip He, Jennifer Dugan Stocks, Melissa L. Johnson
Abstract
Immune checkpoint inhibitor (ICI) Kaplan–Meier (KM) curves often show delayed survival benefit followed by long-term survival in a subgroup of patients. Such outcomes can violate the proportional hazards assumption, leading to a loss of statistical power. We aimed to determine common trends in delayed separation to inform future ICI clinical trials. A literature search was performed using Trialtrove ® to identify phase III trials of antiprogrammed cell death (ligand)-1 (anti-PD-[L]1) agents in locally advanced/metastatic solid tumors published between January 2010 and September 2021. The frequency of delayed separation of overall survival (OS) and progression-free survival (PFS) KM curves, correlation between duration of delayed separation in OS/PFS KM curves, and correlation between duration of delayed separation in OS/PFS KM curves with corresponding hazard ratios (HRs) were assessed in all-comer and PD-L1 enriched populations. Eighty-five studies with OS/PFS KM curves were identified. Most studies showed delayed separation of OS (> 67.9%) and PFS (> 54.5%) KM curves. The correlation between the duration of delayed separation in OS/PFS KM curves was strongest in the PD-L1 enriched population (adjusted R 2 = 0.66). No correlation was seen between the duration of delayed separation of OS KM curves and OS HR. A modest correlation was seen between the duration of delayed separation of PFS KM curves and PFS HR in all-comer and PD-L1 enriched populations (adjusted R 2 = 0.24 and 0.31, respectively). Delayed separation of KM curves was common in clinical trials of anti-PD-(L)1 agents. Understanding delayed separation is key to clinical study designs and assessing outcomes with ICIs.