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

Abstract

Background: 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.

Objective: We aimed to determine common trends in delayed separation to inform future ICI clinical trials.

Patients and methods: 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.

Results: 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 R² = 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 R² = 0.24 and 0.31, respectively).

Conclusions: 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.

Fig. 1

Flowchart of the study selection procedure. ^aSearch terms and conditions included oncology, phase III, PD-L1 antagonist, immune checkpoint inhibitor, randomized, and controlled. For a complete list, please see the Data Supplement (Appendix 1). ^bSome studies were excluded for more than one exclusion criteria. ^cSome studies have both all-comer and PD-L1 enriched populations, or multiple experimental arms versus the same control (e.g., anti-PD-[L]1 plus CT versus CT/other SoC and anti-PD-[L]1 monotherapy versus CT/other SoC). “Comparison” is the statistical analysis performed to compare OS or PFS for individuals treated with one experimental regimen versus control in the all-comer or PD-L1 enriched populations. CPI, checkpoint inhibitor; CT, chemotherapy; IO, immuno-oncology; KM, Kaplan–Meier; OS, overall survival; PD-(L)1, programmed cell death (ligand)-1; PFS, progression-free survival; SoC, standard of care

Fig. 2

Duration of delayed separation of OS and PFS KM curves by treatment regimen and tumor type in A, C the all-comer population and B, D the PD-L1 enriched population. ^aIncludes genitourinary, head and neck cancer, melanoma, women’s cancers, or other solid tumors. The analysis only included studies with a trending treatment effect (HR ≤ 0.85). One study can be used multiple times for each unique comparison. Forest plots show the least squares mean of duration of delay, by regimen and tumor types, using a weighted regression model based on each study's sample size. BSC, best supportive care; CT, chemotherapy; GI, gastrointestinal; HR, hazard ratio; KM, Kaplan–Meier; LSM, least squares mean; OS, overall survival; PD-(L)1, programmed cell death (ligand)-1; PFS, progression-free survival; SoC, standard of care

Fig. 3

Correlation between the duration of delayed separation of OS and PFS KM curves in A the all-comer population and B the PD-L1-enriched population. The area of each circle is proportional to each study’s sample size. The analysis only included studies with a trending treatment effect (HR ≤ 0.85). One study can be used multiple times for each unique comparison. Adj, adjusted; HR, hazard ratio; KM, Kaplan–Meier; OS, overall survival; PD-L1, programmed cell death ligand-1; PFS, progression-free survival; R², regression coefficient

Fig. 4

Correlation between the duration of delayed separation of OS/PFS KM curves and corresponding HRs in A, C the all-comer population and B, D the PD-L1 enriched population. The area of each circle is proportional to each study’s sample size. The analysis only included studies with trending treatment effect (HR ≤ 0.85). One study can be used multiple times for each unique comparison. Adj, adjusted; HR, hazard ratio; KM, Kaplan–Meier; OS, overall survival; PD-L1, programmed cell death ligand-1; PFS, progression-free survival; R², regression coefficient