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Meta-Analysis
. 2025 Jan;20(1):45-56.
doi: 10.1007/s11523-024-01108-2. Epub 2024 Nov 10.

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  1 , Nana Rokutanda  2 , Magdalena Żotkiewicz  3 , Philip He  4 , Jennifer Stocks  2 , Melissa L Johnson  5
Affiliations
Meta-Analysis

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 et al. Target Oncol. 2025 Jan.

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.

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Conflict of interest statement

Declarations. Funding: Open Access funding enabled and organized by Seoul National University Hospital. Conflict of Interest: D.-Y.O. has received research funding from Array, AstraZeneca, BeiGene, Eli Lilly, Handok, MSD, Novartis, and Servier, and consulting or advisory fees from Arcus Biosciences, ASLAN, AstraZeneca, Basilea, Bayer, BeiGene, Bristol Myers Squibb/Celgene, Genentech/Roche, Halozyme, IQVIA, Merck Serono, Novartis, Taiho, Turning Point, Yuhan, and Zymeworks. N.R. is an employee of and holds stock in AstraZeneca. M.Ż. is an employee of AstraZeneca. P.H. is an employee of and holds stock in Daiichi Sankyo. J.S. is an employee of and holds stock in AstraZeneca. M.L.J. has received research funding (to institution) from AbbVie, Acerta, Adaptimmune, Amgen, Apexigen, Arcus Biosciences, Array BioPharma, Artios Pharma, AstraZeneca, Atreca, BeiGene, BerGenBio, BioAlta, Black Diamond, Boehringer Ingelheim, Bristol Myers Squibb, Calithera Biosciences, Carisma Therapeutics, Checkpoint Therapeutics, City of Hope National Medical Center, Corvus Pharmaceuticals, Curis, CytomX, Daiichi Sankyo, Dracen Pharmaceuticals, Dynavax, Elicio Therapeutics, Eli Lilly, EMD Serono, EQRx, Erasca, Exelixis, Fate Therapeutics, Genentech/Roche, Genmab, Genocea Biosciences, GlaxoSmithKline, Gritstone Oncology, Guardant Health, Harpoon, Helsinn Healthcare SA, Hengrui Therapeutics, Hutchison MediPharma, IDEAYA Biosciences, IGM Biosciences, Immunitas Therapeutics, Immunocore, Incyte, Janssen, Jounce Therapeutics, Kadmon Pharmaceuticals, Kartos Therapeutics, Loxo Oncology, Lycera, Memorial Sloan Kettering, Merck, Merus, Mirati Therapeutics, Mythic Therapeutics, NeoImmune Tech, Neovia Oncology, Novartis, Numab Therapeutics, Nuvalent, OncoMed Pharmaceuticals, Palleon Pharmaceuticals, Pfizer, PMV Pharmaceuticals, Rain Therapeutics, RasCal Therapeutics, Regeneron Pharmaceuticals, Relay Therapeutics, Revolution Medicines, Ribon Therapeutics, Rubius Therapeutics, Sanofi, Seven and Eight Biopharmaceuticals/Birdie Biopharmaceuticals, Shattuck Labs, Silicon Therapeutics, Stem CentRx, Syndax Pharmaceuticals, Takeda Pharmaceuticals, Tarveda, TCR2 Therapeutics, Tempest Therapeutics, Tizona Therapeutics, TMUNITY Therapeutics, Turning Point Therapeutics, University of Michigan, Vyriad, WindMIL Therapeutics, and Y-mAbs Therapeutics, and received consulting or advisory fees (to institution) from AbbVie, Amgen, Arcus Biosciences, Arrivent, Astellas, AstraZeneca, Axelia Oncology, Black Diamond, Calithera Biosciences, Daiichi Sankyo, EcoR1, Genentech/Roche, Genmab, Genocea Biosciences, GlaxoSmithKline, Gritstone Oncology, Ideaya Biosciences, Immunocore, iTeos, Janssen, Jazz Pharmaceuticals, Merck, Mirati Therapeutics, Molecular Axiom, Novartis, Oncorus, Pyramid Biosciences, Regeneron Pharmaceuticals, Revolution Medicines, Sanofi-Aventis, SeaGen, Synthekine, Takeda Pharmaceuticals, Turning Point Therapeutics, and VBL Therapeutics. Ethics Approval: Not applicable. Consent to Participate: Not applicable. Consent for Publication: Not applicable. Availability of Data and Material: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. Code Availability: Not applicable. Author Contributions: N.R., J.S., M.Ż., and P.H. contributed to the study design and contributed to the acquisition and analysis of data. D.-Y.O. and N.R. supervised the study. All authors contributed to the interpretation of data, critically revised the manuscript, and provided final approval.

Figures

Fig. 1
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
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
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
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
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