Progression-Free Survival (PFS) as a Surrogate for Overall Survival (OS) in the Front-Line Maintenance Setting for Advanced Ovarian Cancer (OC): A Trial-Level Meta-Analysis
Author(s)
Lei Chen, PhD1, Kalé Kponee-Shovein, ScD2, Jiaxuan Liu, PhD2, Yan Song, PhD2, Qi Hua, MSc2, Jingyi Liu, MSc2, Emanuele Del Fava, PhD3, Karin Yamada, MD1, Mehmet Burcu, PhD1.
1Merck & Co., Inc., Rahway, NJ, USA, 2Analysis Group, Boston, MA, USA, 3MSD, Zurich, Switzerland.
1Merck & Co., Inc., Rahway, NJ, USA, 2Analysis Group, Boston, MA, USA, 3MSD, Zurich, Switzerland.
Presentation Documents
OBJECTIVES: High unmet need persists in the front-line setting for advanced OC, and no approved therapy to date has demonstrated an OS benefit. With OS data requiring years to mature in front-line OC trials, intermediate endpoints like PFS are crucial for accelerating clinical development and informing decision-making. Robust PFS-OS surrogacy can reduce uncertainty around treatment benefits and support stakeholder evaluations. This study assessed PFS-OS surrogacy in the front-line maintenance setting for advanced OC.
METHODS: A systematic literature review (up to 04/18/2024) identified eligible trials in the front-line maintenance setting reporting PFS and OS outcomes. Trial-level associations were assessed via meta-analysis using weighted linear regression models regressing OS hazard ratios (HRs) on PFS HRs. Trials with influential observations, identified by Cook’s distance, were excluded. Surrogacy was evaluated using correlation (R) and determination (R2) coefficients (good surrogacy: ∣R∣≥0.8 or R2 ≥0.65), and the surrogate threshold effect (STE)—the maximum PFS HR predicting a statistically significant non-zero effect on OS—was estimated. Model stability and predictive accuracy were evaluated via leave-one-out cross-validation. Secondary analyses examined alternative PFS definitions and the HRD-negative subpopulation.
RESULTS: Analysis of nine trials (N=4,792; sample sizes: 44 - 888) demonstrated a strong positive trial-level association between PFS and OS (R=0.91, 95% CI: 0.75-0.98; R2 = 0.83, 95% CI: 0.56-0.97). The STE was 0.54, indicating that PFS HRs ≤0.54 would be statistically associated with a reliable OS benefit in similar future trials. Cross-validation showed agreement between observed and predicted OS HRs in eight of nine trials (89%). Secondary analyses aligned with primary findings.
CONCLUSIONS: This study provides compelling and up-to-date evidence supporting PFS as a surrogate for OS in the front-line maintenance setting for advanced OC, underscoring its utility in enabling earlier assessments of treatment efficacy, facilitating regulatory approvals, strengthening reimbursement submissions, and providing timely access to innovative therapies.
METHODS: A systematic literature review (up to 04/18/2024) identified eligible trials in the front-line maintenance setting reporting PFS and OS outcomes. Trial-level associations were assessed via meta-analysis using weighted linear regression models regressing OS hazard ratios (HRs) on PFS HRs. Trials with influential observations, identified by Cook’s distance, were excluded. Surrogacy was evaluated using correlation (R) and determination (R2) coefficients (good surrogacy: ∣R∣≥0.8 or R2 ≥0.65), and the surrogate threshold effect (STE)—the maximum PFS HR predicting a statistically significant non-zero effect on OS—was estimated. Model stability and predictive accuracy were evaluated via leave-one-out cross-validation. Secondary analyses examined alternative PFS definitions and the HRD-negative subpopulation.
RESULTS: Analysis of nine trials (N=4,792; sample sizes: 44 - 888) demonstrated a strong positive trial-level association between PFS and OS (R=0.91, 95% CI: 0.75-0.98; R2 = 0.83, 95% CI: 0.56-0.97). The STE was 0.54, indicating that PFS HRs ≤0.54 would be statistically associated with a reliable OS benefit in similar future trials. Cross-validation showed agreement between observed and predicted OS HRs in eight of nine trials (89%). Secondary analyses aligned with primary findings.
CONCLUSIONS: This study provides compelling and up-to-date evidence supporting PFS as a surrogate for OS in the front-line maintenance setting for advanced OC, underscoring its utility in enabling earlier assessments of treatment efficacy, facilitating regulatory approvals, strengthening reimbursement submissions, and providing timely access to innovative therapies.
Conference/Value in Health Info
2025-05, ISPOR 2025, Montréal, Quebec, CA
Value in Health, Volume 28, Issue S1
Code
CO27
Topic
Clinical Outcomes
Topic Subcategory
Relating Intermediate to Long-term Outcomes
Disease
SDC: Oncology