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Heterogeneity of progression-free-survival surrogacy by sex in randomized trials testing immunotherapy in NSCLC

  • 0Department of Statistics and Quantitative Methods, University of Milano-Bicocca, Milan, Italy.
Jnci Cancer Spectrum +

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August 20, 2025

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August 20, 2025

View abstract on PubMed

Summary

This summary is machine-generated.

Progression-free survival (PFS) is a reliable surrogate for overall survival (OS) in male patients with advanced non-small cell lung cancer receiving immune checkpoint inhibitors (ICIs). However, this surrogacy is not robust in female patients.

Area Of Science

  • Oncology
  • Clinical Trials
  • Biostatistics

Background

  • Progression-free survival (PFS) is often used as a surrogate endpoint for overall survival (OS) in clinical trials for advanced non-small cell lung cancer (NSCLC).
  • Immune checkpoint inhibitors (ICIs) have shown efficacy in treating advanced NSCLC.
  • The validity of PFS as a surrogate for OS may vary based on patient characteristics, such as sex, which has not been previously investigated.

Purpose Of The Study

  • To investigate potential sex-based differences in the trial-level surrogacy of PFS for OS in randomized clinical trials (RCTs) of advanced NSCLC patients treated with ICIs.
  • To assess whether the association between PFS and OS differs between male and female patients.

Main Methods

  • A systematic review of RCTs evaluating ICIs (monotherapy or combination) in advanced NSCLC was conducted.
  • Hazard ratios (HR) for PFS and OS, stratified by patient sex, were extracted.
  • The coefficient of determination (R2) was used to quantify the surrogacy of PFS for OS, overall and in subgroups based on treatment type.

Main Results

  • Twenty RCTs comprising 7,528 male and 3,008 female patients were analyzed.
  • Overall surrogacy of PFS for OS was moderate (adjusted R2=0.69).
  • Significant heterogeneity was observed: PFS was a strong surrogate for OS in males (adjusted R2=0.77) but a poor surrogate in females (adjusted R2=0.31).

Conclusions

  • Progression-free survival serves as a robust surrogate endpoint for overall survival in male patients with advanced NSCLC treated with ICIs.
  • The surrogacy of PFS for OS is not reliable in female patients within the same clinical context.
  • These findings highlight the need for sex-specific considerations in the interpretation of clinical trial endpoints for advanced NSCLC.