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Related Experiment Video

Updated: Oct 9, 2025

Establishing a Competing Risk Regression Nomogram Model for Survival Data
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Robust group sequential designs for trials with survival endpoints and delayed response.

Pranab Ghosh1, Robin Ristl2, Franz König2

  • 1Pfizer Corporation, Cambridge, MA, USA.

Biometrical Journal. Biometrische Zeitschrift
|December 22, 2021
PubMed
Summary

The max-combo test offers a robust alternative to the traditional log-rank test for immuno-oncology clinical trials, especially when delayed treatment effects violate proportional hazards assumptions. This new method allows for early stopping in group sequential designs.

Keywords:
Fleming-Harrington testcancer immunologydelayed responsegroup sequential designimmuno-oncologylate separation of survival curveslog-rank testmax-combo testmodestly weighted log-rank testnonproportional hazards

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Area of Science:

  • Oncology
  • Biostatistics
  • Immunology

Background:

  • Randomized clinical trials in oncology commonly use time-to-event endpoints like progression-free survival and overall survival.
  • The log-rank test is the standard statistical method for analyzing these endpoints, assuming proportional hazards.
  • Immuno-oncology drugs, such as cancer vaccines, often exhibit delayed treatment effects, violating the proportional hazards assumption and potentially making the log-rank test suboptimal.

Purpose of the Study:

  • To investigate the max-combo test as a robust alternative to the log-rank test for analyzing immuno-oncology clinical trials.
  • To implement the max-combo test within a two-stage group sequential design, allowing for early stopping due to overwhelming efficacy.
  • To evaluate the performance of the max-combo test using Fleming and Harrington (1981) weights and Magirr and Burman (2019) modest weights.

Main Methods:

  • The study proposes and investigates the max-combo test, which combines two weighted log-rank statistics.
  • The max-combo test is applied to two-stage group sequential trial designs.
  • Two distinct weighting schemes, Fleming-Harrington and Magirr-Burman modest weights, are examined for the max-combo test.

Main Results:

  • The max-combo test is presented as a more appropriate statistical approach when the proportional hazards assumption is violated.
  • The implementation allows for early efficacy stopping in clinical trials, which is desirable for immuno-oncology agents known to prolong survival.
  • The investigation explores the characteristics of the max-combo test under different weighting strategies.

Conclusions:

  • The max-combo test provides a statistically sound and robust alternative for analyzing time-to-event data in immuno-oncology randomized clinical trials.
  • This approach addresses the challenges posed by delayed treatment effects common in immuno-oncology.
  • The developed methodology supports efficient clinical trial design by enabling early stopping for efficacy.