Group sequential designs for cancer immunotherapy trial with delayed treatment effect

ABSTRACT

Cancer immunotherapy trials are frequently characterized by delayed treatment effects such that the proportional hazards assumption is violated and the log-rank test suffers a substantial loss of statistical power. To increase the efficacy of the trial design, a variety of weighted log-rank tests have been proposed for fixed sample and group sequential trial designs. However, in such a group sequential design, it is often not recommended for futility interim monitoring due to possible delayed treatment effect which could result a high false-negative rate. To resolve this problem, we propose a group sequential design using a piecewise weighted log-rank test which provides an event-driven approach based on number of events after the delayed time. That is, the interim looks will not be conducted until the planned number of events observed after the delay time. Thus, it avoids the possibility of false-negative rate due to the delayed treatment effect. Furthermore, with an event-driven approach, the proposed group sequential design is robust against the underlying survival, accrual and censoring distributions. The group sequential designs using Fleming-Harrington-($\rho ,\gamma$) weighted log-rank test and a new weighted log-rank test are also discussed.

KEYWORDS:

• Cancer clinical trial
• delayed treatment effect
• group sequential design
• weighted log-rank test
• sample size

Acknowledgments

We thank the referees for their constructive comments that have lead to significant improvements in the article. Dr. Wu’s research was supported by the University of New Mexico Comprehensive Cancer Center Support Grant National Cancer Institute (NCI) P30CA118100. Dr. Li’s research was supported by the Comprehensive Cancer Center at St. Jude Children’s Research Hospital and American Lebanese Syrian Associated Charities (ALSAC).

Disclosure statement

No potential conflict of interest was reported by the authors.

Data availability statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study https://www.nature.com/articles/s41591-018-0134-3.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/10543406.2023.2170403

Additional information

Funding

The work was supported by the National Cancer Institute [P30CA118100].