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Challenges with overall survival as an endpoint for efficacy assessment in first line metastatic breast cancer randomized controlled clinical trials and the investigation of truncated overall survival as an alternative endpoint

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Abstract

Background

Overall survival (OS) remains the gold standard to assess treatment benefit in randomized controlled clinical trials (RCT) of advanced cancer. In first line metastatic breast cancer (1 L MBC) where survival typically is several years instead of months, it is increasingly seen that OS-treatment effects dilute over time, with later line therapies strongly influencing OS analyses. We investigate truncated OS (i.e., truncating deaths and follow-up beyond a certain time point from randomization) as a potential alternative endpoint to OS.

Methods

We reanalyze data from two RCTs in 1 L MBC to illustrate how OS results can be driven by early treatment effects. We flexibly model the hazard ratio (HR) according to time since randomization. We conduct simulations to characterize the impact of number of events, sample-size, and recruitment on the power of the log-rank test for OS and for truncated OS considering truncation at 12, 18, or 24 months in presence of non-proportional hazards (non-PH).

Results

The impact of non-PH on the power of a log-rank test for OS may be severe and the power for a truncated OS analysis is higher in situations of non-PH. Statistically significant OS benefit is unlikely to be demonstrated with a log-rank test unless treatment effect is very strong, long-lasting, or only short-term follow-up is included.

Conclusion

Compared with the classical OS endpoint, truncated OS may provide the treating physicians, prescribers, and payers with a more accurate and less biased estimate of treatment benefit more directly attributable to the treatment under investigation.

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Conflict of interest

The authors declare that there is no conflict of interest.

Research support for the study: None

Previous presentations of study: None

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The views expressed in this manuscript are those of the authors and not necessarily their employers.

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Authors and Affiliations

  1. Biostatistics, Roche Products Limited, Welwyn, UK

    Colin Neate MSc

  2. Biostatistics, F. Hoffmann-LaRoche, Basel, Switzerland

    Alexander Strasak PhD & Hans Ulrich Burger PhD

  3. Biostatistics, Genentech, South San Francisco, USA

    Barbara Tong PhD & Lee Kaiser PhD

Authors
  1. Colin Neate MSc
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  2. Alexander Strasak PhD
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  3. Hans Ulrich Burger PhD
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  4. Barbara Tong PhD
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  5. Lee Kaiser PhD
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Corresponding author

Correspondence to Colin Neate MSc.

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Neate, C., Strasak, A., Burger, H. et al. Challenges with overall survival as an endpoint for efficacy assessment in first line metastatic breast cancer randomized controlled clinical trials and the investigation of truncated overall survival as an alternative endpoint. memo 7, 162–168 (2014). https://doi.org/10.1007/s12254-014-0164-6

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  • DOI: https://doi.org/10.1007/s12254-014-0164-6

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