Biomarker enrichment strategies: matching trial design to biomarker credentials

Key Points

  • Many new anticancer treatments are molecular targeted agents and only benefit a subgroup of patients within a histologically defined cancer

  • Heterogeneity of treatment effects requires development of biomarkers to identify patients who could benefit from new treatments

  • Phase III trial designs for evaluation of targeted treatments use biomarker-driven enrichment strategies that range from limiting evaluation to the biomarker-positive subgroup to sequential testing of biomarker-positive, biomarker-negative and overall populations

  • To provide compelling evidence for informing clinical practice, the choice of an appropriate phase III trial design should be guided by the strength of the biomarker's credentials


The use of biomarkers to identify patients who can benefit from treatment with a specific anticancer agent has the potential to both improve patient care and accelerate drug development. The development of targeted agents and their accompanying biomarkers frequently occurs contemporaneously, and confidence in a putative biomarker's performance might, therefore, be insufficient to restrict the definitive testing of a new agent to the subgroup of biomarker-positive patients. This Review considers which clinical trial designs and analysis strategies are appropriate for use in phase III, biomarker-driven, randomized clinical trials, on the basis of pre-existing evidence that the biomarker can successfully identify patients who will respond to the treatment in question. The types of interim monitoring that are appropriate for these trials are also discussed. In addition, enrichment strategies based on the use of prognostic biomarkers to separate a population into subgroups with better and worse outcomes, regardless of treatment, are described. Finally, the possibility of formally using a biomarker during phase II drug development, to select what type of biomarker-driven strategy should be used in the phase III trial, is discussed.

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Figure 1: Biomarker-driven phase III clinical trial designs.
Figure 2: Analysis strategies with biomarker-stratified phase III clinical trials.
Figure 3: Analysis strategies with biomarker-stratified phase III clinical trials.


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Both authors contributed to all aspects of this article, including researching the data for the article, discussions of its content, writing the article, and review and editing of the manuscript before submission.

Correspondence to Boris Freidlin.

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The authors declare no competing financial interests.

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Freidlin, B., Korn, E. Biomarker enrichment strategies: matching trial design to biomarker credentials. Nat Rev Clin Oncol 11, 81–90 (2014).

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