Evaluating Medical Utility of Prognostic & Predictive Biomarkers using Archived Tissue

1. Use of Archived Tissue in Evaluating the Medical Utility of Prognostic & Predictive Biomarkers Richard Simon, D.Sc. Chief, Biometric Research Branch National Cancer Institute http://brb.nci.nih.gov

2. Prognostic & Predictive Biomarkers • Most cancer treatments benefit only a minority of patients to whom they are administered • Being able to predict which patients are likely to benefit would • Save patients from unnecessary toxicity, and enhance their chance of receiving a drug that helps them • Control medical costs • Improve the success rate of clinical drug development

4. Predictive & Prognostic Biomarkers • Predictive biomarkers • Measured before treatment to identify who will or will not benefit from a particular treatment • ER, HER2, KRAS • Prognostic biomarkers • Measured before treatment to indicate long-term outcome for patients untreated or receiving standard treatment • Used to identify who does not require more intensive treatment • OncotypeDx

5. Prognostic and Predictive Biomarkers in Oncology • Single gene or protein measurement • ER protein expression • HER2 amplification • KRAS mutation • Index or classifier that summarizes expression levels of multiple genes • OncotypeDx recurrence score

6. Types of Validation for Prognostic and Predictive Biomarkers • Analytical validation • Accuracy compared to gold-standard assay • Robust and reproducible if there is no gold-standard • Pre-analytical robustness to tissue handling and preparation • Clinical validation/correlation • Does the biomarker predict what it’s supposed to predict for independent data • Clinical/Medical utility • Does use of the biomarker result in patient benefit • Generally by improving treatment decisions • Is it “actionable”

7. Prognostic Factors in Oncology • Most prognostic factors are not used because although they correlate with a clinical endpoint, they have no demonstrated medical utility • They are developed in unfocused studies that use convenience samples of heterogeneous patients for whom tissue is available • They are not reliable because they are exploratory and not prospectively focused on a single factor

8. Predictive Biomarkers • In the past often studied as un-focused post-hoc subset analyses of RCTs. • Numerous subsets examined • No focused pre-specified hypothesis • No control of type I error

9. Prospective Validation of the Medical Utility of a PrognosticBiomarker • Develop biomarker predictive of outcome for low stage patients without chemotherapy. Then • Select low stage patients who are considered good prognosis by biomarker • Randomize them to standard chemotherapy or to no chemotherapy • e.g. MINDACT

10. If predicted risk of recurrence without chemotherapy is sufficiently low, then randomization might be omitted omited and chemotherapy withheld • If their outcome is sufficiently good without chemotherapy, absolute benefit of chemotherapy would be very small • TAILORx

11. Perform Test with Predictive Biomarker Predicted Responsive To New Rx Predicted Non-responsive to New Rx New RX Control New RX Control Prospective Evaluation of a Predictive Biomarker

12. Prospective Evaluation of PredictiveBiomarker • The RCT • focused on a single pre-specified biomarker • sized with sufficient marker + and marker – patients for adequately powered separate analysis of T vs C differences • Evaluating a predictive biomarker does not involve comparison of outcome of marker + vs marker – patient • The purpose of the RCT is not to re-derive or refine the definition of the biomarker

13. R Simon. Using genomics in clinical trial design, Clinical Cancer Research 14:5984-93, 2008 • R Simon and A Maitournim . Evaluating the efficiency of targeted designs for randomized clinical trials. Clinical Cancer Research 10:6759-63, 2004. • R Simon. Roadmap for developing and validating therapeutically relevant genomic classifiers. Journal of Clinical Oncology 23:7332-41, 2005.

14. It may be infeasible or unethical to conduct a new prospective trial to test a hypothesis about a prognostic or predictive biomarker • For tests relating to the use of approved therapeutics • KRAS for anti-EGFR antibodies in colorectal cancer • HER2 for doxorubicin • TAILORx and MINDACT trials require many thousands of patients • Genomic test strategy designs which randomize whether to perform or not perform the test often require tens of thousands of patients

15. In some cases the benefits of a prospective trial can be closely achieved by the carefully planned use of archived tissue from a previously conducted randomized clinical trial

16. Use of Archived Specimens in Evaluation of Prognostic and Predictive BiomarkersRichard M. Simon, Soonmyung Paik and Daniel F. Hayes • Claims of medical utility for prognostic and predictive biomarkers based on analysis of archived tissues can be considered to have either a high or low level of evidence depending on several key factors. • Studies using archived tissues, when conducted under ideal conditions and independently confirmed can provide the highest level of evidence. • Traditional analyses of prognostic or predictive factors, using non analytically validated assays on a convenience sample of tissues and conducted in an exploratory and unfocused manner provide a very low level of evidence for clinical utility.

17. For Level I Evidence • Archived tissue adequate for a successful assay must be available on a sufficiently large number of patients from a phase III trial with a design that enables the appropriate analyses • e.g. For predictive marker, RCT comparing T to Control • Adequate statistical power • The patients included in the evaluation are clearly representative of the patients in the trial. • The test should be analytically and pre-analytically validated for use with archived tissue. • An analysis plan for the biomarker evaluation should be completely specified in writing prior to the performance of the biomarker assays on archived tissue and should be focused on evaluation of a single completely defined classifier. • The results of the analysis should be validated using specimens from a similar, but separate, study

18. Does It Matter If the Randomization in the RCT Was Not “Stratified” By the Test? • No • Stratification improves balance of stratification factors in overall comparisons • Stratification does not improve comparability of treatment (T) and control (C) groups within test positive patients or within test negative patients

19. What Proportion of the Patients Should Have Adequate Archived Tissue Available for a Valid Analysis? • No minimum percentage can be adequately defended • For treatment versus control comparisons within test + patients (or within test – patients), the analysis is internally valid regardless of the proportion with available tissue or the selection factors affecting tissue availability • External validity (generalization of results to the broad population of patients) depends on representativeness of the full study group as well as the proportion with tissue available

20. Does the RCT From Which the Archived Tissues are Taken Need to Be Significant Overall for the T vs C Treatment Comparison? • No • In a fully prospective trial of T vs C with a companion test it is incorrect to require that the overall T vs C comparison be significant to claim that T is better than C for test + patients but not for test – patients • That requirement has been traditionally used to protect against data dredging. It is inappropriate for focused trials of a treatment with a companion test. • Since the requirement is inappropriate for a fully prospective trial, it is also inappropriate for a properly designed prospective-retrospective trial

21. * RCT required for predictive biomarker

22. Revised Levels of Evidence for Tumor Marker Studies

23. Barriers to the Development of Prognostic and Predictive Biomarkers for Clinical Use • Increased complexity and cost of developing new drugs with predictive biomarkers • Difficulty of identifying the appropriate predictive biomarker prior to conduct of phase III clinical trials of new drugs • Inadequate appreciation of the distinction between establishing clinical correlation and medical utility for prognostic markers • Inadequate appreciation of the importance of focused testing of pre-specified marker hypotheses • High costs and time required for prospective validation of prognostic factors for withholding chemotherapy in low-risk populations • Inadequate focus on analytically validating tests • Unavailability of adequate archived tissue from patients on key RCT’s

24. Barriers to the Development of Prognostic and Predictive Biomarkers for Clinical Use • Lack of regulatory guidance for approval of in-vitro diagnostics and of treatments for restricted populations that • is appropriate to the inherent heterogeneity of human cancers • encourages the development of predictive biomarkers • is cognizant of the infeasibility of always addressing treatment by subset questions prospectively • e.g. Difficulty of approving even restriction of a labeling indication based on a compelling prospective-retrospective analyses of KRAS in multiple randomized colorectal cancer trials

25. Conclusions • New biotechnology and knowledge of tumor biology provide important opportunities to improve therapeutic decision-making • Treatment of broad populations with regimens that do not benefit most patients is no longer necessary nor economically sustainable • The established molecular heterogeneity of tumors requires new approaches to the development of cancer treatments • The traditional assumption underlying most clinical trial design that treatment by subset interactions are unlikely is often inappropriate today

26. For establishing medical utility of prognostic and predictive tests, fully prospective trial designs are desirable • It is often not possible, however, to identify the appropriate predictive marker for a drug prior to the conduct of the pivotal trials of that drug • It is often not feasible or ethical to conduct prospective RCT’s for validating predictive markers of approved drugs • It is very expensive and time consuming to conduct prospective trials to evaluate prognostic markers that indicate withholding standard chemotherapy regimens from good risk patients

27. Studies using archived tissues, when conducted under ideal conditions and independently confirmed can provide the highest level of evidence • Barriers to the development, approval and use of effective prognostic and predictive biomarkers that benefit patients and society are substantial

28. Acknowledgements • Soonmyung Paik, NSABP • Daniel Hayes, U. Michigan