Chee Lee, MBBS (Hons), MMedSci (Clin Epid), MBiostat, PhD, FRACP Biomarker-Based Clinical Trials: Practical and Design Considerations Biomarker Any characteristic that can be objectively measured as an indicator of normal or pathological biological processes or the response to a therapy Biomarkers Definitions Working Group. Clin Pharmacol Ther. 69(3):89-95, 2001 No Therapy Factor 1 Neg Factor 1 Pos 100% cure PROGNOSISPROGNOSIS 50% cure 10% cure Pure Prognostic Factor Classifies an individuals baseline risk of having a clinical event Hayes et al. Breast Cancer Res Treat. 1998;52: Factor 1 Neg Factor 1 Pos Classifies the magnitude of an individuals response to treatment Pure Predictive Factor No Therapy 100% cure PROGNOSISPROGNOSIS 50% cure 10% cure Hayes et al. Breast Cancer Res Treat. 1998;52: Factor 1 Neg Factor 1 Pos Marker Can Be Prognostic and Predictive No Therapy 100% cure PROGNOSISPROGNOSIS 50% cure 10% cure Hayes et al. Breast Cancer Res Treat. 1998;52: Predictive Biomarkers Best evaluated in a prospective study with concurrent control arm Different study designs enriched vs unselected designs Can be prospective and retrospective Enrichment Design: Enrol Only Those Thought Likely to Respond Romond et al. N Engl J Med. 2005;353: Lee et al. Med J Aust. 2009;190: 100% 50% 25% Pegram et al. J Clin Oncol. 2005;23: Simulated Phase III Trial in Which 100% of Patients Show a Treatment Effect: 200 Active Patients With Median = 27 Months, 200 Placebo Patients With Median = 22 Months Biomarker+ population Improves mOS from 22 to 27 months (25% improvement) Biomarker- population No benefit with treatment Enrichment Design: Improves Efficiency Prevalence Biomarker+ Relative Efficacy Efficiency Gain 25%100%16 25%50%2.5 50%100%4 50% 1.8 75%100%1.8 75%50%1.3 Gains in efficiency depend on marker prevalence and relative efficacy in biomarker+ and biomarker- patients Simon and Maitournam. Clin Cancer Res. 2004;10: Using Markers to Restrict Trial Eligibility: Beware No difference in benefit based on HER2+ expression 1 After 10 years, new study of Herceptin in HER2- patients? 1. Paik et al. N Engl J Med. 2008;358: Paik. ASCO Abstract NSABP B-47 POPULATION Female Invasive BC Node positive or high-risk node negative HER2 normal STRATIFICATION Age 12 weeks Measurable stage IIIB/IV disease Gefitinib 250 mg/day Carboplatin AUC 5 or 6 paclitaxel 200 mg/m 2 3 weeks* Primary endpoint: PFS (non-inferiority) Secondary endpoints: ORR, OS, QOL, disease-related symptoms, safety Exploratory biomarkers: EGFR mutation, EGFR gene copy number, EGFR protein expression N=1217 Cross-over allowed upon disease progression Probability of PFS At risk: Gefitinib Carboplatin/ paclitaxel Months Gefitinib Carboplatin/ paclitaxel N Events453 (74.4%) 497 (81.7%) HR (95% CI) = (0.651, 0.845) P< Median PFS (months) months progression free61% 74% 6 months progression free48% 48% 12 months progression free25% 7% PFS in ITT Population Primary Cox analysis with covariates. HR