Novel agents pose new challenges. Rather than conventional histological criteria for diagnosis, we may need to re-define how we classify cancers based on the mechanism of pathogenesis and therapy. This may allow greater efficiency in the clinical trial process by selecting populations with a greater liklihood of responding to treatments. Novel surrogates will need validation and acceptance by the scientific community. Starting doses of agents may need to be aimed at inhibiting or interacting with a target rather than the MTD. Dose ranging studies, accepted as a norm in most other therapeutic areas, may be accepted by oncologists to avoid toxicities and optimize the therapy’s interaction with targets.
This slide emphasizes why selecting patients for EGFR TKI therapy by clinical characteristics may be less successful.
In addition to our phase I PARPi + RT study, we are also in the process of initiating a multi-center clinical trial stratifying and treating patients by their prostate cancer gene fusion status. Maha – clinical trial Me – translational component
Role of Predictive Biomarkers as a Measure of Individualized Medicine Maha Hussain, M.D., FACP Professor of Medicine & Urology Associate Director for Clinical Research University of Michigan Comprehensive Cancer Center
Identification of “ active” drugs Appropriate Phase III studies Identification of active and safe combinations Adjuvant Neoadjuvant Overarching Objective “ Impact and Change the Standards of Care” This = Decades & $$$$$$
Nine FDA Approvals for Metastatic Castration Resistant Prostate Cancer in 15 Years
I Prospective, Marker Primary Objective, Well-powered OR Meta-analysis
II Prospective, Marker Secondary Objective
III Retrospective, Outcomes, Multivariate Analysis
IV Retrospective, Outcomes, Univariate
V Retrospective, Correlation with Other Marker, No Outcomes
Tumor Marker Utility Grading System (TMUGS): Levels of Evidence D. Hayes Hayes, et al; J Nat Cancer Institute 88:1456, 1996; Simon R.M., et al. J Natl Cancer Inst. 2009 Most Tumor Marker Studies (Studies of Convenience)
Challenges for Drug Development in the “Era of Targeted Therapies & Personalized Medicine”
Re-define “definitions” of diseases
Morphology or Molecular Profile
How to define a “relevant target”?
where is the marker to be measured, what expression rate is meaningful, tumor heterogeneity ?
Endpoints and new outcome surrogates to be validated
How successful are we in selecting and targeting solid tumors? Target ER Her-2 EGFR C-Kit TS Disease Breast Breast Colon GIST Colon Drug Tamoxifen Herceptin Cetuximab Gleevec 5-FU Response (%) 50-60 15-26 (35) 10 60-70 15-20
Lung Cancer:EGFR Genotype Cannot Be Reliably Determined by Phenotype Jackman DM, et al. J Clin Oncol. 2008;26(May 20 suppl). Abstract 8035. In mutation positive 71%(I-PASS) response as first-line treatment and 42% (INTEREST) as second-line Phenotype of NSCLC Patient Prevalence of EGFR Mutation, Which Enhances Sensitivity to TKIs All 10-15% Elderly 10-15% PS2 10-15% Caucasian never-smokers ~ 35% Asian never-smokers ~ 65%
AR-mediated transcription is directly coupled with the induction of DNA damage
PARP1 function is critical to the pro-tumorigenic functions of the androgen receptor
A ddition of the PARP inhibitor ABT888 improves the response to hormone therapy in preclinical prostate cancer models
Haffner MC, et al: Nat Genet 42:668-75, 2010, Lin C, et al: Cell 139:1069-83, 2009 Haffner M, et al: Clin Cancer Res, 2011
ERG-positive Xenografts are Preferentially Sensitive to PARP inhibitors ( Olaparib) ERG (the predominant ETS gene fusion product) physically interacts with PARP1 PARP1 is required for ERG-associated function (transcription/invasion) ERG-positive xenografts are preferentially sensitive to PARP inhibitors