The Power of Precision Medicine Jonathan J. Keats, PhD

Director of Bioinformatics

Assistant Professor, Integrated Cancer Genomics Scientific Director, Judy and Benard Briskin Center

for Multiple Myeloma Research

Evidence Based Versus Precision Medicine

Getting Clinical Trials Going Takes Commitment

Tumor Board Discussion

Biomarker Name

Biomarker Type Aberration Evidence

Type Indication Drug

BRAF Target Amp Exp_Over Direct Sen Inhibitor of RAF

BRAF Modifier Amp Exp_Over Inferred Sen Inhibitor of MEK

HRAS Modifier Amp Exp_Over Inferred Sen Inhibitor of MEK

INPP4B Modifier Exp_Under Inferred Sen Inhibitor of AKT

Tumor Board Discussion ‘Inhibiting overexpressed wt BRAF with a RAF inhibitor elicits feedback activation through PI3K/AKT. Not with MEK inhibitor. ‘ ‘A hit in parallel PI3K/AKT pathway’. ‘Combination therapy might be most effective against this tumor.’

Dramatic Response in Chemotherapy Resistant Patient

Baseline (03/07/11) Post 2 cycles (05/04/11)

Phase I study of MEK (trametinib) + AKT (GSK2141795) inhibitors

Irrational Marker Positive Expectations à Bad Name

BRAF V600E

What level of response do you expect if 20% of cells have it? Will you do the trial correctly to show the drug worked?

Advanced Genomic Testing – True Somatic Analysis

Allele Frequency is Dangerous for Decision Making

BRAF

What is the purity of the sample tested? What is the copy number state of the mutated gene?

Multiple Assays or Advanced Technology is Needed

High Risk

Biology Trumps Simplicity for Accurate Interpretation

P53 P53 P53P53 P53 P53

Normal BrakesFrontBack

FrontBack

Some Brakes No BrakesFrontBack

75% of patients called high risk, actually have standard risk disease

Risk Adapted Therapy Need Correct Stratification

Mikhael J et al. Mayo Clin Proc 2013; 88:360-376 www.msmart.org

Need to Know: Sensitivity of Current Assays

AF - 12.5% 6.25% 3.1% 1.5% 0.7%

Need to Know: Complex Mixtures – Target Early Events

Final Points to Consider

• Physician education programs will be essential for future success of the approach

–  Many treating physicians do not feel confident they can interpret and leverage results

•  Reports are often convoluted and difficult to interpret • Precision medicine approaches will not always identify new

treatment options but trunk events should be priority –  Sometimes treatments are excluded, which are known to be ineffective or due to genetic links with adverse events

–  Sometimes identifies tumor evolution events creating an uncharacteristic high therapeutic index or synthetic lethality