Rapid Learning Precision Oncology

Part I: Patient’s Perspective Part II: Industry Perspective Part III: Aligning Incentives

Part I: Patient’s Perspective surgery radiation clinical trials experimental methods chemotherapy Thousands of rare molecular subtypes Tens of thousands of treatment combinations Traditional RCTs become problematic

Biopsy Sequence Compare TargetTest Treat Monitor Precision Oncology 2.0 (Today) In silico In vivo In vitro Normal skin cell Sequencing Machines Chromosomes Normal cell Cancer cell Treated cell Scans Patient Biomarkers Original cancer cell Adapted from NY Times

Sequence Compare TargetTest Treat Monitor Precision Oncology 3.0 In silico In vivo In vitro Normal skin cell Sequencing Machines Chromosomes Normal cell Cancer cell Treated cell Scans Patient Biomarkers Adapted from NY Times Original cancer cell Biopsies Biopsy Panomics Networks Treatment Planning Network Analysis Combo Therapies Serum Markers

Molecular Tumor Board Medical, surgical and radiation oncologists, biostatisticians, radiologists, and pathologists + clinical geneticists and specialists in cancer pathways, pharmacology, bioinformatics

Case Reports

No Learning

Rapid Learning Precision Oncology A rapid learning community for cancer Help each patient obtain the best possible outcome Learn as much as possible Disseminate rapidly

10 mTOR AKT PI3K PTEN NRAS BRAF MEK ERK Bcl-2, Bcl-xL, Mcl-1 BAK BAX NOXA, PUMA BIM, BID, BAD p53 MDM 2 p14ARF CDK4/6 p16 Cyclin D MITF MAPK 1 2 NRAS 3 MITF 4 PI3K 5 CDK 6 c-KIT 7 Bcl-2 88 MAPK/ PI3K 99 MAPK/ CDK 10 NRAS/ MAPK/ PI3K Melanoma Molecular Subtypes Subtypes Cell Signaling Pathways Responders Non- Responders

ScientistsClinical Researchers Physicians Patients Human-Machine Knowledge System Patient Models Reference Models SpecimensLabs Clinical Trials PharmaPayers Hospitals

What It Means To Do Our Best Tony Blau MD, U. Washington “Although our ability to exploit knowledge of cancer pathways is in its infancy, we must do our best for today's cancer patients and, in the process, learn as much as possible for the patients of tomorrow.” NCT : Collecting, Analyzing, and Storing Samples From Patients With Metastatic, Triple Negative Breast Cancer Receiving Cisplatin (ITOMIC) University of Washington & NCI ITOMIC: Intensive Trial of OMics in Cancer

Rapid Learning Network Tony Blau U. Washington Andrea Califano Columbia U. Lincoln Nadauld Intermountain Health Keith Flaherty MGH George Demetri Dana Farber Ravi Salgia U. Chicago Mitesh Borad Mayo Clinic Beth Karlan Cedars Sinai Heinz Josef Lenz, USC Joel Neal Stanford

Global Cumulative Treatment Analysis

Part II: Industry Perspective Drug Discovery FDA Approval Trials Phase 1 Trials Phase 2 Trials Phase 3 Year

Replace Large Trials With… Drug Discovery FDA Approval Trials Phase 1 Trials Phase 2 Trials Phase 3 Year

N-of-1 Studies Drug Discovery FDA Approval Year

Replace Discovery With… Drug Discovery FDA Approval Year

All Approved + Investigational Drugs Drug Discovery FDA Approval Year

Years To Months Month Precision Oncology 3.0

GCTA: Many Parallel N-of-1 Trials Month Precision Oncology 3.0

The Search For Cures

Succeed Slowly 1 yr3 yrs5 yrs9 yrs

Fail Fast 1 yr3 yrs5 yrs

Fail Fast 1 yr3 yrs5 yrs

Bed to Bench 1 yr3 yrs5 yrs

Bed to Bench 1 yr3 yrs5 yrs

Tightly Integrate Research and Care Tony Blau MD, U. Washington “Although our ability to exploit knowledge of cancer pathways is in its infancy, we must do our best for today's cancer patients and, in the process, learn as much as possible for the patients of tomorrow.” “…There are still no curative treatments for castration-resistant prostate cancer (CRPC) and, therefore, it remains fatal….Our findings suggest that dual targeting of the Akt and mTOR signaling pathways using MK-2206 and MK-8669 may be effective for treatment of CRPC, particularly for patients with deregulated Rb pathway activity. “ Andrea Califano, PhD, Columbia

Part III. Aligning Incentives Physician applies for compassionate use Pharma provides drug Health plan pays Replicate-small n Fast track approval Lose cost of pills Save years Drug Works Drug Fails

Toolkit Licensing

Rapid Learning Precision Oncology 1.Tightly integrating cancer research, drug development, and clinical care will improve outcomes, accelerate research, and slash time to clinic. 2.Trials are for validation, not discovery. GCTA-like studies are the only way to efficiently search the vast space of targeted therapies x subtypes. 3.Managing an individual’s cancer, and then generalizing to other patients, is much more achievable than “Curing Cancer”. 4.Barriers such as drug access and reimbursement can be overcome by aligning industry’s interests with the those of patients. 5.The FDA has a critical role in predictive pharmacology, toolkit licensing, and single subject INDs for testing rational combination therapies.