Rapid Learning Precision Oncology. Part I: Patient’s Perspective Part II: Industry Perspective...
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Transcript of Rapid Learning Precision Oncology. Part I: Patient’s Perspective Part II: Industry Perspective...
Rapid Learning Precision Oncology
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
experimentalmethods
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 silicoIn 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 silicoIn 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
BiopsiesBiopsy
Panomics
Networks
Treatment
Planning
Network Analysis
Combo Therapies
Serum Markers
Marty
DISCUSS OPPOORTUNITIES FOR AI IN THIS FIGURE (AND ALL FIGURES).
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 OncologyA rapid learning community for
cancer• Help each patient obtain the best possible outcome
• Learn as much as possible
• Disseminate rapidly Learn
Model
AnalyzeTreat
mTOR
AKT
PI3K
PTEN
NRASBRAF
MEK
ERK
Bcl-2, Bcl-xL, Mcl-1
BAKBAX
NOXA, PUMABIM, BID,
BAD
p53
MDM2
p14ARF
CDK4/6 p16
Cyclin D
MITF
MAPK1
2 NRAS
3 MITF
4 PI3K
5 CDK
6 c-KIT
7 Bcl-2
8 8MAPK/ PI3K
9 9MAPK/ CDK
10
10
10
NRAS/ MAPK/ PI3K
Melanoma Molecular SubtypesSubtypes Cell Signaling Pathways
Responders
Non- Responders
Scientists Clinical Researchers Physicians Patients
Human-Machine Knowledge System
PatientModels
ReferenceModels
Specimens
Labs Clinical Trials
PharmaPayersHospitals
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.”
NCT01957514: 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 BlauU.
Washington
Andrea Califano
Columbia U.
Lincoln NadauldIntermountain
Health
Keith Flaherty
MGH
George Demetri Dana
Farber
Ravi SalgiaU. Chicago
Mitesh BoradMayo Clinic
Beth KarlanCedars Sinai
Heinz Josef Lenz, USC
Joel NealStanford
Global Cumulative Treatment Analysis
Part II: Industry Perspective
DrugDiscovery
FDAApproval
TrialsPhase 1
TrialsPhase 2
TrialsPhase 3
Year 1 2 3 4 5 6 7 8 9 10 11 12 13 14 150
JMT
Redraw as a Funnel (one reason it takes so long is that there are 1000’s of drugs that need to be eliminated, to find the few that advance to trials, and the one that is finally marketed. )
Marty Tenenbaum
Consider lopping off everything with big Xs and then making a separate 3 mo time line with a single patient and all the world's drugs. Alt. adapt the tree/maze to tell this part of the story but we will need to make the points about multiple drugs and the ability to agregate learnings aboout multiple patients.
Replace Large Trials With…
DrugDiscovery
FDAApproval
TrialsPhase 1
TrialsPhase 2
TrialsPhase 3
Year 1 2 3 4 5 6 7 8 9 10 11 12 13 14 150
JMT
Redraw as a Funnel (one reason it takes so long is that there are 1000’s of drugs that need to be eliminated, to find the few that advance to trials, and the one that is finally marketed. )
N-of-1 Studies
DrugDiscovery
FDAApproval
Year 1 2 3 4 5 6 7 8 9 10 11 12 13 14 150
JMT
Redraw as a Funnel (one reason it takes so long is that there are 1000’s of drugs that need to be eliminated, to find the few that advance to trials, and the one that is finally marketed. )
Replace Discovery With…
DrugDiscovery
FDAApproval
Year 1 2 3 4 5 6 7 8 9 10 11 12 13 14 150
JMT
Redraw as a Funnel (one reason it takes so long is that there are 1000’s of drugs that need to be eliminated, to find the few that advance to trials, and the one that is finally marketed. )
All Approved + Investigational Drugs
DrugDiscovery
FDAApproval
Year 1 2 3 4 5 6 7 8 9 10 11 12 13 14 150
JMT
Redraw as a Funnel (one reason it takes so long is that there are 1000’s of drugs that need to be eliminated, to find the few that advance to trials, and the one that is finally marketed. )
Years To Months
Month 1 2 2.5 31.5
Precision Oncology 3.0
JMT
Redraw as a Funnel (one reason it takes so long is that there are 1000’s of drugs that need to be eliminated, to find the few that advance to trials, and the one that is finally marketed. )
GCTA: Many Parallel N-of-1 Trials
Month 1 2 2.5 31.5
Precision Oncology 3.0
JMT
Redraw as a Funnel (one reason it takes so long is that there are 1000’s of drugs that need to be eliminated, to find the few that advance to trials, and the one that is finally marketed. )
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 Oncology1. 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.
