Personalized medicines: Challenges and opportunities from bench to patients:

clinician researcher perspective

Janet Dancey, MD FRCPC

Ontario Institute for Cancer Research

NCIC Clinical Trials Group

Personalized Medicine –One concept, a multitude of meanings and perspectives

Patient:I want my doctor to know about

my life, to understand me and my family and to help me reach

decisions that are best for me. I did not want to lose my hair on treatment so we found an option for me that would spare my hair.

Clinician:Which patient or disease

features will alter my approach to

prevention, screening, or treatment?

Scientist:Each patient’s cancer has genetic

changes and each patient has genomic variations that make

them unique. We are looking for those changes that will allow the right patient to receive the right

treatments matched to their genetic fingerprint.

Courtesy of E Eisenhauer 2013

Current status: A few successes – potential far from being realized

Personalized medicine and cancer:A disease of the genome

Challenge in treating cancer:• Every tumour is different

• Every cancer patient is different

International Cancer Genome Consortium

Projects as of April 2013

High rate of abnormalities (driver vs. passenger);Multiple clones that evolve under the selection

pressures including systemic therapySample type, quality and timing matter

Methods of analysis matter

0.0%

10.0%

20.0%

30.0%

40.0%

50.0%

60.0%

70.0%

80.0%

APC BRAF CTNNB1 EGFR KRAS NRAS PIK3CA PTEN RB1 STK11 TP53

Lung carcinoma (all subtypes)

Prostate adenocarcinoma

Breast carcinoma (all subtypes)

Colon adenocarcinoma

Pancreatic ductal adenocarcinoma

Ovarian carcinoma (all subtypes)

Hepatocellular carcinoma

Gastric adenocarcinoma

Renal cell carcinoma

Malignant melanoma

Surveys of mutation databases indicate that most mutations are found in many tumour types

Sanger Institute: http://www.sanger.ac.uk/cosmic, COSMIC v54 Release (Forbes et al., 2011).

Gene Event Type Frequency, %

FGFR1 Amplification 20-25

FGFR2 Mutation 5

PIK3CA Mutation 9

PTEN Mutation deletion 18

CCND1 Amplification 8

CDKN2A Deletion/mutation 45

PDGFRA Amplification mutation

9

EGFR Amplification 10

MCL1 Amplification 10

BRAF Mutation 3

DDR2 Mutation 4

ERBB2 Amplification 2

Emerging “Druggable” Targets in NSCLC-Squamous Subtype

Lung Cancer Molecular Consortium Lung Adenocarcinomas

Kris MG, et al. ASCO 2011. CRA7506. Johnson BE, et al. IASLC WCLC 2011. Abstract O16.01

Hammerman P, et al. IASLC WCLC 2011. Abstract PRS.1

Many potential targets and biomarkers

MET AMP

Mutations found in 54% (280/516)

No mutationdetected KRAS

22%

EGFR17%

NRAS

Doublemutants 3%

AKT1

BRAF 2%

MEK1

HER2PIK3CA 2%

EML4-ALK7%

• Need for rapid, accurate and comprehensive profiling of cancer relevant molecular abnormalities

• Need for repeated testing at critical management decision points

Genetic heterogeneity & emergence of resistance

CMAJ 2012. DOI:10.1503

• Smith G, Pell JP. Parachute use to prevent death and major trauma related to gravitational challenge: systematic review of randomised controlled trials. BMJ 2003;327: 1459–61.

Personalized medicine: role of phase III trials

Crizotinib trials and regulatory approval

• Two single arm trials of 255 patients with locally advanced or metastatic ALK-positive NSCLC

• Crizotinib 250 mg po twice daily

• No data available to show improvement in patient reported outcomes or survival

• 5 of 19 ALK-negative lung carcinoma patients responded; ORR = 26.3% (95% CI 9.1%, 51.2%); 2 additional patients had a single assessment of PR

• Approval of drug and diagnostic test

Study Patients (N) ORR % 95%CI Duration wks.

A 136 50 42%, 59% 42

B 119 61 52%, 70% 48

http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2011/202570s000ltr.pdf

1-yr OS: 74% 2-yr OS: 54%

Personalized medicine: Integration of information

The challenge is not just limited to increasing the knowledge about targeted therapies. A practical framework for clinicians and patients is needed.

Personalized medicine & health care

Dancey et al., Cell 2012