The Genetics of Cancer: Is Personalization of Cancer

Treatment Possible?Keith T. Flaherty, M.D.

Massachusetts General Hospital Cancer Center

Disclosures

• Board of Directors: Clovis Oncology, Loxo Oncology• Scientific Advisory Board: Sanofi, Ziopharm, Oncoceutics, Raze, X4

Therapeutics• Consultant: GSK, Novartis, Roche, Merck, Amgen, Array, Cerulean,

Momenta

Somatic mutation burden by cancer type

Alexandrov et al. Nature 2013

Mutation patterns sort into distinct subgroups

Alexandrov et al. Nature 2013

BRAF, NRAS and NF1 define mutually exclusive subsets of melanoma

Cancer Genome Atlas Research Network et al. TCGA symposium 2012

200

50%

25%

10%

Melanoma: the model of MAP kinase dependence

Sullivan RJ & Flaherty KT. CCR 2014

Recurrent concomitant mutations in BRAF mutant melanoma

Cancer Genome Atlas Research Network et al. TCGA symposium 2012

AKT3

MDM2

BRAF

MITF

Tumor regression V600EBRAF mutant melanoma patients (vemurafenib)

RECIST 30% Decrease

Sosman J et al. NEJM 2012

-100-80-60-40-20

020406080

100

BRAF vs. BRAF/MEK combination in V600EBRAF mutant melanoma patients

Max

imu

m p

erce

nt

red

uct

ion

fro

m b

ase

lin

e m

eas

ure

men

t

Best confirmed response

Complete responsePartial responseProgressive disease

Stable disease

-100

-80

-60

-40

-20

0

20

40

60

80

100

Dabrafenib monotherapy

Dabrafenib 150 mg BID/Trametinib 2 mg QD

Long G et al. ESMO 2012

Tumor regression to erlotinib in EGFR mutant NSCLC

Rizvi N et al. CCR 2011

Tumor regression to crizotinib in ALK translocated NSCLC

Camidge R et al. Lancet Oncol 2012

BRAF inhibition in V600EBRAF melanoma & colon cancer

Kopetz, ASCO 2010

melanoma colorectal

Sosman J et al. NEJM 2012

Feedback mechanisms in the

MAP kinase pathway

Mendoza et al. Trends Biochem Sci. 2011

Vemurafenib (BRAFi) or dabrafenib/trametinib (BRAF/MEKi) in BRAF mutant colorectal cancer

Kopetz, ASCO 2010 Corcoran ASCO 2012

NCI MATCH• Identify

mutations/amplifications/translocations in patient tumor sample - eligibility determination

• Assign patient to relevant agent/regimen• Need to sequence large numbers of tumors

and need to have large numbers of targeted treatments

• Tumor biopsies & sequencing at progression to illuminate resistance mechanisms– De-identified samples submitted to central labs – Whole-exome sequencing (research purposes)

Study agent

Stable Disease,

Complete or partial

response (CR+PR)1

Actionable mutation detected

No additional actionable

mutations, or withdraw consent

Genetic sequencing

Progressive disease

(PD)1

Off study

PD

Continue on study agent

until progression

Check for additional actionable mutations2

YesNo

SCHEMA

1CR, PR, SD, and PD as defined by RECIST2Rebiopsy; if additional mutations, offer new targeted therapy

Eligibility

• Patients with solid tumors or lymphomas whose disease has progressed following at least one line of standard systemic therapy (or with tumors that do not have standard therapy)– Exclude histologies that had been approved by the

FDA or had shown lack of efficacy with an agent• Tumor accessible to biopsy and patient willing

to undergo biopsy• Adults• Performance status ECOG 0-1• Adequate organ function

Patient population considerations

• Target: at least 25% of total enrollment to be patients who have “rare” tumors

• “Common” defined as breast, NSCLC, colon, prostate

Statistical Design

Statistical Considerations (within each drug-by-mutation category)

Primary Endpoint: •Overall Response Rate 5% vs. 25% •One stage design 31 evaluable patients per arm

CLIA lab network

• Genetic platform: Ion Torrent PGM Ampliseq custom panel– About 200 genes– SNV, indel, CNV, targeted translocations

• Validation within and across sites: same SOP

• Selected IHC, FISH• Competitively chosen lab sites:

– MDAnderson (Hamilton)– MGH (Iafrate)– Yale (Sklar)

Tumor Biopsy• Prior to study entry a biopsy (4 cores) FFPE, shipped to

MDACC • Adjacent section H&E stained, examined by pathologist

for tumor content, % necrosis, inflammation, and scanned into high resolution image database

• RNA and DNA extracted from the same tissue section• Planned research assays:

– If sufficient DNA is available, whole-exome sequencing can be performed for research

– RNA will be used for research grade gene expression profiling by either whole-transcriptome or miRNA microarray analysis

• Biopsy on progression

MATCH Assay Workflow and Turnover Time

22

Tissue FixationPath Review

Nucleic Acid Extraction

Library/Template Prep

Sequencing

aMOI Report Review

SangerVerification

Biopsy Received

3 DAYS

1 DAY

1 DAY

1 DAY

1 DAY

3 DAYS

10-14 daysFinal

Report

Tumor content >50%

DNA yield > 20 ng

Library yield > 20 pM

Test fragmentsTotal readReads per BCCoverageNTC, Positive, Negative Controls

Rules of evidence for “actionable” variants• Level 1: Credentialed for selection of an

FDA approved drug• Level 2a: Eligibility trial for an ongoing trial• Level 2b: N-of-1 response (with

mechanistic basis)• Level 3: Preclinical data with known PK/PD

– Selective activity in biomarker-defined model– Functional evidence that alterations in target

lead to upregulation & dependence– Functional evidence of pathway activation as

consequence of loss of function in tumor suppressor

First round of committed agents

Drug Molecular Targets

Afatinib EGFR activating (non NSCLC)

Afatinib HER2 kinase activatingAMG 337 MET amplificationAMG 595 EGFR vIII

AZD 9291 EGFR T790M (non NSCLC)Crizotinib ALK fusions

Crizotinib ROS translocations

Dabrafenib + Trametinib BRAF V600E (nonmelanoma)

GDC 0032 PIK3CA ampl/mut; WT RAS, No PTEN loss

GSK2636771 PTEN Mut, PTEN IHC+

GSK2636771 PTEN Mut, PTEN IHC –

GSK2636771 PTEN wt, PTEN IHC -

JNJ 493 Ampl FGFR 1,2, or 4; FGFR mut

MLN 0128 mTOR mutMLN 0128 TSC1 or TSC2 mutSunitinib KIT mutations

TDM-1 HER 2 ampl (non breast or gastric)

Trametinib BRAF nonV600E or fusions

Trametinib NF1 mut (arm1) GNAQ,GNA11 mut (arm 2)

Trastuzumab/pertuzumab HER2 ampl (non breast or gastric)Vismodegib SMO or PTCH mutVS 6063 NF2 loss

Logistics• Master Protocol with Multi-arm phase II

trials• IND for protocol template

– Arms could be added or deleted without affecting other arms

• Single agents or combinationsf where recommended phase 2 dose is known

• FDA Approved (for a different indication) or investigational agents

• Central IRB• 2400 NCTN sites• CLIA lab network: validated assay

NCI: Developing a National Strategy for Precision Medicine

• NCI-MATCH Clinical trial (Genotype to Phenotype)– Screen for molecular features that may predict response to a drug with a given mechanism of action

• Genomics of Exceptional Responders (Phenotype to Genotype)– Tumor from patients who had an

exceptional response to a drug for which predictive biomarkers are not known

Acknowledgements

MATCH trial leadership: NCI - Alice Chen, Barb Conley, Mickey WilliamsECOG-ACRIN - Peter O’Dwyer, Stan Hamilton