The Genetics of Cancer: Is Personalization of Cancer Treatment

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
200
Cancer Genome Atlas Research Network et al. TCGA symposium 2012
Melanoma:
the model of MAP kinase dependence
25%
50%
10%
Sullivan RJ & Flaherty KT. CCR 2014
Recurrent concomitant mutations in
BRAF mutant melanoma
AKT3
BRAF
MITF
MDM2
Cancer Genome Atlas Research Network et al.
TCGA symposium 2012
Tumor regression V600EBRAF mutant
melanoma patients (vemurafenib)
RECIST 30% Decrease
Sosman J et al. NEJM 2012
Maximum percent reduction from baseline measurement
BRAF vs. BRAF/MEK combination in V600EBRAF mutant
melanoma patients
100
80
60
40
20
0
-20
-40
-60
-80
-100
Dabrafenib monotherapy
Best confirmed response
Progressive disease Partial response
Stable disease
Complete response
100
80
60
40
20
0
-20
-40
-60
-80
-100
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
melanoma
Sosman J et al. NEJM 2012
colorectal
Kopetz, ASCO 2010
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)
SCHEMA
Genetic
sequencing
Actionable
mutation
detected
Study
agent
Stable
Disease,
Complete or
partial
response
(CR+PR)1
Continue on
study agent
until
progression
Progressive
disease
(PD)1
PD
Check for additional
actionable
mutations2
Yes
1CR,
PR, SD, and PD as defined by RECIST
if additional mutations, offer new targeted therapy
2Rebiopsy;
No
No additional
actionable
mutations, or
withdraw consent
Off
study
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
Biopsy Received
3 DAYS
1 DAY
1 DAY
1 DAY
1 DAY
Tumor content >50%
Tissue Fixation
Path Review
DNA yield > 20 ng
Nucleic Acid
Extraction
Library yield > 20 pM
Library/Template Prep
Test fragments
Total read
Reads per BC
Coverage
NTC, Positive, Negative Controls
Sequencing
aMOI Report
Review
Sanger
Verification
3 DAYS
10-14 days
Final Report
22
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
AMG 337
AMG 595
HER2 kinase activating
MET amplification
EGFR vIII
AZD 9291
Crizotinib
EGFR T790M (non NSCLC)
ALK fusions
Crizotinib
ROS translocations
Dabrafenib + Trametinib
GDC 0032
BRAF V600E (nonmelanoma)
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
MLN 0128
MLN 0128
Sunitinib
Ampl FGFR 1,2, or 4; FGFR mut
mTOR mut
TSC1 or TSC2 mut
KIT mutations
TDM-1
HER 2 ampl (non breast or gastric)
Trametinib
Trametinib
BRAF nonV600E or fusions
NF1 mut (arm1) GNAQ,GNA11 mut (arm 2)
Trastuzumab/pertuzumab
Vismodegib
VS 6063
HER2 ampl (non breast or gastric)
SMO or PTCH mut
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 Williams
ECOG-ACRIN - Peter O’Dwyer, Stan Hamilton