Download Not yet - Imedex

Molecular Subtypes:
Not Quite Ready for Prime Time
Scott Kopetz, MD, PhD.
Department of GI Medical Oncology
MD Anderson Cancer Center
Individual Biomarkers versus
Molecular Subtypes
• Individual biomarkers:
YES
– Microsatellite instability in all patients
• For adjuvant decisions in Stage II and screening for HNPCC
– KRAS, NRAS, BRAF in all metastatic patients
• For consideration of EGFR sensitivity and prognosis
• Molecular subtypes
– 200 gene…400 gene…whole exome sequencing
– Gene expression profiles
– Proteomic panels
NOT YET
Why not yet….?
• We need studies to evaluate the benefit from
extended molecular testing (beyond KRAS,
NRAS, BRAF)
• We need to define the molecular subtypes by
gene expression
• We need validated assays to move into the clinic
3
Why not yet….?
• We need studies to evaluate the benefit from
extended molecular testing (beyond KRAS,
NRAS, BRAF)
• We need to define the molecular subtypes by
gene expression
• We need validated assays to move into the clinic
4
“My panel is bigger than yours…”
5
Integrating into Clinical Trials:
Increase in Prospective Enrichment
2007-08
2011-12
Novel
enriched
EGFR
enriched
Novel
enriched
3%
9%
13%
40%
EGFR
enriched
Unenriche
d
Kopetz, et al JCO ‘08, updated from clinicaltrials.gov
Unenriche
d
Paucity of High-Frequency Targets Means
Large Screening Efforts Needed
100’s <3% frequency
Currently “actionable”
Not actionable
Screening size for a 20 patient
proof-of-principle study
Timeline for Biomarker Testing
Consent
Tissue
Acquisition
Block
Selection,
Extraction
Testing
Completed
Results
Relayed
Median Time:
6 calendar days
28 calendar days
33 calendar days
ATTACC Program:
Assessment of Targeted Therapies Against Colorectal Cancer
Eligibility
• 5-FU refractory disease
• ECOG PS 0-1
• Tissue available for molecular testing
Screening
• Patients undergo biomarker assessment
• CLIA-certified assays
Allocation
• Based on biomarker, patients allocated to one of
several treatment protocols
• Patients not expressing biomarker of interest are
treated in unenriched protocols
S. Kopetz, PI
Enrichment
Therapeutic
Mechanism
Akt inhibitor
Current Screening
Panel
MD Anderson ATTACC Program:
Biomarker Screening for 5-FU
Refractory Metastatic CRC
PTEN Loss or PIK3CAmut
MK-2206
CpG Island Methylation
Demethylator
Mitotic inhib
Azacitadine + XELOX
Nab-paclitaxel
HER2 overexpression
HER2 mutation
HER2 inhibition
ERB family inhib
Trastuzumab +/- EGFR
TBA
IonTorrent 50 gene panel
-IonProton 400 gene
Exon 3,4 KRAS or NRAS mutant RAF inhibition
ERK inhibition
CpG Methylation Panel
LY3009120
Biomed Valley
BRAF+EGFR+irino
Immunohistochemistry
Vemurafenib +cetux+ irino
BRAF Mutation
PTEN Loss/KRAS WT
PI3K-beta inhibitor
SAR26031
Aquired RAS mutation
MEK + EGFR inhibition Panitum + Trametinib
-PTEN, MET, HER2 expression
KRAS, NRAS, EGFR ectodomain mutation in
EGFR ectodomain mutation
Alternate EGFR
cfDNA/plasma
Dual MEK, PI3K
KRAS and PIK3CA mutation
N=550
enrolled
Agent(s)
Panitumumab
BYL719 and MEK162
CTLA4 and PD1 panel
Nivolumumab, Ipilumumb
Microsatellite instability
MSI High
Triple KRAS/BRAF/NRAS WT
EGFR+HER2
Cetuximab + trastuzumab
The Reality of Screening Studies
1 in 5 Patients Allocation to Enrichment Study
10%
13%
20%
48%
2%
42%
4%
9%
Allocated to Study
Regorafenib
Poor PS/Death
Treatment at home
19% enriched companion study
Treatment off protocol
Ineligibility
Overall, 42% study enrollment, including
23% unenriched study
Withdrew consent
Through 3/1/13, N=250, first new treatment on ATTACC
Practical Considerations for
Enrichment Studies
• Enrichment strategies require…
– Consenting patients for screening
– Explaining the study
– High research staff utilization per “screen failure”
• Patient-satisfaction is very dependent on biomarker
turn-around time
– Obtaining outside paraffin blocks is rate-limiting step
– How long should one delay treatment waiting for a 5%
frequency biomarker?
• Other experimental options need to be available
– Enrichment study is hard to justify to patients in isolation
19124802
Example:
ASSIGN Study:
Pails
FOLFOX/Bev x 8
then
Maintenance
Kras
5-FU/Bev + drug A
Braf
Chemo + drug B
PIK3CA
PTEN
AKT
5-FU/Bev + drug C
BOTH
5-FU/Bev + drug D
WT/WT
5-FU/Bev + drug E
COLON CANCER TASK FORCE , NCI GI STEERING
COMMITTEE
STUDY DESIGN
DNA-based
Screening
Trial, based
on NCI
MATCH study
Endpoint PFS
N = TBD but likely
3000 – 5000
Slide from P. O’Dwyer
SPECTAColor
CLINICAL CENTERS
Screening Effort
Goal: 600 pts/year
Enroll: 10-15% of screened
BIOBANKING

Treating and recruiting patients
Sending
Tumor tissue
Providing
clinical data
Sending
gDNA/cDNA
Performing BM analyses
Slide from S. Tejpar
Protocols
Answering if
patient eligible
for study
EORTC Headquarters
Maintaining Sample Tracking tool,
eCRF and results database
Centralizing and storing samples
Extracting gDNA/RNA
DIAGNOSTICS
LABORATORIES
Enrollment
Providing
results
Flexibility &
Centralization
To date… Limited Prospective
Biomarker Success in CRC
New or Anticipated
Agents/Indications
–
–
–
–
No new biomarkerdirected therapy
Bevacizumab (2nd line)
Ziv-aflibercept
Regorafenib
TAS-102
Wrong premise, wrong implementation, or still too early?
Why not yet….?
• We need studies to evaluate the benefit from
extended molecular testing (beyond KRAS,
NRAS, BRAF)
• We need to define the molecular subtypes by
gene expression
• We need validated assays to move into the clinic
17
Two Approaches to Biomarker Integration
• Individual Biomarker Perspective
– Biomarkers are paired with individual drugs
Drug X
Biomarker A
• Taxonomy Perspective
– Move to a “Taxonomy” Perspective
Drug X
Two Approaches to Biomarker Integration
• Individual Biomarker Perspective
– Biomarkers are paired with individual drugs
Drug X
Biomarker A
• Taxonomy Perspective
– Move to a “Taxonomy” Perspective
Drug X
Definitions
Taxidermy = Stuffing
Taxonomy = Grouping based
on common patterns
CRC Taxonomy Hasn’t Been Defined To Date
Lymphoma
Her2-pos
Luminal B
Luminal A
Basal
Breast Cancer
Colorectal Cancer
?
Sotiriou et al NEJM, 2009; Alizadeh et al, Nature 2000
Gene Expression Tests are “Fit for Purpose”
Prognostic Assays
≠
Taxonomy / Molecular
Classification Assays
45%
3-year Recurrence Risk
40%
35%
30%
25%
20%
15%
10%
5%
0%
0 10 20 30 40 50 60 70
Recurrence Score
22
KRAS Poorly Recapitulates Taxonomy
Budinska et al ASCO ‘12
Published Molecular Subtypes of Colorectal Cancer
TCGA
T:220
Swiss
T:445 V:774
30 genes
PETACC3
T:1113 V:720
54 genes
AMC-AJCCII90
MSI/CIMP (30%): BRAFm,
hypermutated
Inflammatory
(18%): MSI,
benefit FOLFIRI
CIN (30%)
Invasive (40%)
Goblet (14%): MSI, TA cetux res (14%):
crypt top, Wnt low, no MSS, stem cell,
benefit adj CT, good MET-inh sensitive,
worse survival
prognosis
Surface crypt (26%): KRASm,
EMT low, Wnt low, papillary or
serrated phenotype
TA cetux sensitive
(18%): MSS, high
EGFR ligands, good
prognosis
Lower crypt (30%): EMT low,
Wnt high, tubular phenotype
CCS1 (50%): CIN+, KRASm and TP53m, left colon, Wnt
high
CIMP+ (11%): Mesenchymal (19%):
MSI, BRAFm, EMT/ CSC high Wnt
immune up, low, poor prognosis,
BRAFm, desmoplastic
mucinous
CCS2 (25%): MSI, CIMP+,
BRAFm, right colon
T:90 V:1074
146 genes
French
T:443 V:1058
57 genes
Agendia
T:188 V:543
32/53/102 genes
dMMR (20%):
CIN immune down (20%): sessile serrated
conventional precursor
precursor, BRAFm,
immune up
A-type (22%): BRAFm,
MSI/dMMR, epithelial
proliferative
KRASm
(10%):
serrated,
CIMP+
Stem-like (18%): MSS,
Enterocyte (18%):
Wnt high, crypt base,
crypt top ,Wnt low
benefit CT and FOLFIRI,
worse survival
CSC
(10%):
serrated,
poor
survival
Mixed (14%):
Wnt high, CSC
high, tubular
CCS3 (25%): poorly dif, EMT,
invasion, migration and TGF-β
signaling, no benefit cetuximab
CIN normal
(10%):
CIN Wnt up (30%): conventional
serrated,
precursor
poor survival
A-type (62%): low mutation, MSS, epithelial proliferative, benefit adjuvant
CT
C-type (16%):
mesenchymal,
no benefit CT
Melbourne
T:209 V:443
128 genes
Good prognosis (40%)
Poor prognosis (60%): immune down/ cell signaling, ECM and focal
adhesion pathways up
Slide from Rodrigo Dienstmann
PIs: Justin Guinney
Rodrigo Dienstmann
Consensus clusters
CLUSTER 2
CLUSTER 3
CLUSTER 4
CLUSTER 1
ASCO 2014 Clinical Symposium: Colorectal Cancer: Not Just One Disease
Why not yet….?
• We need studies to evaluate the benefit from
extended molecular testing (beyond KRAS,
NRAS, BRAF)
• We need to define the molecular subtypes by
gene expression
• We need validated assays to move into the clinic
27
Development of Validated Assay is Nontrivial
“The same rigor that we use for development of the drug has to go
into the biomarker development” R. Pazdur (FDA)
28
Conclusion
• Everyone should be testing for MSI and KRAS,
NRAS, BRAF
• We need to do the studies to demonstrate
benefit of more extended molecular profiling
– Low yields for actionable mutations
– Need more and better novel therapies
• A consensus is building for defining the subsets
• The assays need to be built, and moved into
clinical labs.
29