Not Quite Ready for Prime Time Scott Kopetz MD PhD Department of GI Medical Oncology MD Anderson Cancer Center NOT YET YES Individual Biomarkers versus Molecular Subtypes Individual biomarkers ID: 602572
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Slide1
Molecular Subtypes:Not Quite Ready for Prime Time
Scott Kopetz, MD, PhD. Department of GI Medical OncologyMD Anderson Cancer CenterSlide2
NOT YET
YESIndividual Biomarkers versus Molecular Subtypes
Individual biomarkers:Microsatellite instability in all patientsFor 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 panelsSlide3
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 expressionWe need validated assays to move into the clinic3Slide4
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 expressionWe need validated assays to move into the clinic4Slide5
“My panel is bigger than yours…”
5Slide6
Integrating into Clinical Trials:Increase in Prospective Enrichment
Kopetz, et al JCO ‘08, updated from clinicaltrials.gov
40%
2007-08
2011-12Slide7
Paucity of High-Frequency Targets Means Large Screening Efforts Needed
Currently “actionable”
Not actionable
Screening size for a 20 patient
proof-of-principle study
100’s <3% frequencySlide8
Timeline for Biomarker Testing
6 calendar days
28 calendar days
33 calendar days
Median Time:Slide9
ATTACC Program: Assessment of Targeted T
herapies Against Colorectal Cancer S. Kopetz, PISlide10
CpG
Island Methylation
Demethylator
Azacitadine
+ XELOX
Mitotic
inhib
Nab-paclitaxel
BRAF Mutation
BRAF+EGFR+irino
Vemurafenib
+
cetux
+
irino
MD Anderson ATTACC Program:
Biomarker Screening for 5-FU Refractory Metastatic CRC
PTEN Loss or PIK3CAmut
Akt
inhibitor MK-2206
Exon 3,4 KRAS or NRAS mutant RAF
inhibition
LY3009120
ERK inhibition Biomed Valley
HER2 overexpression
HER2 inhibition
Trastuzumab +/- EGFR
HER2 mutation ERB family
inhib
TBA
Enrichment
Therapeutic Agent(s)
Mechanism
PTEN Loss/KRAS WT PI3K-beta inhibitor SAR26031
Aquired
RAS mutation MEK + EGFR inhibition
Panitum
+
Trametinib
EGFR
ectodomain
mutation Alternate EGFR
Panitumumab
KRAS and PIK3CA mutation Dual MEK, PI3K BYL719 and MEK162
MSI High CTLA4 and PD1
Nivolumumab
,
Ipilumumb
Triple KRAS/BRAF/NRAS WT EGFR+HER2 Cetuximab + trastuzumab
N=550
enrolled
Current Screening Panel
IonTorrent
50 gene panel
-
IonProton
400 gene
CpG
Methylation Panel
Immunohistochemistry
-PTEN
, MET, HER2 expression
KRAS
, NRAS, EGFR
ectodomain
mutation in
cfDNA
/plasma
Microsatellite instability panelSlide11
The Reality of Screening Studies
1 in 5 Patients Allocation to Enrichment StudyThrough 3/1/13, N=250, first new treatment on ATTACC
19% enriched companion study
Overall, 42
%
study enrollment, including
23% unenriched
studySlide12
Practical Considerations for Enrichment Studies
Enrichment strategies require…Consenting patients for screeningExplaining the studyHigh research staff utilization per “screen failure”Patient-satisfaction is very dependent on biomarker turn-around timeObtaining outside paraffin blocks is rate-limiting stepHow long should one delay treatment waiting for a 5% frequency biomarker? Other experimental options need to be availableEnrichment study is hard to justify to patients in isolationSlide13
Example:
19124802
Slide14
BOTH
PailsKras
Braf
PIK3CA
PTEN
AKT
WT/WT
STUDY DESIGN
DNA-based
Screening
Trial, based on NCI MATCH study
5-FU/Bev
+
drug A
Chemo
+
drug B
5-FU/Bev
+
drug C
5-FU/Bev
+
drug D
5-FU/Bev
+
drug E
FOLFOX/Bev x 8
then
Maintenance
Endpoint PFS
N = TBD but likely
3000 – 5000
Slide from P. O’Dwyer
ASSIGN Study:
COLON CANCER TASK FORCE , NCI GI STEERING COMMITTEESlide15
Flexibility & Centralization
Providing
clinical data
Sending
gDNA
/
cDNA
Sending
Tumor tissue
Providing
results
BIOBANKING
Centralizing and storing samples
Extracting
gDNA
/RNA
CLINICAL CENTERS
Treating and recruiting patients
EORTC
Headquarters
Maintaining Sample Tracking tool,
eCRF
and
results
database
DIAGNOSTICS
LABORATORIES
Performing BM analyses
Answering if
patient eligible
for study
Screening Effort
Protocols
Enrollment
SPECTAColor
Goal: 600
pts
/year
Enroll: 10-15% of screened
Slide from S. TejparSlide16
To date… Limited Prospective Biomarker Success in CRC
New or Anticipated Agents/IndicationsBevacizumab (2nd line)Ziv-afliberceptRegorafenibTAS-102
No
n
ew
b
iomarker-directed therapy
Wrong
premise
, wrong
implementation
, or still too early?Slide17
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 expressionWe need validated assays to move into the clinic17Slide18
Two Approaches to Biomarker IntegrationIndividual Biomarker PerspectiveBiomarkers are paired with individual drugs
Taxonomy PerspectiveMove to a “Taxonomy” Perspective
Drug X
Biomarker A
Drug XSlide19
Two Approaches to Biomarker IntegrationIndividual Biomarker PerspectiveBiomarkers are paired with individual drugs
Taxonomy PerspectiveMove to a “Taxonomy” Perspective
Drug X
Biomarker A
Drug XSlide20
Definitions
Taxidermy = StuffingTaxonomy = Grouping based on common patternsSlide21
CRC Taxonomy Hasn’t Been Defined To Date
Sotiriou et al NEJM, 2009; Alizadeh et al, Nature 2000
Basal
Luminal A
Luminal B
Her2-pos
?
Breast Cancer
Lymphoma
Colorectal CancerSlide22
Gene Expression Tests are “Fit for Purpose”Prognostic Assays
Taxonomy / Molecular Classification Assays22
≠Slide23
KRAS Poorly Recapitulates
Taxonomy
Budinska
et al ASCO ‘12Slide24
Melbourne
T:209 V:443128 genesAgendia
T:188 V:543
32/53/102 genes
French
T:443 V:1058
57 genes
AMC-AJCCII-90
T:90 V:1074
146 genes
PETACC3
T:1113 V:720
54 genes
TCGA
T:220
Good prognosis (40%)
Poor prognosis (60%): immune down/ cell signaling, ECM and focal adhesion pathways up
A-type (22%):
BRAFm
, MSI/
dMMR
, epithelial proliferative
A-type (62%): low mutation, MSS, epithelial proliferative, benefit adjuvant CT
C
-type (16%):
mesenchymal
, no benefit CT
CIN immune down (20%): conventional precursor
dMMR
(20%): sessile serrated precursor,
BRAFm
, immune up
CSC (10%): serrated,
poor survival
CIN
Wnt
up (30%): conventional precursor
CIN normal (10%):
serrated, poor survival
KRASm
(10%): serrated, CIMP+
CCS1 (50%):
CIN+,
KRASm
and
TP53m,
left colon,
Wnt
high
CCS2 (25%):
MSI, CIMP+,
BRAFm
, right
colon
CCS3 (25%):
poorly
dif
, EMT, invasion, migration and TGF
-
β signaling, no benefit
cetuximab
MSI/CIMP (30
%):
BRAFm
,
hypermutated
CIN (
30
%)
Invasive (40%)
Surface crypt (26%):
KRASm
, EMT
low,
Wnt
low, papillary or serrated
phenotype
Lower crypt (30%):
EMT low
,
Wnt
high,
tubular
phenotype
Mesenchymal
(19%): EMT/ CSC high
Wnt
low, poor prognosis,
BRAFm
,
desmoplastic
CIMP+ (11%): MSI,
BRAFm
, immune up, mucinous
Mixed (14%):
Wnt
high, CSC
high, tubular
Swiss
T:445 V:774
30 genes
Goblet (14%): MSI, crypt top,
Wnt
low, no benefit
adj
CT, good prognosis
Inflammatory (18%): MSI, benefit FOLFIRI
Enterocyte (18%): crypt top ,
Wnt
low
TA
cetux
sensitive (18%):
MSS, high EGFR ligands, good prognosis
TA
cetux
res (14%): MSS, stem cell, MET-
inh
sensitive, worse survival
Published Molecular Subtypes of Colorectal Cancer
Slide from Rodrigo
DienstmannSlide25
PIs: Justin
Guinney
Rodrigo
DienstmannSlide26
CLUSTER 2
CLUSTER 3
CLUSTER 4
CLUSTER 1
Consensus clusters
ASCO 2014
Clinical Symposium: Colorectal Cancer: Not Just One DiseaseSlide27
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 expressionWe need validated assays to move into the clinic27Slide28
Development of Validated Assay is Nontrivial
28“The same rigor that we use for development of the drug has to go into the biomarker development” R. Pazdur (FDA)Slide29
ConclusionEveryone should be testing for MSI and KRAS, NRAS, BRAFWe need to do the studies to demonstrate benefit of more extended molecular profiling
Low yields for actionable mutationsNeed more and better novel therapiesA consensus is building for defining the subsetsThe assays need to be built, and moved into clinical labs.29