the personalized cancer medicine initiative at vanderbilt · the personalized cancer medicine...
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The Personalized Cancer Medicine Initiative at
Vanderbilt
October 26, 2009
William Pao, MD, PhD Assistant Director, Personalized Cancer Medicine
Vanderbilt-Ingram Cancer Center
Jemal et al ‘09
Cancer in the United States, 2009
New Cases Deaths
Lung 219,440 Lung 159,390
Breast 192,370 Colorectal 49,920
Prostate 192,280 Breast 40,170
Colorectal 146,970 Prostate 27,360
Adeno
Squam
Large
Small
Traditional View of Lung Cancer
Small Cell Lung Cancer (SCLC) Non-Small Cell Lung Cancer (NSCLC): Adenocarcinoma Squamous cell carcinoma Large cell carcinoma
30 Yrs’ Research:
Effect of Standard Chemotherapy
in NSCLC Has Reached a Plateau
1207 pts Response rate – 19% Median TTP – 3.7 mos Median OS – 8 mos
Schiller et al ‘02
Iressa and Tarceva –
Related Agents that Target EGFR
ATP
Dramatic Response to Gefitinib
K DFG L L
Tyrosine kinase
745
K DFG Y Y Y Y TM
718 964
EGF ligand binding autophos
GXGXXG
858
LREA
861
Exon: 18 19 20 21 22 23 24
EGFR Mutations Associated with Sensitivity to Gefitinib/Erlotinib
G719A/C L858R deletion L861Q
Lynch et al ’04; Paez et al ‘04; Pao et al ‘04
Predictors of Response
to Gefitinib/Erlotinib
Clinical Predictors
NSCLC 10%
Female 18%
Adenocarcinoma 12%
Never smoker 30%
Molecular Predictors
KRAS mutn <1%
EGFR mutn >70%
Rnd Ph III Trial: Iressa Pan ASian Study (IPASS: Gefitinib vs Chemo, upfront)
EGFR mutation positive EGFR mutation negative
HR (95% CI) = 0.48 (0.36, 0.64) p<0.0001
No. events gefitinib: 97 No. events Chemo: 111
Gefitinib (n=132) Carboplatin / paclitaxel (n=129)
HR (95% CI) = 2.85 (2.05, 3.98) p<0.0001
No. events gefitinib: 88 No. events Chemo: 70
132 71 31 11 3 0 129 37 7 2 1 0
108 103
0 4 8 12 16 20 24
Gefitinib C/P
0.0
0.2
0.4
0.6
0.8
1.0
Pro
bab
ility
of
pro
gre
ssio
n-f
ree
su
rviv
al
At risk : 91 4 2 1 0 0 85 14 1 0 0 0
21 58
0 4 8 12 16 20 24
0.0
0.2
0.4
0.6
0.8
1.0
Pro
bab
ility
of
pro
gre
ssio
n-f
ree
su
rviv
al
Gefitinib (n=91) Carboplatin / paclitaxel (n=85)
Months Months
Gefitinib RR 71% Gefitinib RR 1%
Mok et al ‘09
EML4
ALK KINASE
E13a;A20
E20;A20
E6a/b;A20
E14;A20
E2a/b;A20
E13b;A20
E14;A20
E15;A20
E18;A20
KINASE
KINASE
KINASE
KINASE
KINASE
KINASE
KINASE
KINASE
KINASE
2 6 13 14 15 18 20
20
V1
V2
V3a/b
V4
V5a/b
V6
V7
“V4”
“V5”
Fusions Involving the ALK Tyrosine Kinase Define Another Subset of NSCLC (Soda et al ‘07)
Tumor Size Change
Duration of Response (Weeks)
-100
-80
-60
-40
-20
0
20
40
Green - PR Blue - SD Black - PD
% o
f b
est
ch
an
ge f
rom
baseli
ne
8+ 20
40 8+
12 2+ 13+ 15+ 8+
23+ 15+
2+
16
8+
4+
One patient had clinical progression and discontinued without radiographic confirmation.
Kwak et al PASCO ‘09
Tumor Responses to PF-02341066 for NSCLC Evaluable Patients with ALK Fusions
Adeno
Squam
Large
Small
Traditional View of Lung Cancer
Small Cell Lung Cancer (SCLC) Non-Small Cell Lung Cancer (NSCLC): Adenocarcinoma Squamous cell carcinoma Large cell carcinoma
Adeno
Squam
Large
Small
KRAS
Unknown
EGFR HER2
BRAF
ALK fusion
PIK3CA
MEK1
ROS fusion
PDGFR amp
2009: Lung Adenoca-
Multiple Molecular Subsets
KRAS
Unknown
EGFR HER2
BRAF
ALK fusion
PIK3CA
MEK1
ROS fusion
PDGFR amp
• Mutations associated with drug sensitivity G719X, exon 19 del, L858R, L861Q • Mutations associated with 1ry drug resistance exon 20 dup • Mutations associated with 2ry drug resistance L747S, D761Y, T854A, T790M MET amplification
2009: Lung Adenoca- Multiple Molecular Subsets
Melanoma: Also Comprised of Clinically Relevant Molecular Subsets
Phase II Trial of Imatinib in
KIT-Mutant Melanoma
(Carvajal et al PASCO ‘09)
Phase II Trial of BRAF Inhibitor
(PLX-4302) in BRAF-Mutant Melanoma
(Flaherty, Sosman, Puzanov et al PASCO ’09)
-100
-75
-50
-25
0
25
50
75
100
%C
ha
ng
e F
rom
Ba
se
lin
e
(Su
m o
f L
es
ion
Siz
e)
(RECIST cutoff for PR, 30%)
n=27 Evaluable Patients
Interim Best Overall Response in Extension Cohort Patients
70% Response Rate (18 PRs and 1 CR)
M1a
M1b
M1c
As of 8/21/09
BRAFV600E Melanoma Patient PET Scan at Baseline
and Day +15 After PLX4032 Treatment at 960 mg BID
Cancers Driven by Mutant Kinases and Targeted by
Specific Kinase Inhibitors
Disease Target Kinase inhibitor
Chronic myelogenous leukemia BCR-ABL Imatinib
Gastrointestinal stromal tumor Mutant KIT or PDGFRa Imatinib
Lung adenocarcinoma Mutant EGFR Gefitinib/Erlotinib
Lung adenocarcinoma EML4-ALK ALK inhibitors (in development)
Melanoma Mutant BRAF BRAF inhibitors (in development)
Melanoma Mutant KIT Imatinib
Ongoing Efforts to Sequence Cancer Genomes/Identify Drug Targets
Goals of the VICC PCMI
• To establish ‘reflex’ testing of ‘common’ clinically relevant genetic alterations in lung cancers and melanomas.
• To develop a clinically-applicable high-throughput molecular genotyping facility for ‘rarer’ genetic variants.
• To develop bioinformatic algorithms to report genetic results in the electronic medical record in ways that are clinically useful for practicing oncologists.
– Collaboration among Depts of Medicine, Pathology, BioInformatics, and VICC
– Sounds simple, but…requires high level of collaboration/coordination
Aim 1
• To establish reflex testing of ‘common’ clinically
relevant genetic alterations in lung cancers and
melanomas.
– Melanoma
• BRAF
• KIT
– Lung adenocarcinoma
• EGFR
• KRAS
• ALK
Aim 2
• To develop a clinically-applicable high-
throughput molecular genotyping facility for
‘rarer’ genetic variants.
Position AA mutant Nucleotide mutant
G719
p.G719C c.2155G>T
p.G719S c.2155G>A
p.G719A c.2156G>C
T790 p.T790M c.2369C>T
L858 p.L858R c.2573T>G
L861 p.L861Q c.2582T>A
EGFR
G12
p.G12C c.34G>T
p.G12S c.34G>A
p.G12R c.34G>C
p.G12V c.35G>T
p.G12A c.35G>C
p.G12D c.35G>A
G13
p.G13C c.37G>T
p.G13S c.37G>A
P.G13R c.37G>C
p.G13D c.38G>A
p.G13A c.38G>C
Q61
p.Q61K c.181C>A
p.Q61R c.182A>G
p.Q61L c.182A>T
p.Q61H c.183A>T
p.Q61H c.183A>C
KRAS
NRAS
Q61
p.Q61K c.181C>A
p.Q61L c.182A>T
p.Q61R c.182A>G
H1047 p.H1047R c.3140A>G
E542 p.E542K c.1624G>A
E545 p.E545K c.1633G>A
PIK3CA
Q56 p.Q56N c.167A>C
K57 p.K57N c.171G>T
D67 p.D67N c.199G>A
MEK1 (MAP2K1)
E17 p.E17K c.49G>A
AKT1
R233 p.R233* c.697C>T
PTEN
Position AA mutant Nucleotide mutant
G469 p.G469A c.1406G>C
L597 p.L597V c.1789C>G
V600 p.V600E c.1799T>A
BRAF
Version 1: 36 Somatic Point Mutations in 8 Genes Relevant toTargeted Therapy in Lung Adenocarcinoma
Lung Adenocarcinoma Comprehensive Screen (5 Panels)
Q209
p.Q209P c.626A>C
p.Q209L
p.Q209L
c.626A>T
c.625_626CA>TT
Position AA Nucleotide
V600
p.V600R c.1798_1799GT>AG
p.V600K c.1798_1799GT>AA
p.V600E
p.V600E
p.V600M
p.V600G
V600D (call E)
c.1799T>A
c1799_1800 TG>AA
c1798G>A
c1799T>G
c1799_1800 TG>AT
G12
p.G12C c.34G>T
p.G12S c.34G>A
p.G12R c.34G>C
p.G12V c.35G>T
p.G12A c.35G>C
p.G12D c.35G>A
p.G12N c.34_35GG>AA
G13 p.G13A c.38G>C
p.G13V c.38G>T
p.G13R c.37G>T
p.G13D c.38G>A
Q61 p.Q61E c.181C>G
p.Q61H c.183A>T
p.Q61H c.183A>C
p.Q61L
p.Q61L
p.Q61L
c.182A>T
c.181_182CA>TT
c.182_183AA>TG
p.Q61K
p.Q61K
c.181C>A
c.180_181AC>TA
p.Q61P c.182A>C
p.Q61R
p.Q61R
p.Q61R
c.182A>G
c.180_181AC>TA
c.182_183AA>GG
NRAS
GNAQ
p.S45P c133T>C
S45 p.S45F c134C>T
S37
p.S45Y
p.S37F
p.S37Y
c134C>A
c.110C>T
c110C>A
CTNNB1 (B-CAT)
K642 p.K642E c.1924A>G
L576 p.L576P c.1727T>C
W557 p.W557R c.1669T>C
p.W557R c.1669T>A
V559 p.V559A
p.V559D
c.1676T>C
c.1676T>A
D816 p.D816H c.2446G>C
KIT
BRAF
Version 1: 45 Somatic Point Mutations in 5 Genes Relevant to Targeted Therapy in Melanoma
Melanoma Comprehensive Screen
(5 Panels)
A: Green T: Red G: Blue C: Black
NRAS_G12 (34R)
BRAF _V600 (1799)
NRAS_Q61 (182)
KIT_V559 (1676)
B-CAT_S45 (133R)
NRAS_G12 (35)
NRAS_G13 (38R)
KIT_K642 (1924)
NRAS_Q61 (181)
B-CAT_S37 (110)
B-CATS45 (134R)
BRAF_V600 (1798)
NRAS_G13 (37R)
NRAS_Q61 (183R)
KIT_W557 (1669)
KIT_L576 (1727)
KIT_D816 (2446)
GNAQ_Q209 (626)
PCR-Based Sizing Assays for Insertions/Deletions in Lung Adenocarcinoma
H1650: E19del = 15 bp del E20ins = WT H20ins = WT
H1781: E19del = WT E20ins = 3 bp ins H20ins = WT
Lung Ca Sample: E19del = WT E20ins = 6 bp ins H20ins = WT
E20i E19d H20i
Aim 3
• To develop bioinformatic algorithms to report
genetic results in the electronic medical record
in ways that are clinically useful for practicing
oncologists.
– The ‘propensity to prescribe’
Current Medical Oncology Provider ‘White
Board’
Proposed Medical Oncology Provider ‘White Board’
Demographics Diagnosis/
Stage
Relevant
Biomarkers
Disease
Status
Current Tx CBC Che
m
Imaging Trial
Status
GW 55AF NSCLC
Adenocarcinoma
Stage IV
EGFR+ Metastatic Erlotinib
since 6/7/08
11:33 11:33 Last CT
CAP 8/7/09
Consider
2nd-gen
EGFR
TKI if
POD
JD 68WF NSCLC
Adenocarcinoma
Stage II
KRAS+ Recurrent
Metastatic
Carboplatin/
Paclitaxel
s/p 2 cycles;
started
7/15/09
- - Last CT
CAP
7/12/09
Consider
KRAS
trial;
unlikely
to
respond
to EGFR
TKI
DS 45WM NSCLC
Adenocarcinoma
Stage IV
ALK+ Metastatic Untreated - - Today -
pending
Consider
ALK trial
WP 55M Malignant
Melanoma
Stage II
BRAF+ Recurrent
Metastatic
PLX-0432
since
08/12/08
- - Last CT
CAP
9/22/09
-
DS 42M Malignant
Melanoma
Stage IV
KIT+ Metastatic Interferon-
alfa2b
- - Last CT
CAP 7/7/09
Consider
imatinib
Summary/Future Directions
• Personalized Cancer Medicine Initiative launched at
VICC
• Multiplex genotyping platforms nearly developed
• Implementation into CLIA labs planned
• Reflex testing already initiated for some mutations
• Consents written
• Molecular results to be placed in chart
• Bioinformatics to provide clinical decision support
• Importantly, PCMI will serve as a template to move
forward with other cancers, genetic results
Potential Benefits of Tailoring Therapy According to the
Genetic Makeup of Tumors
Using EGFR mutations in NSCLC as an example:
• Make more informed medical decisions
• Higher probability of desired outcomes
• Reduced probability of negative side effects – Chemo: intravenous, nausea, vomiting, hair loss,
neutropenia, kidney failure
– Iressa/Tarceva: oral, rash, diarrhea
Potential Benefits of Tailoring Therapy According to the Genetic Makeup of Tumors
• Reduced healthcare costs
Standard Approach:
2 cycles carbo/paclitaxel/bevacizumab $29,170
(wait 6 weeks to determine response)
followed by
2 cycles of pemetrexed $21,868
(wait 6 weeks to determine response)
Total: $51,038
Molecularly Tailored Approach:
Multiplex mutation test $2,000
(>70% chance of response if known EGFR mutation)
Erlotinib (90d) $13,671
Total: $17,671
Acknowledgements
• Pao Lab
– MarKeesa Duke
– Laurel Fohn
– Katie Hutchinson
– Zengliu Su
– Paula Woods
• VICC
– Jennifer Pientepol
• Pathology
– Cheryl Coffin
– Cindy Vnencak-Jones
• Medicine
– David Johnson
– Jeff Sosman
• Bioinformatics
– Dan Masys
– Mia Levy
– Russ Waitman
• MGH
– A. John Iafrate
• Funding
– Anonymous Foundation
– VICC CCSG
– TJ Martell Foundation