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