Genotype-Driven Lung Cancer Treatment

AAAS-FDLI Colloquium on Personalized MedicineOctober 27, 2009

William Pao, MD, PhDAssistant Director, Personalized Cancer Medicine

Vanderbilt-Ingram Cancer CenterNashville, TN

Disclosure Information

I have the following financial relationships to disclose:

Patent licensed to MolecularMD for EGFR T790M testing

Consulting for MolecularMD

Day 0

Case Report

• 55 yo Caucasian woman• 9 pk-yr smoking history• s/p RLL and LUL lobectomies for lung adenocarcinoma• 2 years later, recurrence with bilateral pulm nodules• Progression on systemic chemotherapy

Jemal et al ‘09Jemal 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

Lung Cancer Facts– Risk factors

• 10% “never smokers” (<100 cigarettes in a lifetime)• 50% former smokers

– NSCLC has 4 stages• St I-IIIA – potentially curable by surgery• But 60% diagnosed at incurable stages (IIIB/IV)

NSCLC histologies: Adenocarcinoma Squamous cell carcinoma Large cell carcinoma

5-Year Overall Survival (Clinical Stage)

Goldstraw et al ‘07

30 Yrs’ Research: Effect of Standard Chemotherapy in Metastatic NSCLC

Has Reached a Plateau

1207 ptsResponse rate – 19%Median TTP – 3.7 mosMedian OS – 8 mos

Schiller et al ‘02

Gefitinib and Erlotinib –Related Quinazoline EGFR-TKIs

OSI-774ErlotinibTarceva

ATP

ZD1839GefitinibIressa

K K

PI3K

AKT

Survival

Grb-2SOS

RAS

RAF

MEK

MAPK

Proliferation

Ligand

Ligand-bindingdomain

PTEN

mTOR STAT 3/5

Schematic of EGFR Signaling Pathway

Gefitinib & erlotinibblock signaling here

Phase I/II/III Results

• Phase I - gefitinib– Unexpected objective regressions in 10/100 patients with NSCLC

• Phase II - gefitinib– 10/28% RRs in US/Japan for gefitinib – 2003 FDA approval (2nd-

line)

• Phase III – erlotinib vs placebo– 9% vs <1% RR; 6.7 vs. 4.7 mo OS – 2004 FDA approval (2nd-line)

• Mild side effects– acneiform rash and diarrhea

Baselga et al ’02; Herbst et al ’02; Ranson et al ’02; Nakagawa et al ’03; Fukuoka et al ’03;

Kris et al ‘03; Shepherd et al ‘05

Dramatic Response to Gefitinib

Day 0 4 months

Case Report

• 55 yo Caucasian woman• 9 pk-yr smoking history• s/p RLL and LUL lobectomies for lung adenocarcinoma• 2 years later, recurrence with bilateral pulm nodules• Progression on systemic chemotherapy• Response to erlotinib

Who Responds to Gefitinib or Erlotinib (2003)?

• No clear association with EGFR expression • Clinical predictors

– Female – Never smoker– Adenocarcinoma – esp. bronchioloalveolar

subtype – Japanese

(Miller et al JCO ’04; Fukuoka et al JCO ’03)

• Are there molecular predictors of sensitivity?

K DFG L L

Tyrosine kinase

745

K DFG Y Y Y YTM

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 L858Rdeletion L861Q

Lynch et al ’04; Paez et al ‘04; Pao et al ‘04

Prospective Trials of EGFR-TKIs in NSCLCStudy Agent RR % PFS* OS*

Patients with EGFR mutant tumors (1st line)

Paz-Ares Erlotinib 31/38 82 13 NR

Morikawa Gefitinib 13/20 65 NR NR

Sunaga Gefitinib 16/21 77 13 NR

Sutani Gefitinib 21/27 77 9 15

Inoue Gefitinib 12/16 75 10 NR

Asahina Gefitinib 12/16 75 9 NR

Sequist Gefitinib 17/26 65 12 21**

Total 122/164 74

Unselected Populations (2nd line)

ISEL Gefitinib 77/959 8 3 6

BR.21 Erlotinib 38/427 9 2 7

*measured in months; **includes 5 atypical mutations; NR – not reached

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: 97No. 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: 88No. events Chemo: 70

132 71 31 11 3 0129 37 7 2 1 0

108103

0 4 8 12 16 20 24

GefitinibC/P

0.0

0.2

0.4

0.6

0.8

1.0

Pro

bab

ilit

y o

f p

rog

ressio

n-f

ree

su

rviv

al

At risk :91 4 2 1 0 085 14 1 0 0 0

2158

0 4 8 12 16 20 240.0

0.2

0.4

0.6

0.8

1.0

Pro

bab

ilit

y o

f p

rog

ressio

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

Are There Molecular Predictors of Resistance to EGFR-TKIs?

• Primary resistance– Tumors that are refractory to treatment with either

gefitinib or erlotinib– The majority of patients– Are these all EGFR wildtype tumors?

K K

PI3K

AKT

Survival

Grb-2SOS

RAS

RAF

MEK

MAPK

Proliferation

Ligand

Ligand-bindingdomain

PTEN

mTOR

1

2

3

4

STAT 3/5

1 = both EGFR and HER2

Mutations in the ERBB Pathway in NSCLC

KRAS Mutations in NSCLC: A Negative Predictor for Response to EGFR TKIs

Retrospective Drug N Responses RR (%)

Pao ’05 G/E 9 0 0

Tsao (BR.21) ’06 E 20 1 5

Fujimoto ’06 G 6 0 0

Van Zandwijk ’06 G 3 0 0

Han ’06 G 9 0 0

Hirsch (ISEL) ’06 G 6 0 0

Massarelli ’07 G/E 16 0 0

Subtotal 69 1 1

Prospective Drug N Responses RR (%)

Miller ’06 E 19 0 0

Giaccone ’06 E 10 0 0

Jackman ‘07 E 6 0 0

Subtotal 35 0 0

Total 104 1 1

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%

How to Select EGFR-TKI Therapy?

ScenarioEGFR

MutationKRAS

MutationTreatment

1 + - Gefitinib or Erlotinib

2 - - Trial of drug?

3 - + Alternative agents

4 + + Likely contamination

• 50% of never smokers with adenoca have EGFR mutations• 19% of former smokers with adenoca have EGFR mutations• 4% of current smokers with adenoca have EGFR mutations• 15% of never smokers have KRAS mutations

Pham et al ‘06

Day 0 4 months 25 months

Case Report

• 55 yo Caucasian woman• 9 pk-yr smoking history• s/p RLL and LUL lobectomies for lung adenocarcinoma• 2 years later, recurrence with bilateral pulm nodules• Progression on systemic chemotherapy• Response to erlotinib• Acquired resistance

Day 0 4 months 25 months

Case Report

Growing bone lesion Growing lung lesion

Drug Contact Residues Are Commonly Affected (T790M, T854A)

Adapted fromYun et al ’07;Bean et al ‘08

92%

4%

4%

T790M without MET

40%

T790M with MET10%

MET alone10%

unknown40%

MET Amplification Occurs in ~20% of Cases, With or Without T790M Mutations

Engelman et al ’07; Bean et al ‘07

Day 0 4 months 25 months

Case Report

Exon 19 del

Erlotinib

T790Mno MET

BIBW2992?

Is this unique?Are there other examples?

EML4

ALK KINASE

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

chan

ge

fro

m

bas

elin

e

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

chan

ge

fro

m

bas

elin

e

Tumor Responses to PF-02341066 for NSCLC Evaluable Patients with ALK Fusions – Kwak et al

PASCO ‘09

Tumor Responses to PF-02341066 for NSCLC Evaluable Patients with ALK Fusions – Kwak et al

PASCO ‘09

8+8+2020

4040

8+8+ 12122+2+ 13

+13

+ 15+

15+

8+8+

23+

23+

15+

15+

2+2+

1616

8+8+

4+4+

One patient had clinical progression and discontinued without radiographic confirmation.

Adeno

Squam

Large

Small

Traditional View of Lung Cancer

Small Cell Lung Cancer (SCLC)

Non-Small Cell Lung Cancer (NSCLC):AdenocarcinomaSquamous cell carcinomaLarge cell carcinoma

Adeno

Squam

Large

Small

KRAS

Unknown

1987: KRAS Mutations in Lung Adenoca

Adeno

Squam

Large

Small

KRAS

Unknown

EGFR

2004: EGFR Mutations Identified

Adeno

Squam

Large

Small

KRAS

Unknown

EGFRHER2

BRAF

ALK fusionPIK3CA

MEK1

ROS fusionPDGFR amp

2009: Lung Adenoca-Multiple Molecular Subsets

KRAS

Unknown

EGFRHER2

BRAF

ALK fusionPIK3CA

MEK1

ROS fusionPDGFR amp

• Mutations associated with drug sensitivityG719X, exon 19 del, L858R, L861Q

• Mutations associated with 1ry drug resistanceexon 20 dup

• Mutations associated with 2ry drug resistanceL747S, D761Y, T854A, T790MMET amplification

2009: Lung Adenoca-Multiple Molecular Subsets

Molecularly Tailored Therapy

Mutation Prediction

EGFR exon 19 del/L858R Sens to EGFR TKIs

KRAS Res to EGFR TKIs

EGFR T790M/D761Y/T854A Res to EGFR TKIs; sens to new TKIs?

MET amplification Sens to MET TKIs

MEK1 Sens to MEK inhibitors

HER2 Sens to HER2 TKIs

BRAF Sens to BRAF inhibitors

ALK fusions Sens to ALK inhibitors

PDGFR amplification Sens to PDGFR inhibitors

PIK3CA PIK3CA inhibitors?

ROS fusion Sens to ROS inhibitors?

Position AA mutant Nucleotide mutant

G719p.G719C c.2155G>Tp.G719S c.2155G>Ap.G719A c.2156G>C

T790 p.T790M c.2369C>TL858 p.L858R c.2573T>GL861 p.L861Q c.2582T>A

EGFR

G12

p.G12C c.34G>Tp.G12S c.34G>Ap.G12R c.34G>Cp.G12V c.35G>Tp.G12A c.35G>Cp.G12D c.35G>A

G13

p.G13C c.37G>Tp.G13S c.37G>AP.G13R c.37G>Cp.G13D c.38G>Ap.G13A c.38G>C

Q61

p.Q61K c.181C>Ap.Q61R c.182A>Gp.Q61L c.182A>Tp.Q61H c.183A>Tp.Q61H c.183A>C

KRAS

NRAS

Q61p.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>CK57 p.K57N c.171G>TD67 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 SNaPShot: 36 Somatic Point Mutations in 8 Genes Relevant to Targeted Therapy

in Lung Adenocarcinoma

+ PCR-based sizing assays for EGFR ex 19 dels, EGFR ex 20 ins’s, HER2 20 ins’s+ ALK assessment

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 by2 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) $13,671Total: $17,671

Day 0

Successes/Limitations

Successes

• Molecular subsets of NSCLC defined

• Greater likelihood of expected outcomes

• Can prioritize treatment regimens– Will be necessary as more agents

become available

• Can rationally develop trials

• Cost savings

Limitations• Some small molecular subsets (~1%

= 2,100 pts)• Diagnostic molecular assays labor-

intensive• May take 2-3 weeks to get result• Different mutns assessed by different

technologies– Translocations/ Pt

mutns/insertions/deletions

• RR/PFS vs OS• Practicing oncologists not familiar

with various tests

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