never-smoker with lung cancer in southern california

Lung cancer in Never-smokersA clinical entity with increasing clinical relevance in Southern

CaliforniaThe role of chemotherapy and updates from ASCO2009

Sai-Hong Ignatius Ou, MD PhDAssociate Clinical Professor

Ignatius.ou@uci.edu

Chao Family Comprehensive Cancer CenterDepartment of Medicine, Division of Hematology-Oncology

University of California Irvine Medical Center, Orange, CA 92868

Genetic Epidemiology Research InstituteDepartment of Epidemiology School of Medicine

University of California Irvine, Irvine, CA92697

Patient case• 56 yo Chinese never-smoking female, mother of 2, no PMHx• Routine health check-up (asymptomatic) right chest opacity

on CXR• CT-PET fusion revealed RML mass 1.8 cm (SUV 5.2) and right

mediastinal and subcarinal LN involvement• VAT revealed pleural nodules (Lobectomy + mediastinal LN

resection aborted, RML mass wedge resection and pleural nodules biopsy performed)

• Lung mass & pleural nodules: well-differentiated adenocarcinoma with BAC features

• MRI of brain negative• Stage: T4 N2 M0 (current staging) or T1 N2 M1 (new staging)

Global Cancer deaths

Sun Nature Review cancer 2007; 7 : 778-790

Global distribution of never-smokers

Sun Nature Review cancer 2007; 7 : 778-790

NSCLC Epidemiology (Orange, San Diego, & Imperial County 1995 to 2003; N=11,969)

Variable Number Percent

Age 68.3 years +/- 0.1 SE ---

Gender Male Female

64705497

54.145.9

Smoking status Smoker Non-smoker

8762942

90.39.7

Stage Localized Regional Metastatic

239930715907

21.127.051.9

Characteristics of NSCLC according to smoking status

Characteristics of Asian subgroupsTotal

Ever-smoker Never-smoker PN (%)^ 891 (73.9) 314 (26.1)Median age [years] (95% CI) 68 (47-83) 66 (44-86) .0359*Sex Male Female

671 (75.3)220 (24.7)

83 (26.4)231 (73.6) < .0001

Histology Adenocarcinoma BAC Large cell Squamous cell Undifferentiated

361 (40.5)25 (2.8)55 (6.2)

183 (20.5)267 (30.0)

178 (56.7)23 (7.3)18 (5.7)16 (5.1)

79 (25.2) < .0001AJCC stage Stage 1 Stage 2 Stage 3 Stage 4 Unknown

92 (10.3)42 (4.7)

203 (22.8)420 (47.1)134 (15.0)

31 (9.9)5 (1.6)

49 (15.6)190 (60.5)39 (12.4) .0003

Proportion of NSCLC patients by gender & smoking status

*percentage calculated across the row*percentage calculated across the row

Percentages of Never-smokers in Southern California

Proportion of NSCLC who were never-smokers5 major Asian subgroups and period of diagnosis

Effect of Smoking on overall survival

Major EGFR signaling pathways

Expression pattern of EGFR in NSCLC

EFGR Expression by IHC and SurvivalMeta-analysis

Meert et al, Eur Respir J 2002; 20: 975-981

Gefitinib [Iressa® (ZD1839)]MW=446

CI

F

N

O NH

N

O

O

N

NH

N

O

O

N

Erlotinib [Tarceva™ (OSI-774)]MW=430

O

O

H3C

H3CO

O

NH

N

N

Structures of EGFR-TK Inhibitors (Quinazolines)

BR21 OS

Shepherd NEJM 2005; 353: 123-132

Erlotinib (N=488)

Placebo (N=243)

Median Survival

6.7 mo 4.7 mo

1-Year Survival

31.2% 21.5%

ISEL OS

At 7.2 months median follow-upOS: 5.6 months vs 5.1 months1 yr survival rate: 27% vs 21%HR 0.89, [0.77-1.02]; P = 0.087

At 10.2 months median follow-upHR 0.89, [0.79-1.01]; P = 0.074

Thatcher et al, Lancet 2005; 366: 1527-1537

ISEL Adenocarcinoma OS

At 7.2 months median follow-upOS: 6.3 months vs 5.4 months1 yr survival rate: 30% vs 18%HR 0.84, [0.68-1.03]; P = 0.089

At 10.2 months median follow-upHR 0.84, [0.70-1.02]; P = 0.072

Thatcher et al, Lancet 2005; 366: 1527-1537

Overall Survival of ISELAsian vs. non-Asian

Chang JTO 2006; 1: 847-855

1. Asians have higher proportion of never-smokers with lung

cancer2. Asian seems to response and have better survival to inhibitors

of Epidermal Growth Factor Receptor (EGFR)

Why?

Discovery of activating EGFR mutations in NSCLC

List of EGFR mutations in NSCLC

Sharma Nature Review Cancer 2007; 7: 169-181

Distribution of EGFR mutations

Shigematsu Gazdar Int J Cancer 2006; 118: 257-262

EGFR mutation incidence by cigarette-smoking status

Pham et al JCO 2006; 24: 1700-1704Pham et al JCO 2006; 24: 1700-1704

How would you treat the patient?

• Tarceva?• Chemotherapy?

– which combination?

• Screen for EGFR mutation?

Not all mutations are the same!!!

List of EGFR mutations in NSCLC

Sharma Nature Review Cancer 2007; 7: 169-181

Differential response of exon 19 deletions & L858R point mutation to TKIs

Riely et al, Clin Cancer Res 2006; 12: 839-844

Differential response of exon 19 deletions & L858R point mutation to TKIs

Exon 19 deletion L858R mutation P

N 22 10

CR 9% 0%

PR 64% 50%

ORR 73% 50% 0.25

Median OS 38 mo 17 mo 0.0384

Median TTP 24 mo 10 mo 0.04

Median Duration of Rx for CR/PR 16 mo 13 mo 0.46

Median duration of RX for SD 26 mo 10 mo 0.01

Jackman et al, Clin Cancer Res 2006; 12: 3908-3914

No K-ras mutation identifiedRR: gefitinib (78%) vs erlotinib (33%) (P = 0.035)

Acquired resistance to oral EGFR TKI

• T790M mutation (70%)• c-met over-expression (8%)

Arcila PASCO 2009

List of EGFR mutations in NSCLC

Sharma Nature Review Cancer 2007; 7: 169-181

BIBW2992

• Orally available• Irreversible inhibitor of EGFR1 and EGFR2

– Binds covalently to Cys773 within the catalytic cleft of the ATP-binding pocket of EGFR

• Inhibits to a significant level in vitro phosphorylation of EGFR in NSCLC cell lines with T790M mutation

EGFR-TKIsSelectivity

IC50 (nM)

EGFR-1 HER-2Erlotinib (Tarceva) 2 350Gefitinib (Iressa) 23 3700

BIBW2992 (Tovok) 0.5 14Lapatinib (GW572016) 11 9

EGFR-TKIsIn vitro EGFR activity

IC50 (nM)

Cell line BIBW2992 GefitinibNCI-H1666 (EGFR WT) 7 100

NCI-H3255 (L858R) 6 50NCI-H1975 (L858R + T790M) 93 resistant

1200.22 Patient 146 yo Hispanic Female Never-smoker

Exon19 deletion

8/20/2008 9/15/2008

1200.22 Patient 1 46 yo Hispanic Female Never-smoker

Exon19 deletion

3/2/2009

1200.22 Patient 263 yo Vietnamese Female Never-smoker

Exon19 deletion

12/16/2008 1/9/2009

1200.22 Patient 263 yo Vietnamese Female Never-smoker

Exon19 deletion

2/9/2009 3/9/2009

Global trial registration trial of BIBW2992

• EGFR mutation positive patients• BIBW2992 versus Pemetrexed/Cisplatin• Primary endpoint: Progression-Free survival

How would you treat the patient now?

• EGFR mutation analysis is negative (wild-type)

Clinical Activity Observed in a Phase 1 Dose-Escalation Trial of an Oral MET and

ALK Inhibitor PF-02341066

EL Kwak1, DR Camidge2, J Clark1, GI Shapiro3, RG Maki4, MJ Ratain5, B Solomon6, Y-J Bang7, S-H Ou8, R Salgia5

1. Massachusetts General Hospital 5. University of Chicago Cancer Center

2. University of Colorado Cancer Center 6. Peter MacCallum Cancer Centre

3. Dana-Farber Cancer Institute 7. Seoul National University4. Memorial Sloan-Kettering Cancer Center 8. University of California at Irvine

PF-02341066

Potent & selective ATP competitive inhibitor of MET and ALK kinases and their oncogenic variants

ON

N

Cl

F

Cl

NN

N

Kinase IC50 (nM)

Mean Selectivity

Ratioα

c-Met 8 ---

ALK 20 2X

RON 248 31X

Axl 308 39X

Tie-2 448 56X

Trk A 580 73X

Trk B 399 50X

PF2341066 was >100X selective for Met/ALK across a panel of 150 additional kinases.

PF2341066 was >100X selective for Met/ALK across a panel of 150 additional kinases.

MET/HGFRMET/HGFR ALKALK

YYPP

YYPP

TMTM

YYPP

YYPP

YYPP

YYPP

SEMA

TMTMExtracellular

Intracellular

YYPP

YYPP

Kinase

YYPP

YYPPYYPPYYPP

YYPP

YYPP

TMTM

YYPP

YYPP

YYPP

YYPP

TMTMExtracellular

Intracellular

YYPP

YYPP

Kinase

YYPP

YYPP

YYPP

YYPP

YYPP

YYPP

YYPP

YYPP

KinaseYY

PP

YYPP

YYPP

YYPP

YYPP

YYPP

YYPP

YYPP

Kinase

Cytoplasmic Fusion Variants of ALK

Cytoplasmic Fusion Variants of ALK

NPM-ALKNPM-ALK EML4-ALKEML4-ALK

Initial characterization of EML4-ALK fusion in NSCLC

Soda Nature 2007; 448:561-566 Soda Nature 2007; 448:561-566

Schema of EML4-ALk NSCLC translocations

Wong Cancer 2009; 115; 1723-1733Wong Cancer 2009; 115; 1723-1733

EML4-ALK NSCLC Adenocarcinoma comparisons (N = 209)

Wong Cancer 2009; 115; 1723-1733Wong Cancer 2009; 115; 1723-1733

EML4-ALK positive

EML4-ALK negative

Total P

Median age 59 (51-61)

64 (55-71)

64 (54.5-71)

0.018

Smoking status Never-smoker Ever-smoker

10 (90.9)1 (9.1)

117 (59.1)81 (40.9)

127 (60.8)82 (39.2) 0.053

EGFR Mutated Wildtype

0 (0)11 (100)

121 (61.1077 (38.9)

121 (57.9)88 (42.1) < 0.001

~250 kb ~300 kb

t(2;5) ALK genebreakpoint region

2p23 regionTelomere Centromere

3’ 5’

Break-Apart FISH Assay for ALK Fusion Genes

Potential Fusion Partners:

• EML4• KIF5B• TGF

EML4-ALK Patients: Waterfall PlotTumor Responses to PF-02341066 for NSCLC Patients with EML4-ALK FusionsTumor Responses to PF-02341066 for NSCLC Patients with EML4-ALK Fusions

For 2 patients whose best response was PD, patients discontinued prior to first on-study scanFor 2 patients whose best response was PD, patients discontinued prior to first on-study scan

Tumor Size ChangeDuration of Response (Weeks)

-100

-80

-60

-40

-20

0

Blue - SD Black - PD Green - PR

% o

f Bes

t Cha

nge

from

B

asel

ine

2222 1616161620202020

40404040

8+8+8+8+ 121212124+4+4+4+

13+13+13+13+15+15+15+15+

8+8+8+8+23+23+23+23+ 15+15+15+15+

2+2+2+2+

48 YO Female Non-Smoker with EML4-ALK NSCLC

Pre-Treatment Pre-Treatment After 2 Cycles PF-02341066After 2 Cycles PF-02341066

My own pt51 yo Caucasian Male NSCLC

Failed Tarceva, on 6th line Rx before enrolling in c-met trialBefore and After c-met inhibitor

Before After 2 months of c-met

Planned Global registration trial for PF-02341066

• EML4-ALK positive NSCLC patients• PF-02341066 versus Pemetrexed/Cisplatin• Primary endpoint: PFS

1st & 2nd -line treatment for Never-smoker with NSCLC

EGFR Mutation Positive(~60%)

EML4-ALK translocation

Positive(~5%)

EGFR WTEGFR UnknownEGFR not tested

(~35%)

06-62

08-01

07-40

A8081007

A8081005

08-49PF-00299804

1200.32

1200.42

The End

Proportion of male NSCLC never-smokerBy period of diagnosis and 5 Asian subgroups

Proportion of female NSCLC never-smokerBy period of diagnosis and 5 ethnicities

1st & 2nd line Rx of NSCLC in ever-smokers• First line

– ATTRACT-1 (UCI-07-72)• Carboplatin/paclitaxel +/- ASA402

– CP13-0811 (UCI-09-05)• Carboplatin/gemcitabine/Erbitux +/- IMC-A12

• Second line– UCI-04-60

• Docetaxel or alimta +/- erbitux

– UCI-09-04• Tarceva +/- CP-751,871

– ATTRACT-2 (UCI-08-66)• Docetaxel +/- ASA404

Adjuvant Rx

• ECOG1505– Cisplatin + gemcitabine

/navelbine/alimta/taxotere +/- avastin

• MARGRIT (UCI-07-57)– Adjuvant MAGE vaccine

Never-smoker SmokerHR 95% CI P HR 95% CI P

Ethnicity* Caucasian Asian African-American Hispanic

1.0000.8661.1260.843

(0.751-0.999)(0.796-1.592)(0.714-0.996)

.0483

.8938

.0446

1.0000.8660.9870.981

(0.807-0.928)(0.901-1.081)(0.923-1.043)

< .0001.7800.5450

Gender Male Female

1.0000.786 (0.707-0.874) < .0001

1.0000.841 (0.814-0.868) < .0001

AJCC stage 1 2 3 4

1.002.7882.2423.033

(2.053-3.785)(1.784-2.818)(2.465-3.731)

< .0001< .0001< .0001

1.001.6752.0092.893

(1.537-1.826)(1.885-2.142)(2.729-3.068)

< .0001< .0001< .0001

Age 1.015 (1.011-1.019) < .0001 1.012 (1.010-1.013) < .0001

Cox models for Never-smokers and Smokers

Place of birth-North America

Smoker (%)* Never-smoker (%)*Canada All (N=176) Male Female

162 (92.1%)79 (95.2%)83 (89.2%)

14 (7.9%)4 (4.8%)

10 (10.8%)

Mexico All (N=647) Male Female

516 (79.8%)373 (91.6%)143 (59.6%)

131 (20.3%)34 (8.4%)

97 (40.4%)

Interplay between CA repeats and promoter polymorphism in EGFR gene

Nomura PLoS Med 2007; 4 (4):e125

California Cancer Registry

http://statecancerprofiles.cancer.gov/

Birthplace of Asian patients

Filipino Vietnamese Chinese Japanese Koreans

All Never-smoker

Smoker All Never-smoker

Smoker All Never-smoker

Smoker All Never-smoker

Smoker All Never-smoker

Smoker

N 446 113 333 396 114 282 137 47 90 148 22 126 78 18 60

Native-born Yes (%) No (%)

410 (91.9)

36 (8.1)

107 (94.7)

6 (5.3)

303 (91.0)

30 (9.0)

342 (86.4)

54 (13.6)

101 (88.6)

13 (11.4)

241 (85.5)

41 (14.5)

111 (81.0)

26 (19.0)

36 (76.6)

11 (23.4)

75 (83.3)

15 (16.7)

73 (49.3)

75 (50.7)

14 (63.6)

8 (36.4)

59 (46.8)

67 (53.2)

57 (73.1)

21 (26.9)

12 (66.7)

6 (33.3)

45 (75.0)

15 925.0)

Proportion of never-smokers by Asian subgroups

OS according to stage stratified by smoking status

Pharmodynamic blockade of EGFR pathway

Positions of Mutations Detected in HER1/EGFR Tyrosine Kinase Domain in NSCLC

747-750

Activation loop

L858

G719

TM K DFG Y Y Y Y

AutophosphorylationTyrosine kinaseEGF ligand binding

K R H DFGGXGXXG L L Y

718 745 776 835 858 861 869 964

18 19 20 21 22 23 24

757-750

Exon:

Paez:

Lynch:

Pao:

Tumor with point mutation (amino acid substitution)

Tumor with in-frame deletion

EGF = endothelial growth factor; TM = transmembrane. Adapted from: Pao et al. Proc Natl Acad Sci U S A. 2004;101:13306; Lynch et al. N Engl J Med. 2004;350:2129; Paez et al. Science. 2004;304:1497.

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