NSCLCProgress in the treatmentOptimal Treatment with EGFR-TKI Therapy

Gefitinib vs. Erlotinib

蔡 俊 明蔡 俊 明Chun-Ming Tsai, MDChun-Ming Tsai, MD

Section of Thoracic Oncology Section of Thoracic Oncology Chest DepartmentChest Department

Taipei Veterans General HospitalTaipei Veterans General Hospital

School of MedicineSchool of MedicineNational Yang-Ming UniversityNational Yang-Ming University

EGFR Signaling Biomarkers & Inhibitors

Tumour cellTumour cellproliferationproliferation

PI3K

MAPK

Tumour cellTumour cellsurvivalsurvival

Akt

mTOR

STAT 3/5

Grb-2

Ras

Raf

MEK

ATP

Anti-EGFR AbsCetuximab, Panitumumab, Matuzumab, h-R3, MDX-447

Anti-HER1,HER2,HER4 TKIsGefitinib, Erlotinib, BIBW-2992, PKI-166, GW-572016, CI-1033, AEE788

RAS farnesyltransferase inhibitorsMMS214662, R115777, SCH66336

RAF inhibitorsSorafenib, L-779450

MEK inhibitorsCI-1040, U-0126

mTOR inhibitorsTemsirolimus, RAD001

II

II

II

II

II

II

ATP

SOS

Small molecule Small molecule tyrosine kinase inhibitorstyrosine kinase inhibitors

EGFR Mutations in Adenocarcinoma

33 33

40

29

1013 11

5

0

10

20

30

40

50

60

Ethnicity Gender Smoking Hx Histology

Response Rate vs. Clinical Background

Clinical Background vs. EGFR Mutations

EG

FR

mu

tati

on

(%

)R

R (

%)

32

38

47

30

710

72

0

10

20

30

40

50

60

Ethnicity Gender Smoking Hx Histology

Asian

Non-Asi

an

Femal

e

Mal

e Never

Ever

Adeno

Non-Aden

o

Asian

Non-Asi

an

Femal

e

Mal

e Never

Ever

Adeno

Non-Aden

o

Mitsudomi, IJCO, 2006

Gefitinib- and erlotinib-sensitizing mutations of EGFR

T854A E884KE884K

L747S

D761Y

Mutations associated with drug resistance

Mutations associated with drug sensitivitySharma, et al.

Nat Rev Cancer 2007

100 55 125 288 283 104 102 100 55 125 288 283 104 102

TAX317 TAX320 JMEI IDEAL1 IDEAL2 TAX317 TAX320 JMEI IDEAL1 IDEAL2

2929

Gef

itini

b

7.67.66.56.5

66.866.8 58.658.6

11.811.818.418.4

Gef

itini

b3535

100 55 125 288 283 104 102 100 55 125 288 283 104 102

TAX317 TAX320 JMEI IDEAL1 IDEAL2 TAX317 TAX320 JMEI IDEAL1 IDEAL2

22223131

BS

C

Erlo

tinib

4.74.76.76.7

2828

5353

8.98.9

100 55 125 288 283 104 102 563 1126 243 488100 55 125 288 283 104 102 563 1126 243 488

TAX317 TAX320 JMEI IDEAL1 IDEAL2 ISEL BR21TAX317 TAX320 JMEI IDEAL1 IDEAL2 ISEL BR21

21212727

BS

CG

efiti

nib

5.15.1 5.65.6

3232

4848

88

HR= 0.89HR= 0.89P= 0.087P= 0.087

0.700.70< 0.001< 0.001

~27

~60

~10

~40

428

100 55 125 288 283 100 55 125 288 283

TAX317 TAX320 JMEI TAX317 TAX320 JMEI

1919

30302929 3232 3030

BS

CD

ocet

axel

Doc

etax

el

Pem

etre

xed

4.64.6

7.97.977

5.75.7

8.38.3

1-yr

Sur

viva

l (%

)

MS

(m)

DC

R (%

)1-

yr S

urvi

val (

%)

M

S (m

)

D

CR

(%)

00

44

88

1212

00

1010202030304040

47.347.3

63.463.4

46.646.653.153.1 54.154.1

0

15

30

45

60

75

9.19.18.88.86.76.75.85.8

Doc

etax

el

~~ 7070

~~ 8080

~~ 1414

~~ 4747

117

~60

~27

~10

~40

428

Salvage Treatment in Non-Small Cell Lung Salvage Treatment in Non-Small Cell Lung CancerCancer

Comparison of Comparison of Docetaxel, PemetrexedDocetaxel, Pemetrexed & & EGFR-TKIsEGFR-TKIs GefitinibGefitinib

BR.21 versus ISEL placebo-controlled studies

Favours EGFR TKI Favours placeboHR

0.40 0.60 0.80 1.00 1.20

Erlotinib (BR.21)1

30% reduction in risk of deathp=0.001 Gefitinib (ISEL)2

11% reduction in risk of deathNot significant

1Shepherd FA, et al. N Engl J Med 2005;353:123–322Thatcher N, et al. Lancet 2005;366:1527–37

Why Gefitinib Failed? BR21 vs ISEL

Patient selection and inclusion criteria

Criteria for inclusion in ISEL and BR21 clinical trials

ISEL: development of progressive disease within 90 days of the preceding round of chemotherapy (early relapse)

BR21: no selection for early relapse

100 55 125 288 283 104 102 100 55 125 288 283 104 102

TAX317 TAX320 JMEI IDEAL1 IDEAL2 TAX317 TAX320 JMEI IDEAL1 IDEAL2

2929

Gef

itini

b

7.67.66.56.5

66.866.8 58.658.6

11.811.818.418.4

Gef

itini

b3535

100 55 125 288 283 104 102 100 55 125 288 283 104 102

TAX317 TAX320 JMEI IDEAL1 IDEAL2 TAX317 TAX320 JMEI IDEAL1 IDEAL2

22223131

BS

C

Erlo

tinib

4.74.76.76.7

2828

5353

8.98.9

100 55 125 288 283 104 102 563 1126 243 488100 55 125 288 283 104 102 563 1126 243 488

TAX317 TAX320 JMEI IDEAL1 IDEAL2 ISEL BR21TAX317 TAX320 JMEI IDEAL1 IDEAL2 ISEL BR21

21212727

BS

CG

efiti

nib

5.15.1 5.65.6

3232

4848

88

HR= 0.89HR= 0.89P= 0.087P= 0.087

0.700.70< 0.0001< 0.0001

~27

~60

~10

~40

428

Salvage Treatment in Non-Small Cell Lung Salvage Treatment in Non-Small Cell Lung CancerCancer

Comparison of Comparison of Docetaxel, PemetrexedDocetaxel, Pemetrexed & & EGFR-TKIsEGFR-TKIs 100 55 125 288 283 100 55 125 288 283

TAX317 TAX320 JMEI TAX317 TAX320 JMEI

1919

30302929 3232 3030

BS

CD

ocet

axel

Doc

etax

el

Pem

etre

xed

4.64.6

7.97.977

5.75.7

8.38.3

1-yr

Sur

viva

l (%

)

MS

(m)

DC

R (%

)1-

yr S

urvi

val (

%)

M

S (m

)

D

CR

(%)

00

44

88

1212

00

1010202030304040

47.347.3

63.463.4

46.646.653.153.1 54.154.1

0

15

30

45

60

75

9.19.18.88.86.76.75.85.8

Doc

etax

el

GefitinibGefitinib

~~ 7070

~~ 8080

~~ 1414

~~ 4747

117

~60

~27

~10

~40

428

Consistent OS with placebo in BR.21 and ISEL demonstrates similar study populations

Pro

po

rtio

n s

urv

ivin

g

1.0

0.8

0.6

0.4

0.2

00 2 4 6 8 10 12 14 16 18 20 22 24 26 28

Time (months)

Placebo (BR.21)1

Placebo (ISEL)2

1Shepherd FA, et al. N Engl J Med 2005;353:123–322Thatcher N, et al. Lancet 2005;366:1527–37

Why Gefitinib Failed? BR21 vs ISEL

Drug dosing

Erlotinib and GefitinibSimilar structures, Different activity?

• Structural differences may affectStructural differences may affect– plasma, tumour and normal tissue distributionplasma, tumour and normal tissue distribution– metabolismmetabolism– in-vitro activityin-vitro activity– clinical efficacy and toxicityclinical efficacy and toxicity

Erlotinib Gefitinib

O

OO

O

NH

N

N

CI

F

N

O NH

N

O

O

NH

O

O

N

MW 429.2 MW 446.9

Erlotinib is less lipophilic than gefitinib

cLogP = 3.30 cLogP = 3.87

Three-fold difference in lipophilicity Greater susceptibility to metabolism Increased biliary elimination Increased protein binding Reduced free drug plasma concentration

Erlotinib Gefitinib

O

OO

O

NH

N

N

CI

F

N

O NH

N

O

O

NH

O

O

N

MW 429.2 MW 446.9

Differences in activity of major metabolites

Li J, et al. Clin Cancer Res 2007;13:3731–7McKillop D, et al. Xenobiotica 2006;36:29–39

OSI-420 Desmethyl-gefitinib

Activity in cells = Erlotinib ≈ 10% of gefitinib

Activity in xenograft models = Erlotinib Minimal

Gefitinib

CI

F

N

O NH

N

O

O

NH

O

O

N

H

Desmethyl-gefitinibErlotinib

O

OO

O

NH

N

N

OSI-420

H

MW 429.2 MW 446.9

• Dose-proportional CDose-proportional Cmaxmax and AUC and AUC• Repeated daily dosing does not result in drug accumulationRepeated daily dosing does not result in drug accumulation• High plasma exposure at 150mg/day p.o.High plasma exposure at 150mg/day p.o.

Hidalgo M, et al. J Clin Oncol 2001;19:3267–79Hidalgo M, et al. J Clin Oncol 2001;19:3267–79

Ranson M, et al. J Clin Oncol 2002;20:2240–50Ranson M, et al. J Clin Oncol 2002;20:2240–50

Cmax (ng/mL) AUC0–24 (ng·hour/L)

Erlotinib Erlotinib 150mg/day150mg/day

Gefitinib Gefitinib 225mg/day225mg/day

Gefitinib Gefitinib 525mg/day525mg/day

Gefitinib Gefitinib 700mg/day700mg/day

2,500

2,000

1,500

1,000

500

0

45,00040,00035,00030,00025,00020,00015,00010,000

5,0000

Erlotinib phase I monotherapy studies pharmacokinetics (daily dosing schedule)

EGFREGFRL858RL858R is More Sensitive to Gefitinib than EGFR is More Sensitive to Gefitinib than EGFRWTWT

Paez, Science 2004

A549 H1666 H3255Gefitinib (1.0 µM) - + - + - +

PARP

-tubulin

-116 kDa- 89 kDa

Gefitinib induces apoptosis in the H3255

250 mg p.o.250 mg p.o.~ ~ 0.40.4 MM

400-600 mg p.o.400-600 mg p.o.~ ~ 1.1 -1.1 - 1.41.4 MM

Cell lineCell line Cell Cell Type*Type* PgpPgp EGFR mutationEGFR mutation GefitinibGefitinib

ICIC5050 ( (M)M)Ras mutatiRas mutati

on**on**11 H23H23 AA 11 -- 10.676 ± 0.192710.676 ± 0.1927 K-ras 12K-ras 12

22 H125H125 ASAS 00 -- 15.822 ± 0.078915.822 ± 0.0789 --

33 H226H226 SS 00 -- 8.9903 ± 0.68328.9903 ± 0.6832 --

44 H322H322 BACBAC 00 -- 0.2689 ± 0.05540.2689 ± 0.0554 --

55 H358H358 BACBAC 00 -- 6.0863 ± 0.05746.0863 ± 0.0574 K-ras 12K-ras 12

66 H460H460 LCLC 00 -- 10.089 ± 0.23210.089 ± 0.232 K-ras 61K-ras 61

77 H522H522 AA 00 -- 12.679 ± 0.29912.679 ± 0.299 --

88 H647H647 ASAS 00 -- 12.474 ± 0.21512.474 ± 0.215 K-ras 13K-ras 13

99 H820H820 AA 00 del 746-749, T790M, Metdel 746-749, T790M, Met 4.7165 ± 0.01124.7165 ± 0.0112 --

1010 H838H838 ASAS 00 -- 12.372 ± 0.13712.372 ± 0.137 --

1111 H1155H1155 LCLC 177.2177.2 -- 7.0430 ± 0.06007.0430 ± 0.0600 K-ras 61K-ras 61

1212 H1299H1299 LCLC 161.5161.5 -- 6.6.1619 1619 ±± 0.0.08090809 N-ras 61N-ras 61

1313 H3255H3255 AA 00 L858RL858R 0.0042 ± 0.00020.0042 ± 0.0002 --

1414 HCC827HCC827 AA 00 del 746-750del 746-750 0.0025 ± 0.00010.0025 ± 0.0001 --

1515 PC-9PC-9 AA NENE del 746-750del 746-750 0.0235 ± 0.0000

Cell lines with high levels of induced PgpCell lines with high levels of induced Pgp

1515 H23 A0.1H23 A0.1 AA 61.461.4 -- 12.593 ± 0.310412.593 ± 0.3104 K-ras 12K-ras 12

1616 H23 A0.3H23 A0.3 AA 129.4129.4 -- 12.008 ± 0.555012.008 ± 0.5550 K-ras 12K-ras 12

Characteristics of the Tested Cell Lines

* A: adenocarcinoma; AS: adenosquamous carcinoma; BAC: bronchioloalveolar cell carcinoma; LC: large cell carcinoma; S: squamous cell carcinoma* A: adenocarcinoma; AS: adenosquamous carcinoma; BAC: bronchioloalveolar cell carcinoma; LC: large cell carcinoma; S: squamous cell carcinoma** Mitsudomi, et al. Oncogene 1991.** Mitsudomi, et al. Oncogene 1991.

NSCLC cell lines: in vitro surrogates of in vivo drug sensitivity

Gefitinib response of Erlotinib-Refractory Lung Cancer Gefitinib response of Erlotinib-Refractory Lung Cancer Involving Meninges Involving Meninges – – Role of EGFR MutationRole of EGFR Mutation

70 y/o Japanese-American woman, never smoked70 y/o Japanese-American woman, never smokedStage IV adenocarcinoma, RML with rib metastasesStage IV adenocarcinoma, RML with rib metastases

2002/022002/02 Mediastinoscopic LN biopsyMediastinoscopic LN biopsy

2002/042002/04 TRIBUTE trial (TXL+Ca+erlotinib)TRIBUTE trial (TXL+Ca+erlotinib) 42%42%2003/112003/11 WBRT due to brain metsWBRT due to brain mets2004/082004/08 Hemiparesis, diplopia, incontinence Hemiparesis, diplopia, incontinence

(bowel & bladder), wheelchair bound(bowel & bladder), wheelchair boundBrain & spine MRI: leptomengeal Brain & spine MRI: leptomengeal carcinocarcino

matosismatosis

2004/102004/10 Could not tolerated temozolomide+CPT-11Could not tolerated temozolomide+CPT-11in progression. ECOG PS 4in progression. ECOG PS 4

2004/102004/10 On gefitinibOn gefitinibSymptoms: significantly improved in 3 wksSymptoms: significantly improved in 3 wks

2005/022005/02 Ambulating independently with a walkerAmbulating independently with a walker2005/04 2005/04 ECOG PS 2ECOG PS 22005/062005/06 Aspiration pneumonia and died.Aspiration pneumonia and died.

Prior Prior to gefitinib 2 to gefitinib 2 msms

Choong NW, Nature CP Oncol 3:50, 2006Choong NW, Nature CP Oncol 3:50, 2006

Prior to gefitinib 2 ms 4.5 MsPrior to gefitinib 2 ms 4.5 Ms

EGFR Mutations & Their Effects on Sensitivity & EGFR Mutations & Their Effects on Sensitivity &

Resistance Towards Inhibition by EGFR TKIsResistance Towards Inhibition by EGFR TKIs

Choong NW, Nature CP Oncol 3:50, 2006Choong NW, Nature CP Oncol 3:50, 2006

Gefitinib (mean conc.) Erlotinib (median conc.)225 mg/day 0.16μg/ml (0.03-0.32) [0.358μmol/L]

300 mg/day 0.24μg/ml

1000 mg/day 1.1 μg/ml 150 mg/day 1.26 0.62μg/ml (0.33-2.64) [2.9μmol/L]

Costa, JCO, 26:1182, 2008

Differential Responses to Erlotinib in EGFR-Mutated NSCLC With Acquired

Resistance to Gefitinib Carrying the L747S or T790M Secondary Mutations

Costa, JCO, 26:1182, 2008

Differential Responses to Erlotinib in EGFR-Mutated NSCLC With Acquired

Resistance to Gefitinib Carrying the L747S or T790M Secondary Mutations

Identification of Agents That Overcome Identification of Agents That Overcome T790M-Mediated ResistanceT790M-Mediated Resistance

Screen Screen 4747 known kinase inhibitors known kinase inhibitorsfor ability to inhibit H1975 proliferationfor ability to inhibit H1975 proliferation

> 85% inhibition at 2 > 85% inhibition at 2 MM

Identification 3 compoundsIdentification 3 compoundsCL-387,785; EKB-569; CI-1033CL-387,785; EKB-569; CI-1033

Determine IC50Determine IC50 Measure EGFRMeasure EGFRAutophos inhibitionAutophos inhibition

Ambit BiosciencesAmbit Biosciences

Compound ICCompound IC5050 ( (µµM)M)

CI-1033CI-1033

0.0230.023

EKB-569 EKB-569

0.0330.033

CL-387,785CL-387,785

0.0510.051

SU-11464SU-11464

0.4500.450

ZD6474ZD6474

1.9001.900

GW572016GW572016

3.5003.500

GefitinibGefitinib

6.6006.600

PKI-166PKI-166

7.7007.700

ErlotinibErlotinib

10.00010.000

Inhibition of H1975 cell proliferationInhibition of H1975 cell proliferation

Compound ICCompound IC5050 ( (µµM)M)

CI-1033CI-1033

0.0230.023

EKB-569 EKB-569

0.0330.033

CL-387,785CL-387,785

0.0510.051

SU-11464SU-11464

0.4500.450

ZD6474ZD6474

1.9001.900

GW572016GW572016

3.5003.500

GefitinibGefitinib

6.6006.600

PKI-166PKI-166

7.7007.700

ErlotinibErlotinib

10.00010.000

Inhibition of H1975 cell proliferationInhibition of H1975 cell proliferation

Erlotinib and Gefitinib: AE profiles*

Incidence of AEs (%)*Incidence of AEs (%)*

Erlotinib (n=485)Erlotinib (n=485) GefitinibGefitinib (n=1,126)(n=1,126)

AllAll Grade 3+Grade 3+ AllAll Grade 3+Grade 3+

RashRash 7676 99 3737 22

DiarrheaDiarrhea 5555 66 2727 33

NauseaNausea 4040 33 1717 11

AnorexiaAnorexia 6969 99 1717 22

VomitingVomiting 2525 33 1414 11

Dry skinDry skin 1212 00 1111 00

Comparison of Erlotinib (TarcevaTM) versus Gefitinib (Iressa®) as Salvage therapy for the

Treatment of Advanced NSCLC Patients: Retrospective Paired matched analysis

Sungkyunkwan University, School of MedicineSamsung Medical Center

Myung-Ju Ahn, M.D.

CharacteristicsGefitinib (N=174)

Erlotinib (N=174)

P-value

AgeMedian (Range) 58.0 (25.0-87.0) 59.0 (20.0-82.0)

≤ 60 years 100 100NA

〉 60 years 74 74

SexMale 111 111

NAFemale 63 63

ECOG0-1 116 116

NA≥ 2 58 58

Histology Adenocarcinoma 125 125

NANon-adenoca. 49 49

No of prior chemo

≤2 145 145NA

2< 29 29

SmokingNever smoker 87 98

0.237Current or Ever 87 76

Gfitinib: 2002-2005; Erlotinib: 2006-2008Gefitinib: 316 vs Erlotinib: 257 (Matched Age, Sex, PS, Smoking, No of PriorTx) Gfitinib: 2002-2005; Erlotinib: 2006-2008Gefitinib: 316 vs Erlotinib: 257 (Matched Age, Sex, PS, Smoking, No of PriorTx)

Ahn et al, Unpublished data

Baseline CharacteristicsBaseline Characteristics

36%36%

72%72%

50-56%50-56%

Tumor response: Tumor response:

ResponseResponse Gefitinib Gefitinib (N=174)(N=174)

ErlotinibErlotinib(N=174)(N=174) P-valueP-value

CRCR 33 11

--

PRPR 4444 5151

SDSD 4545 5757

PDPD 7373 6060

Not evaluableNot evaluable 99 55

Overall responseOverall response 27.0%27.0% 29.8%29.8% NSNS

Disease control rateDisease control rate 52.8%52.8% 62.6%62.6% 0.1030.103

Ahn et al, Unpublished data

(A) Kaplan-Meier curves for overall survival in all patients and (B) Comparison Kaplan-Meier curves for overall survival between gefitinib- and erlotinib treated patients

(A) Kaplan-Meier curves for overall survival in all patients and (B) Comparison Kaplan-Meier curves for overall survival between gefitinib- and erlotinib treated patients

0 12 24 36 48 60

Months

0.0

0.2

0.4

0.6

0.8

1.0

Pro

bability (Overa

ll S

urv

ival)

0 12 24 36 48 60

Months

0.0

0.2

0.4

0.6

0.8

1.0

Pro

bability (Overa

ll S

urv

ival)

Gefitinib

Erlotinib

(A) Total OS; Median 10.7 months(A) Total OS; Median 10.7 months

(B) Gefitinib OS; Median 10.0 months Erlotinib OS; Median 12.4 months

(p=0.07)

(B) Gefitinib OS; Median 10.0 months Erlotinib OS; Median 12.4 months

(p=0.07)

Ahn et al, Unpublished data

Study scheme

Statistics Target N =48 for each group

Simon’s optimal two-stage design

P0=10%, P1=25%, α-error 5%, ß-error 20%, 10% drop-out rates 1st stage: responders > 2/18 2nd stage: additional 25 pts

Methods

RANDOMIZATION

Gefitinib250mg/d Q4wKs

Erlotinib150mg/d Q4wks

REEVALUAT ION

REEVALUAT ION

UntilDisease

progression or

Intolerable toxicities

4 w

eeks

8 w

eeks

At least 2 of 3

Adenoca. Female Never smoker

or

EGFR mutant

Patients’ Characteristics

Characteristics Characteristics All All (n=96, %)(n=96, %)

GefitinibGefitinib(n=48, %)(n=48, %)

ErlotinibErlotinib(n=48, %)(n=48, %)

P valueP value

Age (yrs)Age (yrs) MedianMedianRange Range

595932-8332-83

606037-8337-83

565632-8132-81 0.1610.161

Sex Sex MaleMaleFemale Female

14 (14.6)14 (14.6)82 82 (85.4)(85.4)

7 (14.6)7 (14.6)41 (85.4)41 (85.4)

7 (14.6)7 (14.6)41 (85.4)41 (85.4) 1.0001.000

ECOG PSECOG PS 1122

82 (85.4)82 (85.4)14 (14.6)14 (14.6)

41 (85.4)41 (85.4)7 (14.6)7 (14.6)

41 (85.4)41 (85.4)7 (14.6)7 (14.6) 1.0001.000

Stage Stage IIIBIIIBIVIVRecurredRecurred

12 (12.5)12 (12.5)69 (71.9)69 (71.9)13 (13.5)13 (13.5)

7 (14.6)7 (14.6)35 (72.9)35 (72.9)6 (12.5)6 (12.5)

5 (10.4)5 (10.4)34 (70.8)34 (70.8)7 (14.6)7 (14.6)

0.4890.489

HistologyHistologyAdenocarcinomaAdenocarcinomaSquamousSquamousOthersOthers

87 87 (90.6)(90.6)6 (6.3)6 (6.3)3 (3.1)3 (3.1)

44 (91.7)44 (91.7)3 (6.3)3 (6.3)1 (2.1)1 (2.1)

43 (89.6)43 (89.6)3 (6.3)3 (6.3)2 (4.1)2 (4.1)

0.7980.798

Prior Prior treatmenttreatment

Neoadjuvant CCRTNeoadjuvant CCRTAdjuvant CCRTAdjuvant CCRTAdjuvant ChemoAdjuvant ChemoDefinitive CCRTDefinitive CCRTPlatinum ChemoPlatinum Chemo

2 (2.1)2 (2.1)3 (3.1)3 (3.1)5 (5.2)5 (5.2)3 (3.1)3 (3.1)

93 (96.9)93 (96.9)

1 (2.1)1 (2.1)2 (4.2)2 (4.2)2 (4.2)2 (4.2)2 (4.2)2 (4.2)

45 (93.8)45 (93.8)

1 (2.1)1 (2.1)1 (2.1)1 (2.1)3 (6.3)3 (6.3)1 (2.1)1 (2.1)

48 (100)48 (100)

0.0780.078

SmokingSmoking Ever-smokerEver-smokerNever-smokerNever-smoker

6 (6.2)6 (6.2)90 90 (93.7)(93.7)

4 (8.3)4 (8.3)44 (91.7)44 (91.7)

2 (4.2)2 (4.2)46 (95.8)46 (95.8) 0.5120.512

EGFR EGFR mutationmutation

EGFR mutationEGFR mutationWild typeWild typeNot testedNot tested

17 (17.7)17 (17.7)23 (24.0)23 (24.0)56 (58.3)56 (58.3)

9 (18.8)9 (18.8)8 (16.7)8 (16.7)

31 (64.6)31 (64.6)

8 (16.7)8 (16.7)15 (31.3)15 (31.3)25 (52.1)25 (52.1)

0.2430.243

Response Rates

Numbers of treatment cycles : median 5 (range, 0.5-20), total 605 cyclesNumbers of treatment cycles : median 5 (range, 0.5-20), total 605 cycles Gefitinib group: median 6 (range, 0.5-19), total 331 cyclesGefitinib group: median 6 (range, 0.5-19), total 331 cycles Erlotinib group: median 4 (range, 0.5-20), total 274 cyclesErlotinib group: median 4 (range, 0.5-20), total 274 cycles

Gefitinib Gefitinib Erlotinib Erlotinib

PP value valueN N (n=48)(n=48) %%

N N (n=48)(n=48) %%

CRCR 11 2.12.1 11 2.12.1

0.9420.942

PRPR 2222 45.845.8 1818 37.537.5

SDSD 1212 25.025.0 1313 27.127.1

PDPD 1212 25.025.0 1515 31.331.3

NENE 11 2.12.1 11 2.12.1

ORRORR 2323 47.9 (33.8-62.0)47.9 (33.8-62.0) 1919 39.6 (25.8-53.4)39.6 (25.8-53.4) 0.4110.411

DCRDCR 3535 72.9 (60.3-85.4)72.9 (60.3-85.4) 3232 66.7 (53.4-80.0)66.7 (53.4-80.0) 0.5050.505

Survival Curves

Median follow-up duration: 11.5 months (range, 6.7-20.8)

Median (95% CI)

20.4 months (8.8-32.0)

4.8 months (2.7-6.9)

Gefitinib

Erlotinib

PFS by Treatment

P=0.167

Median PFS (95% CI)

4.9 months (1.5-8.3)

3.1 months (0.0-6.4)

OS and PFS

OS

PFS

ToxicitiesGefitinib Erlotinib

Toxicity grade Toxicity grade

1 2 3 Total 1 2 3 Total P value

Skin rash 25 (52.1) 4 (8.3) 1 (2.1) 30 (62.5) 14 (29.2) 16 (33.3) 5 (10.4) 35 (72.9) 0.003

Dry skin 8 (16.7) 0 (0) - 8 (16.7) 9 (18.8) 1 (2.1) - 10 (20.9) 0.733

Paronychia 4 (8.3) 1 (2.1) - 5 (10.4) 4 (8.3) 0 (0) - 4 (8.3) 0.767

Diarrhea 8 (16.7) 8 (16.7) - 16 (33.4) 14 (29.2) 3 (6.3) - 17 (35.5) 0.238

Mucositis 1 (2.1) 2 (4.2) - 3 (6.3) 4 (8.3) 1 (2.1) - 5 (10.4) 0.300

Fatigue 0 (0) 0 (0) - 0 (0) 5 (10.4) 3 (3.1) - 8 (16.7) 0.027

Anorexia 7 (14.6) 0 (0) - 7 (14.6) 4 (8.3) 1 (2.1) - 5 (10.4) 0.587

Alopecia 3 (6.3) - - 3 (6.3) 1 (2.1) - - 1 (2.1) 0.463

Neuropathy 2 (4.2) 2 (4.2) - 4 (8.4) 3 (6.3) 0 (0) - 3 (6.3) 0.414

Infection¶ - - 1 (2.1) 1 (2.1) - - 1 (2.1) 1 (2.1) 1.000

ILD - - - - - - - - -

¶ Except 3 mortalities from pneumonia. (2 of gefitinib and 1 of erlotinib)

Clinical Outcomes in Patients with

EGFR Mutations

Pooled Analysis of NSCLC Patients Treated with Pooled Analysis of NSCLC Patients Treated with

Either an EGFR TKI or ChemotherapyEither an EGFR TKI or Chemotherapy

L Paz-Ares, et al.

ESMO/ECCO Berlin 2009J Cell Mol Med 2010 14:51-69

Summary of search strategy

Reports identified from broad literature search (n=564)

Studies retained for full paper review (n=175)

Studies identified from ASCO 2008–9 search (+n=42)

Excluded based on abstract or title: no clinical data

related to question (- n=431)

Excluded (n=121)• PFS/TTP/n not reported for pts with mutations (n=96) • EGFR-TKIs given sequentially or as maintenance or adjuvant therapy (n=10)• Data duplicated in another publication (n=15)

Studies included (n=54)

Summary of data included

Erlotinib Gefitinib Chemotherapy

Pts treated in any line; n 365 1,069 375

Pts treated

in first-line setting57% 57% 95%

Total number of patients = 1,809

(65% treated in first-line setting)

Median PFS from individual studies

90% accuracy intervals (any line of therapy)

Erlotinib

Gefitinib

Chemotherapy

Pooled median PFS(95% accuracy interval)

13.2 (12.0–14.7)

9.8 (9.2–10.4)

5.9 (5.3–6.5)

Permutation test for estimated pooled median PFS (1,000 iterations)EGFR TKI vs chemotherapy p=0.000 (two-sided)

Erlotinib N = 365 (2/12)

Gefitinib N = 1069 (19/39)

Chemotherapy N = 375

Poo

led

stud

ies

EGFR mutation-positive disease:efficacy of therapeutic options

SATURN study design

Stratification factors: EGFR IHC (positive vs negative vs indeterminate) Stage (IIIB vs IV) ECOG PS (0 vs 1) CT regimen (cis/gem vs carbo/doc vs others) Smoking history (current vs former vs never) Region

1:1

Chemonaïve advanced

NSCLCn=1,949

Non-PDn=889

4 cycles of 1st-line platinum-based doublet*

Placebo PD

Erlotinib150mg/day

PD

Mandatory tumour sampling

*Cisplatin/paclitaxel; cisplatin/gemcitabine; cisplatin/docetaxel cisplatin/vinorelbine; carboplatin/gemcitabine; carboplatin/docetaxel carboplatin/paclitaxelEGFR = epidermal growth factor receptor; IHC = immunohistochemistry

Co-primary endpoints: PFS in all patients PFS in patients with EGFR IHC+ tumours

Secondary endpoints: Overall survival (OS) in all patients and those with EGFR

IHC+ tumours, OS and PFS in EGFR IHC– tumours; biomarker analyses; safety; time to symptom progression; quality of life (QoL)

Randomized phase III study of platinum-doublet CT followed by gefitinib vs continued CT in pts with advanced NSCL

C: Results of WJTOG trial LBA#8012

AllOS- Adenocarcinoma

WJTOG 0203 - OS

All Non-Squamous cell ca

SATURN - OS

WJTOG0203: Hazard Ratios for Death according to the Subgroup Analysis

0.4 0.6 0.8 1.0 1.2

Favourserlotinib

Favoursplacebo

HR

Male

Female

Caucasian

Asian

Adenocarcinoma

Squamous-cell

Never smoker

Former smoker

Current smoker

HR (95% CI) n

0.88 (0.74–1.05) 659

0.64 (0.46–0.91) 230

0.86 (0.73–1.01) 746

0.66 (0.42–1.05) 131

0.77 (0.61–0.97) 403

0.86 (0.68–1.10) 360

0.69 (0.45–1.05) 152

0.75 (0.56–1.00) 244

0.88 (0.72–1.08) 493

SATURN: OS subgroup analyses by clinical characteristics

All 0.81 (0.70–0.95) 889

SATURN: PFS (wild type vs. squamous)

Log-rank p=0.0148

HR=0.76 (0.60–0.95)

Squamous-cell carcinoma

1.0

0.8

0.6

0.4

0.2

0

Time (weeks)

0 8 16 24 32 40 48 56 64 72 80 88

Erlotinib (n=166)

Placebo (n=193)

PFS probability

Log-rank p=0.0185

HR=0.78 (0.63–0.96)1.0

0.8

0.6

0.4

0.2

0

Time (weeks)

Erlotinib (n=199)

Placebo (n=189)

0 8 16 24 32 40 48 56 64 72 80 88 96

EGFR wild-type

Comparison of gefitinib and erlotinib in Taiwanese patients with Comparison of gefitinib and erlotinib in Taiwanese patients with advanced NSCLC: A retrospective multi-center studyadvanced NSCLC: A retrospective multi-center study

胸腔醫學會 胸腔醫學會 2009 2009 北榮 范紋健北榮 范紋健

Total: 1122 Female 45%Never/light smoker 53%Adenocarcinoma 77%Stage IV 79%Chemo-naive 41%

Gefitinib Erlotinib* P

N 715 407

ORR 34.4% 35.6% 0.68

DCR 58.9% 65.6% 0.02

PFS 3.6 m 4.6 m

* Erlotinib group: more male, smoker and non-adeno.

Response and Resistance in a NResponse and Resistance in a NSCLC Patient With SCLC Patient With

an EGFR Mutation* and Leptomean EGFR Mutation* and Leptomeningeal Metastases ningeal Metastases

Treated With High-Dose GefitinibTreated With High-Dose Gefitinib

Pasi A. Ja¨nne and Bruce E. Johnson JCO 2006 12/2004

09/2004

*Exon 19 deletion, IC50: 10-50 nM.

Efficacy of Erlotinib for Brain and Leptomeningeal Metastases in Patients with Lung Adenocarcinoma Who Showed In

itial Good Response to Gefitinib

Katayama, et al. JTO 2009

PD

6 (60%)

SD

4 (40%)Response of Brain Metastases (total N=10)

0 - 20039Duration of Intracranial Disease Control (days) *

126 - 632379MS

29 - 9964TTP

95%CIDaysSurvival time

13.0 - 45.47 (29.2)DCR

0 - 19.62 (8.3)ORR

17 (70.8)PD

5 (20.8)SD

2 (8.3)PR

95%CIN (%)Response

PD

6 (60%)

SD

4 (40%)Response of Brain Metastases (total N=10)

0 - 20039Duration of Intracranial Disease Control (days) *

126 - 632379MS

29 - 9964TTP

95%CIDaysSurvival time

13.0 - 45.47 (29.2)DCR

0 - 19.62 (8.3)ORR

17 (70.8)PD

5 (20.8)SD

2 (8.3)PR

95%CIN (%)Response

ORR: objective response rate, DCR: desease control rate (CR+PR+SD)MS: median survival, TTP= time to progression

* All 4 cases with intra-cranial disease control had progression of extra-cranial lesions.

Response to erlotinib based on RECIST (N=24)

Phase II Study of Erlotinib in NSCLC Patients Who

Failed Prior GefitinibShih et al, WCLC 2007

07/13/2006

10/09/2006Intracranial lesions: minimal response

Erlotinib after gefitinib failure

F/1953 Adenocarcinoma, RLL with brain metastasisF/1953 Adenocarcinoma, RLL with brain metastasis

20032003

01– 0201– 02

WBRTWBRT

20032003

03 – 0603 – 06

Gem/CisGem/CisX 6X 6

20042004

02 – 0602 – 06

DocDocX 6X 6

2004 - 052004 - 05

10 – 0210 – 02

NVB/IfoNVB/IfoX 6X 6

2005 20082005 2008

05 04 05 04

2007200704 – 0504 – 05WBRTWBRT

200802/12-25Erlotinib

2008/02/05 2008/02/262008/02/05 2008/02/26 2008/04/222008/04/22

GefitinibGefitinib

GefitinibGefitinib (250 mg daily)(250 mg daily)

ErlotinibErlotinib (150 mg daily)(150 mg daily)

Mean steady-state serum Mean steady-state serum level level ((MM))

0.40.4 1.12 – 3.41.12 – 3.4

ICIC5050 ((M)M) of NSCLC cell lines of NSCLC cell lines

－ － wild typewild type － － activating mutants activating mutants

> > 11< < 0.050.05

> > 11< < 0.050.05

Patients harbouring tumors Patients harbouring tumors with activating-EGFR with activating-EGFR mutations mutations

Preferred,Preferred,less toxicity less toxicity

Active,Active,more toxicmore toxic

Patients harbouring wild-type Patients harbouring wild-type EGFR tumors EGFR tumors InactiveInactive

Modestly active, Modestly active, preferred over gefitinib, preferred over gefitinib,

but chemotherapy but chemotherapy better better

Clinical Implications:Clinical Implications:

Tsai CM, 2010Tsai CM, 2010

GefitinibGefitinib (250 mg daily)(250 mg daily)

ErlotinibErlotinib (150 mg daily)(150 mg daily)

Enriched patientsEnriched patientsIPASS population*IPASS population* ActiveActive Active, more toxicActive, more toxic

Non IPASS populationNon IPASS population Likely inactiveLikely inactivePreferred over gefitinib, Preferred over gefitinib,

but chemotherapy but chemotherapy better better

Patients harbouring tumors Patients harbouring tumors with activating-EGFR with activating-EGFR mutations have brain mutations have brain metastasismetastasis

ActiveActiveMore active and toxic; More active and toxic;

also could defer until gealso could defer until gefitinib failure (?)fitinib failure (?)

Clinical Implications:Clinical Implications:

Tsai CM, 2010Tsai CM, 2010* Adenocarcinoma in never or ex-light smokers* Adenocarcinoma in never or ex-light smokers