Rossana BerardiClinica di Oncologia Medica

Università Politecnica delle

Marche Ospedali Riuniti di Ancona

TK Inhibitors in NSCLC

Intracellular mTKI Targets

EGFR

PDGFR

VEGFR

AblJAK

Src

Raf

MAPK

MEKERK Ras

PI3-KAKT

Raf

MAPK

MEK ERKRas

PI3-K AKT

Tumor Cell Endothelial Cell

Pro

life

rati

on

/S

urv

ival

Met

asta

sis

An

gio

gen

esis

Tra

nsc

rip

tio

n

STAT

ErlotinibErlotinibLapatinibLapatinib

GefitinibGefitinibVandetanibVandetanib

Sunitinib

Sorafenib

DasatinibNilotinibNilotinibImatinibImatinib

AxitinibMotesanibMotesanib

Obiettivo

CURARE IL TUMORE

DEL POLMONE

CURARE

IL TUMORE DEL POLMONE del Sig. Rossi

Si va verso una Si va verso una TERAPIA SU MISURA TERAPIA SU MISURA

FR Hirsch JTO 2008;3:1468-1481Ohe Y, Clin Cancer Res. 2008 Jul 1;14(13):4206-12

.

The Epidermal Growth Factor Pathway

Ciardiello F, et al. EGFR Antagonists in Cancer Treatment. N Engl J Med. 2008:358:1160-1174.

TARCEVA

indicato nel trattamento di pazienti adulti con carcinoma polmonare non a piccole cellule (NSCLC)

localmente avanzato o metastatico dopo fallimento di uno o più trattamenti

chemioterarpici

http://www.emea.europa.eu/humandocs/Humans/EPAR/tareva

indicazione include la prima linea di trattamento

IRESSA è indicato nel trattamento di pazienti adulti con

carcinoma polmonare non a piccole cellule (NSCLC)localmente avanzato o metastatico con mutazione attivante l’EGFR-TK

Approvazione EMEA 24 giugno 2009

http://www.emea.europa.eu/humandocs/Humans/EPAR/iressa/iressa.htm

1st/2nd/3rd-Line NSCLC TREATMENT EGFR TKIs Clinical Development Route

20012001 20022002 2003 2004 2003 2004 2005 2007 2008 2005 2007 2008

GEF

ITIN

IBER

LOTI

NIB

Phase IIDEAL I & II

BR.21BR.21

ISEL

Phase I

INTACT 1&2

TALENT&TRIBUTE

INVITE INVITE

INTERESTINTEREST

IPASSIPASS

TRUSTTRUST

Phase II

RRAANNDDOOM M I I SSEE

ERLOTINIB*ERLOTINIB* 150 mg daily150 mg daily

NSCLC unsuitable to

receive CT stratified by:

-Centre-Performance

status 0/1 vs 2/3

-Response to prior Rx

(CR/PR:SD:PD)-Prior regimens

(1 vs 2)-Prior platinum

(yes vs no)

Placebo “150 mg” daily

* 2:1randomisa

tion

F Shepherd et al, N Eng J Med 2005

BR.21 STUDY DESIGN

Erlotinib prolunga

significativamente la

sopravvivenza nei pazienti con NSCLC avanzato

Shepherd FA, et al. N Engl J Med 2005Shepherd FA, et al. N Engl J Med 2005

00 55 1010 1515 2020 2525 3030

Sop

ravviv

en

za (

%)

Sop

ravviv

en

za (

%)

1.001.00

0.750.75

0.500.50

0.250.25

00

TarcevaTarceva

PlaceboPlacebo

Tempo (mesi)Tempo (mesi)

Autore Terapia N RR (%)

PFSMedianaOS (m)

1-aaOS (%)

Shepherd

TarcevaPlacebo

427211

8.9<1

2.2 1.8

6.7 4.7

31% 22%

SECONDA LINEA

TRUST PHASE IV STUDYTaRceva LUng Cancer Survival Treatment

Erlotinib (BR.21), n=488

Placebo (BR.21), n=243

Median PFS: erlotinib 2.2 mo vs placebo 1.8 mo (p<0.001)

Su

rviv

al d

istr

ibu

tion

fu

ncti

on

1.00

0.75

0.50

0.25

00 5 10 15 20 25 30

PFS (months)

BR.21BR.2111

Median PFS: 3.2 moTRUST2

Erlotinib (TRUST), n=6,580

1Shepherd FA, et al. N Engl J Med 2005 2 M Reck et al, ESMO 2008

Progression Free Survival in UE Subpopulation

TRUST vs BR.21: an indirect comparisonTRUST vs BR.21: an indirect comparison

Su

rviv

al d

istr

ibu

tion

fu

ncti

on

Survival time (months)

1.00

0.75

0.50

0.25

00 5 10 15 20 25 30

Erlotinib (BR.21), n=488

Placebo (BR.21), n=243

Median OS: 7.9 months (28% censored)TRUST 2

Erlotinib (TRUST), n=6,580

Overall Survival in UE Subpopulation

Median OS: erlotinib 6.7 mo vs placebo 4.7 mo (p<0.001)BR.211

1Shepherd FA, et al. N Engl J Med 2005

2 M Reck et al, ESMO 2008

TRUST vs BR.21: an indirect comparisonTRUST vs BR.21: an indirect comparison

NEW OPTIONS IN A-NSCLC Prolongation of Disease

Control

RS Herbst et al, ASCO 2003

SATURN TRIAL DESIGN

F Cappuzzo et al, P ESMO 2009

F Cappuzzo et al, P ESMO 2009

SATURN: PFS (all patients)PRIMARY END-

POINT

SATURN: OS* (all patients, ITT)

0 3 6 9 12 15 18 21 24 27 30 33 36Time (months)

OS

pro

bab

ilit

y

1.0

0.8

0.6

0.4

0.2

0

Erlotinib (n=438)

Placebo (n=451)

11.0 12.0

*OS is measured from time of randomisation into the maintenance phase;

ITT = intent-to-treat population

HR=0.81 (0.70–0.95)

Log-rank p=0.0088

F Cappuzzo et al, P ESMO 2009

1.00.4

Subgroup analysis of PFS

All

Male

Female

Caucasian

Asian

Adenocarcinoma

Squamous-cell

Never smoker

Former smoker

Current smoker

HR (95% CI) n0.71 (0.62–0.82) 884

0.78 (0.66–0.92) 654

0.56 (0.42–0.76) 230

0.75 (0.64–0.88) 744

0.58 (0.38–0.87) 128

0.60 (0.48–0.75) 401

0.76 (0.60–0.95) 359

0.56 (0.38–0.81) 152

0.66 (0.50–0.88) 242

0.80 (0.67–0.97) 490

0.6 0.8 1.2

Favourserlotinib

Favoursplacebo

HR

Log-rank p<0.0001HR=0.60

(0.48–0.75)

PFS probability1.0

0.8

0.6

0.4

0.2

Time (weeks)0 8 162432404856647280

88

Erlotinib (n=204)

Placebo (n=197)

Adenocarcinoma

Log-rank p=0.0148HR=0.76

(0.60–0.95)

Squamous-cell carcinoma

1.0

0.8

0.6

0.4

0.2

Time (weeks)0 8 162432404856647280

88

Erlotinib (n=166)

Placebo (n=193)

PFS probability

SATURN: PFS based on histology

Zd1839-Iressa in refractary lung cancer

IDEAL 1 (Europe) - GEM/CDDP RR Median OS

250 mg 18. 4% 7.6 moR

500 mg 19.0% 8.1 mo

IDEAL 2 (US) - Carbo/Taxol RR Median OS

250 mg 11.8% 6.1 moR

500 mg 8.8% 6.0 mo

INTACT Trials

GEM/CDDP + Iressa

GEM/CDDP + Placebo

CarboCDDP/Paclitaxel + Iressa

CarboCDDP/Paclitaxel + Placebo

1200 patientsNo differences (October 2002)

Previously untreated

NSCLC patients

(N = 1217)

Up to six 3-wk cycles

Gefitinib 250 mg/day PO(n = 609)

Paclitaxel 200 mg/m2 IV on Day 1 +Carboplatin AUC 5-6 mg/mL/min IV on Day 1

(n = 608)

Mok TS, et al. N Engl J Med. 2009;361:247-257.

IPASS Study Design

Characteristic Gefitinib(n = 609)

Paclitaxel/Carboplatin(n = 608)

Female, % 79.5 79.1

Median age, yrs (range) 57 (24-84) 57 (25-84)

Smoking history, % Nonsmoker Former light smoker

93.86.1

93.66.2

WHO PS, % 0 1 2

25.864.210.0

26.562.810.7

Disease stage at entry, % IIIB IV Unknown

24.675.4

0

23.776.20.2

Mok TS, et al. N Engl J Med. 2009;361:247-257.

Baseline Characteristics

609453 (74.4%)

608497 (81.7%)

NEvents

HR (95% CI) = 0.741 (0.651, 0.845) p<0.0001

Gefitinib

Primary objective exceeded: Gefitinib demonstrated superiority relative to carboplatin /

paclitaxel in terms of PFS

Carboplatin /

paclitaxel

Carboplatin / paclitaxel

Gefitinib

Median PFS (months)4 months progression-free6 months progression-free12 months progression-free

5.761%48%25%

5.874%48%7%

609 212 76 24 5 0608 118 22 3 1 0

363412

0 4 8 12 16 20 24 Months0.0

0.2

0.4

0.6

0.8

1.0Probabilityof PFS

At risk :

Objective response rate 43% vs 32% p=0.0001

IPASS: PFS e ORR

EGFR mutations: the strongest predictor of

response

85% circadi queste mutazioni

delezioni multinucleotidiche “in-frame” (ESONE 19)

mutazioni puntiformi

(ESONE 21)

MUTAZIONI DI EGFR

Mutazioni più frequenti: delezione

esone 19 o sostituzione L858R

dell’esone 21

Stratification of NSCLC according to activating mutations

PFS: 14 mo with erlotinib in pts with EGFR mutationsSharma, Haber & Settleman. Nat Rev Cancer 2010

MS Tsao et al, N Engl J Med 2005

BR.21 study: EGFR mutation status predicts response…

……but not survivalbut not survival

nResponse rate (%) p value

EGFR Mutation statusEGFR Mutation status11

Wild-type*Wild-type* 106106 880.050.05

MutantMutant†† 1010 3030

EGFR protein expression (IHC)EGFR protein expression (IHC)22

NegativeNegative 8080 44NSNS

PositivePositive 106 106 1111

EGFR gene copy number (FISH)EGFR gene copy number (FISH)22

NegativeNegative33 4141 220.030.03

PositivePositive33 2525 2020

EGFR Mutation Status, % Gefitinib(n = 609)

Paclitaxel/Carboplatin(n = 608)

Negative 14.9 14.0

Positive• Exon 19 deletion*• Exon 21 L858R*• Exon 20 T790M*• Other*

21.710.810.50.80.5

21.212.27.71.01.2

Unknown 63.4 64.8*11 patients had multiple EGFR mutations and are counted for each mutation present.

Mok TS, et al. N Engl J Med. 2009;361:247-257.

IPASS Baseline Characteristics: EGFR Status

IPASS: Main Findings: Significance of EGFR Mutation Status Significant interaction between treatment and EGFR mutation status

– In EGFR mutation–positive subgroup, significantly longer PFS with gefitinib (HR: 0.48; 95% CI: 0.36-0.64; P < .001)

– In EGFR mutation–negative subgroup, significantly shorter PFS with gefitinib (HR: 2.85; 95% CI: 2.05-3.98; P < .001)

Mok TS, et al. N Engl J Med. 2009;361:247-257. Reproduced with permission. Copyright © 2009 Massachusetts Medical Society. All rights reserved.

EGFR Mutation Positive

HR: 0.48 (95% CI: 0.36-0.64; P < .001)

Pro

bab

ilit

y o

f P

FS

Mos Since Randomization

GefitinibPaclitaxel/carboplatin

1.0

0.8

0.6

0.4

0.2

00 4 8 12 16 20 24

EGFR Mutation Negative

HR: 2.85 (95% CI: 2.05-3.98; P < .001)

Pro

bab

ilit

y o

f P

FS

Mos Since Randomization

Gefitinib

Paclitaxel/carboplatin

1.0

0.8

0.6

0.4

0.2

00 4 8 12 16 20 24

EventsGefitinib: 97 (73.5%)Pac/carbo: 111 (86.0%)

EventsGefitinib: 88 (96.7%) Pac/carbo: 70 (82.4%)

IPASS Main Findings: Response Rates

Significantly higher ORR with gefitinib than carboplatin-paclitaxel

– Driven by EGFR mutation–positive subgroup

Significantly higher quality of life improvements with gefitinib than paclitaxel/carboplatin

Rates of symptom reduction similar between arms

ORR, % Gefitinib Paclitaxel/Carboplatin

P Value

Overall population 43.0 32.2 < .001

EGFR mutation positive 71.2 47.3 < .001

EGFR wild type 1.1 23.5 .001

Mok TS, et al. N Engl J Med. 2009;361:247-257.

IPASS: diversa Risposta Tumorale nei pz EGFR M+ ed EGFR M-

0

10

20

30

40

50

60

70

80

EGFR M+ EGFR M-

Gefitinib Carboplatino/ paclitaxel

EGFR M+ odds ratio (IC 95%) = 2.75 (1.65 - 4.60), p<0.0001

EGFR M- odds ratio (IC 95%) = 0.04 (0.01 to 0.27), p=0.0001

Risposta

tumorale

(%)

(n=132)(n=129) (n=91) (n=85)

Odds ratio >1 implica una maggior probabilità di risposta con gefitinib

71,2%

47,31%

1,1%23,5%

Mok T NEJM 2009

Efficacy results from the randomised phase III OPTIMAL (CTONG 0802) study comparing first-line erlotinib versus carboplatin (CBDCA) plus gemcitabine (GEM), in Chinese

advanced non-small-cell lung cancer (NSCLC) patients (pts) with EGFR activating mutations

Caicun Zhou,1 Yi-long Wu,2 Gongyan Chen,3 Jifeng Feng,4 Xiaoqing Liu,5 Changli Wang,6 Shucai Zhang,7 Jie Wang,8 Songwen Zhou,1 Shengxiang Ren,1 on behalf of the OPTIMAL investigators

1Shanghai Pulmonary Hospital, Tongji University, Shanghai; 2Guangdong Lung Cancer Institute, Guangdong General Hospital & Guangdong Academy of Medical Sciences,

Guangzhou; 3The Cancer Hospital of Harbin Medical University, Harbin; 4Jiangsu Province Cancer Hospital, Nanjing; 5307 Hospital of the Academy of Military Medical Sciences, Cancer

Center, Beijing; 6Tianjin Cancer Hospital, Tianjin; 7Beijing Chest Hospital, Beijing; 8Peking University School of Oncology, Beijing Cancer Hospital, Beijing; China

ESMO 2010

OPTIMAL study design

Erlotinib 150mg/day Chemonaїve

Stage IIIB/IV NSCLC

EGFR Act Mut+ (exon 19 deletion or exon 21

L858R mutation)

ECOG PS 0–2

(n=165)Gemcitabine (1,000 mg/m2

d1,8) Carboplatin (AUC5 d1)q3w, up to 4 cycles

R

Act Mut+ = activating mutations; ECOG = Eastern Cooperative Oncology Group; PS = performance status HRQoL = health-related quality of life; FACT-L = Functional Assessment of Cancer Therapy-Lung; LCSS = lung cancer symptom scale

1:1

Primary endpoint Progression-free survival (PFS)

Secondary endpoints Overall survival (OS), objective response rate (ORR),

time to disease progression, duration of response, safety, HRQoL (FACT-L, LCSS), exploratory biomarker analyses

Stratification factors Mutation type

Histology Smoking status

Efficacy assessment Every 6 weeks

OPTIMAL PFS: primary analysis (ITT)

PF

S p

rob

abil

ity

1.0

0.8

0.6

0.4

0.2

0

HR=0.16 (0.10–0.26)Log-rank p<0.0001

Time (months)

0 5 10 15 20

Patients at riskErlotinib 82 70 51 15 2

Gem/carbo (n=72)Erlotinib (n=82)

Gem/carbo72 26 4 0 0

OPTIMAL PFS: updated analysis (ITT)

HR=0.16 (0.10–0.26)Log-rank p<0.0001

Time (months)

Gem/carbo (n=72)Erlotinib (n=82)

13.14.6

PF

S p

rob

abil

ity

1.0

0.8

0.6

0.4

0.2

00 5 10 15 20

Patients at riskErlotinib 82 70 51 20 2

Gem/carbo72 26 4 0 0

Subgroup analysis of PFS

OverallStage IV

Stage IIIBFemale

MaleAge ≥65Age <65

PS 0–1PS 2

Never smokerCurrent/former smoker

AdenocarcinomaNon-adenocarcinoma

0 0.5 1.0 1.5

0.16 (0.10–0.26) 1540.18 (0.11–0.28) 138 0.27 (0.06–1.16) 160.13 (0.07–0.24) 910.26 (0.14–0.50) 630.17 (0.07–0.43) 380.19 (0.11–0.31) 1160.16 (0.10–0.26) 1440.21 (0.04–1.28) 100.14 (0.08–0.25) 1090.21 (0.09–0.49) 450.17 (0.11–0.28) 1340.22 (0.06–0.73) 20

HR (95% Cl) n

HRFavours erlotinib Favours gem/carbo

Best tumour response*

Erlotinib

[n=82]

n (%)

Gem/carbo

[n=72]

n (%)

CR 2 (2) 0 (0)

PR 66 (81) 26 (36)

ORR 68 (83) 26 (36) p<0.0001

SD 11 (13) 33 (46)

DCR 79 (96) 59 (82) p=0.002

PD 3 (4) 12 (17)

*in evaluable patients; CR = complete response; PR = partial response; SD = stable disease;DCR = disease control rate (CR + PR + SD)

K-RAS mutations?

Mutazioni k-RAS: fattore prognostico

negativo e fattore predittivo di

resistenza primaria ai TKI

Resistance to EGFR TK inhibitors

Acquired resistance to EGFR TK inhibitors

MET amplification: Proto-oncogene detected in 4 of 18 pts with initial response to gefitinib or erlotinib, who then had progressive disease

Found to cause resistance by ErbB3 (HER3)- dependent activation of PI3K

Inhibition of MET signaling in these cells restored sensitivity to gefitinib

Engelman et al, Science 2007; 316:1039-43

Amplificazione MET responsabile del 10-

20% delle resistenze ai TKI per

attivazione attraverso HER3 di PI3K e

AKT (indipendente da EGFR)

ARQ-197=oral c-met inhibitor

Dual EGFR-MET inhibition for overcoming MET-

mediated resistance to EGFRinhibitors

ALK Pathway

1. Inamura K et al. J Thorac Oncol 2008;3:13–17 2. Soda M et al. Proc Natl Acad Sci U S A 2008;105:19893–19897Figure based on: Chiarle R et al. Nat Rev Cancer 2008;8(1):11–23; Mossé YP et al. Clin Cancer Res 2009;15(18):5609–5614; and Data on file. Pfizer Inc.

*Subcellular localization of the ALK fusion gene, while likely to occur inthe cytoplasm, is not confirmed.1,2

TranslocationOr

ALK ALK fusion protein*

Tumor cellproliferation

Inversion

Cell survival

PI3KPI3K

BADBAD

AKTAKT

STAT3/5STAT3/5

mTORmTOR

S6KS6K

RASRAS

MEKMEK

ErKErK

PLC-PLC-YY

PIPPIP22

IPIP33

Clinical Activity of the Oral ALK Inhibitor,

Crizotinib (PF-02341066), in Patients with ALK-positive Non-Small Cell Lung Cancer

Bang Y,1 Kwak EL,2 Shaw A,2 Camidge DR,3 Iafrate AJ,2 Maki RG,4

Solomon B,5 Ou SI,6 Salgia R,7 Clark J2

1Seoul National University, Seoul, Korea; 2Massachusetts General Hospital, Boston, MA, USA; 3University of Colorado Cancer Center, Aurora, CO, USA; 4Memorial Sloan-Kettering Cancer Center, New York, NY, USA;

5Peter MacCallum Cancer Centre, East Melbourne, Australia; 6University of California at Irvine, Irvine, CA, USA; 7University of Chicago Cancer Center, Chicago, IL, USA

Abstract 3ASCO Annual Meeting 2010

1Shaw AT et al. J Clin Oncol 2009;27:4247–4253

Platinum-based chemotherapy EGFR TKI

Patients with ALK-positive NSCLC Do not Appear to Respond to EGFR TKIs

TTP for EGFR TKI1TTP for chemotherapy1

Months0 12 24 36 48 60

100

80

60

40

20

0

EML4–ALK

EGFR

WT/WT

%

Months0 12 24 36 48 60

100

80

60

40

20

0

%EML4–ALK

EGFRWT/WT

*WT/WT = wild type: no ALK fusion or EGFR mutation

Selectivity findings

• Crizotinib – ALK and c-MET inhibition at clinically relevant dose levels

• Crizotinib – low probability of pharmacologically relevant inhibition of any other kinase at clinically relevant dose levels

Cellular selectivity on 10 of 13 relevant hits

Upstate 102 kinase

13 kinase “hits” <100X selective

for c-MET

Kinase % InhibitionMet(h) 94Tie2(h) 103

TrkA(h) 102ALK(h) 100

TrkB(h) 100Abl(T315I)(h) 98

Yes(h) 96Lck(h) 95

Rse(h) [SKY] 94

Axl(h) 93

Fes(h) 93

Lyn(h) 93

Arg(m) 91

Ros(h) 90

CDK2/cyclinE(h) 87

Fms(h) 84EphB4(h) 80Bmx(h) 79

EphB2(h) 77Fgr(h) 73Fyn(h) 68IR(h) 64

CDK7/cyclinH/MAT1(h) 58cSRC(h) 58

IGF-1R(h) 56Aurora-A(h) 54

Syk(h) 52FGFR3(h) 50PKCµ(h) 50BTK(h) 35

CDK1/cyclinB(h) 25p70S6K(h) 24PRK2(h) 22

PAR-1Bα(h) 21PKBß(h) 21Ret(h) 21

GSK3ß(h) 18Flt3(h) 17

MAPK1(h) 17ZAP-70(h) 17

Abl(h) 16c-RAF(h) 16PKD2(h) 15

ROCK-II(h) 14Rsk3(h) 14

GSK3α(h) 11CDK5/p35(h) 10PDGFRα(h) 10

Rsk1(h) 7SGK(h) 6

CHK1(h) 5ErbB4(h) 5Rsk2(h) 5

JNK1α1(h) 4PKBα(h) 4Blk(m) 3

CDK3/cyclinE(h) 3PKCι(h) 3PKCθ(h) 3

CDK2/cyclinA(h) 2PAK2(h) 2PKCßI(h) 2Pim-1(h) 1PKCη(h) 1

SAPK4(h) 1CaMKII(r) 0MKK7ß(h) 0CaMKIV(h) -1CHK2(h) -1CK2(h) -1

JNK2α2(h) -1MKK6(h) -1CK1δ(h) -2PKCα(h) -2

MAPK2(h) -3MEK1(h) -3PKCδ(h) -3PKCε(h) -3Plk3(h) -3

PKCßII(h) -5MSK1(h) -6

PDGFRß(h) -6PKCζ(h) -6

SAPK3(h) -6MAPKAP-K2(h) -7

PKA(h) -7AMPK(r) -9

CDK6/cyclinD3(h) -9CSK(h) -9

SAPK2a(h) -9JNK3(h) -10PKBγ(h) -10IKKα(h) -11NEK2(h) -11

*The cellular kinase activities were measured using ELISA capture method

KinaseIC50 (nM)mean*

Selectivity ratio

c-MET 8 –

ALK 20 2X

RON298 34X

189 22X

Axl294 34X

322 37X

Tie-2 448 52X

Trk A 580 67X

Trk B 399 46X

Abl 1,159 166X

IRK 2,887 334X

Lck 2,741 283X

Sky >10,000 >1,000X

VEGFR2 >10,000 >1,000X

PDGFR >10,000 >1,000X

Crizotinib (PF-02341066)

Crizotinib Selectivity ProfileCrizotinib: inhibits ALK and c-met

Clinical and Demographic Features of Patients with ALK-positive NSCLC

N=82Mean (range) age, years 51 (25–78)

Gender, male/female 43/39

Performance status,* n (%)

0 24 (29)

1 44 (54)2 13 (16)3 1 (1)

Race, n (%) Caucasian 46 (56)Asian 29 (35)

Smoking history, n (%)

Never smoker 62 (76)Former smoker 19 (23)Current smoker 1 (1)

Histology, n (%) Adenocarcinoma 79 (96)

Squamous 1 (1)

Other 2 (2)

Prior treatment regimens, n (%)

0 5 (6)

1 27 (33)

2 15 (18)

≥3 34 (41)

Not reported 1 (1)

*Performance status = Eastern Cooperative Oncology Group

60

40

20

0

–20

–40

–60

–80

–100

Progressive disease

Stable disease

Confirmed partial response

Confirmed complete response

Max

imum

cha

nge

in tu

mor

siz

e (%

)

–30%

Tumor Responses to Crizotinib for Patients with ALK-positive NSCLC

*Partial response patients with 100% change have non-target disease present

*

• Treatment with crizotinib resulted in impressive clinical activity in patients with ALK-positive advanced NSCLC

– ORR: 57%

– DCR at 8 weeks: 87%

– PFS probability at 6 months: 72%

Median PFS has Not been Reached 70% of Patients in Follow-up for PFS

1.00

0.75

0.50

0.25

0.00Pro

gres

sion

-fre

e su

rviv

al p

roba

bili

ty

0 2.5 5.0 7.5 10.0 12.5 15.0 17.5

Progression-free survival (months)

PFS probability at 6 months: 72% (95% CI: 61, 83%) 

Median follow-up for PFS: 6.4 months (25–75% percentile: 3.5–10 months) 95% Hall–Wellner confidence bands

Treatment-related Grade 3/4 Adverse Events in ALK-positive NSCLC

Adverse eventGrade 3

n (%)Grade 4

n (%)

Any adverse event 10 (12) 1 (1)

ALT elevation* 4 (5) 1 (1)

AST elevation 5 (6) 0

Lymphopenia 2 (2) 0

Hypophosphatemia 1 (1) 0

Neutropenia 1 (1) 0

Hypoxia 1 (1) 0

Dyspnea 1 (1) 0

Pulmonary embolism 1 (1) 0

*Based on laboratory data (n=71), ALT increase to grade 1, 52%; to grade 2, 4% (In preclinical toxicology studies, no histologic changes in the liver were observed) 1 patient discontinued for ALT elevation

A-NSCLC Clinical Practice 1st-Line Options Options in 2010

SQUAMOUSSQUAMOUS& NOS PTS& NOS PTS

NON SQUAMOUSNON SQUAMOUSLC PTSLC PTS

P-based CT (**)+ Bevacizumab in selected patients(**) Cb+Pac > Cis+Gem

P-based Doublets:Cis+GemcitabineCis+Docetaxel

better than Cis+Vin or Cb+Pac

EGFR Mut+EGFR Mut+PTSPTS

P-based Doublets:

Cis+Pemetrexed better than Cis+ Gemcitabine

P-based CT+Cetuximab (*)(*) According to registration for EGFR status and CT

Gefitinib

P-based CT+Cetuximab(*)

Courtesy Dr De Marinis

Progressi nel

2010?

We will need strategies…

GREAT (Group REsearch And Trials)MD Oncologists: Azzurra Onofri Data Managers: Alessandra

Lucarelli Chiara Pierantoni

Michela BurattiniResearch Nurse: Fabiana Marcucci Chest Surgeons: Armando

SabbatiniPathologist: Alfredo Santinelli Alessandro BrunelliPharmacists: Celestino Bufarini Radiologist: Gianluca Valeri

Andrea Marinozzi