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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