1. TK Inhibitors in NSCLC Rossana Berardi
Clinica di Oncologia Medica Università Politecnica delle Marche Ospedali Riuniti di Ancona

2. Intracellular mTKI Targets
Vandetanib
AKT
PI3-K
Erlotinib
Lapatinib
Gefitinib
EGFR
Proliferation/Survival
ERK
MEK
Raf
Ras
Sunitinib
Sorafenib
Motesanib
VEGFR
MAPK
MAPK
Src
Axitinib
Angiogenesis
Dasatinib
Ras
Raf
MEK
ERK
STAT
JAK
Abl
Nilotinib
Imatinib
PDGFR
PI3-K
AKT
Transcription
Metastasis
Tumor Cell
Endothelial Cell

3. IL TUMORE DEL POLMONE del Sig. Rossi
Obiettivo
CURARE
IL TUMORE DEL POLMONE del Sig. Rossi
CURARE
IL TUMORE DEL POLMONE
Si va verso una
TERAPIA SU MISURA
FR Hirsch JTO 2008;3:
Ohe Y, Clin Cancer Res Jul 1;14(13): .

4. The Epidermal Growth Factor Pathway
Ciardiello F, et al. EGFR Antagonists in Cancer Treatment. N Engl J Med. 2008:358:

5. 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 5

6. indicazione include la prima linea di trattamento
Approvazione EMEA 24 giugno 2009
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 6

7. 1st/2nd/3rd-Line NSCLC TREATMENT EGFR TKIs Clinical Development Route
GEFITINIB
Phase I
IDEAL I & II
BR.21
ISEL
INTACT 1&2
TALENT&TRIBUTE
INVITE
INTEREST
IPASS
TRUST
Phase II
ERLOTINIB 7

8. BR.21 STUDY DESIGN ERLOTINIB* 150 mg daily Placebo “150 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)
ERLOTINIB* 150 mg daily R A N D
OM I S E
* 2:1 randomisation
Placebo “150 mg” daily
F Shepherd et al, N Eng J Med 2005 8

9. Shepherd FA, et al. N Engl J Med 2005
SECONDA
LINEA
Sopravvivenza (%)
1.00
0.75
0.50
0.25
Tarceva
Placebo
Tempo (mesi)
Erlotinib prolunga significativamente la sopravvivenza nei pazienti con NSCLC avanzato
Un discorso a parte merita Erlotinib che, nell'unico studio pubblicato, è stato confrontato a placebo in pazienti anche pesantemente pretrattatti. L' end point primario era la sopravvivenza globale e quelli secondari la risposta globale, la sopravvivenza libera da progressione, la durata della risposta, la tossicità e la qualità di vita. Rispetto al placebo l'inibitore della tirosin kinasi è certamente più efficace con una mediana di sopravvivenza di 6.7 verso 4,7 mesi, un tasso di risposta del 8.9% con durata di 7.9 mesi, una sopravvivenza libera da progressione di 2.2 mesi verso 1,8 con HR di 0.61, ed infine con un significativo miglioramento della qualità di vita per tosse, dispnea e dolore. I vantaggi, pur presenti, sono abbastanza modesti c'è da dire però che, a parte la tossicità cutanea e la diarrea, il trattamento è certamente ben tollerato
Studio registrativo. Br21 Il farmaco, infatti, è stato registrato per il trattamento di seconda linea del NSCLC. Da ricordare riduzione dei sintomi.
Autore
Terapia N
RR (%)
PFS
Mediana
OS (m)
1-aa
OS (%)
Shepherd
Tarceva
Placebo
427
211
8.9
<1
2.2
1.8
6.7
4.7
31%
22%
Shepherd FA, et al. N Engl J Med 2005

10. TRUST PHASE IV STUDY TaRceva LUng Cancer Survival Treatment
N>7000 in 31 paesi del mondo (531 centri) 10

11. TRUST vs BR.21: an indirect comparison
Progression Free Survival in UE Subpopulation
1.00
0.75
0.50
0.25
BR.211
Median PFS: erlotinib 2.2 mo vs placebo 1.8 mo (p<0.001)
TRUST2
Median PFS: 3.2 mo
Survival distribution function
Erlotinib (TRUST), n=6,580
Erlotinib (BR.21), n=488
Placebo (BR.21), n=243
Although a simple comparison is difficult, the median PFS in TRUST was somewhat longer than that reported for the erlotinib treatment arm in BR21.
NOTE: this slide contains a PowerPoint animation. Please view in slideshow mode.
PFS (months)
1Shepherd FA, et al. N Engl J Med M Reck et al, ESMO 2008

12. TRUST vs BR.21: an indirect comparison
Overall Survival in UE Subpopulation
1.00
0.75
0.50
0.25
BR.211
Median OS: erlotinib 6.7 mo vs placebo 4.7 mo (p<0.001)
TRUST 2
Median OS: 7.9 months (28% censored)
Survival distribution function
Erlotinib (TRUST), n=6,580
Erlotinib (BR.21), n=488
Placebo (BR.21), n=243
Survival time (months)
1Shepherd FA, et al. N Engl J Med 2005
2 M Reck et al, ESMO 2008

14. NEW OPTIONS IN A-NSCLC Prolongation of Disease Control
It is exactly for these results that it is possible suppose a role for these new biological agents with a sequential use after the induction with active citotoxic drugs for a maintenance of response as a single agent as Roy Herbst has presented during last ASCO meeeting with this slide.
RS Herbst et al, ASCO 2003

15. SATURN TRIAL DESIGN
F Cappuzzo et al, P ESMO 2009

16. SATURN: PFS (all patients)
PRIMARY END-POINT
F Cappuzzo et al, P ESMO 2009

17. SATURN: OS* (all patients, ITT)
1.0
0.8
0.6
0.4
0.2
HR=0.81 (0.70–0.95)
Log-rank p=0.0088
OS probability
Erlotinib (n=438)
Placebo (n=451)
11.0
12.0
Time (months)
*OS is measured from time of randomisation into the maintenance phase; ITT = intent-to-treat population
F Cappuzzo et al, P ESMO 2009

18. Subgroup analysis of PFS
HR (95% CI) n
0.71 (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
All
Male
Female
Caucasian
Asian
Adenocarcinoma
Squamous-cell
Never smoker
Former smoker
Current smoker
escopfsba_t_2000
escopfsdm_t_2000 for bac and non-bac
Escopfss2_t_2000 for smoking status
Bac and non-bac are subgroup of adeno. Order needs to be:
Adeno
bac
non-bac
Squamous
other
Check for other races – not available
BAC vs Other = escopfsaba_t_2000
SCC/ADK/others = escopfsdm_t_2000
Non-SCC vs others = see mail
Race = escopfs2_t_2000
Smoke/Gender = ettpfsgr01_t_2000
Rash = ettpfsgr25_t_2000
0.4
0.6
0.8
1.0
1.2
Favours erlotinib HR
Favours placebo

19. SATURN: PFS based on histology Squamous-cell carcinoma
Adenocarcinoma
Squamous-cell carcinoma
PFS probability
PFS probability
1.0
0.8
0.6
0.4
0.2
1.0
0.8
0.6
0.4
0.2
HR=0.60 (0.48–0.75)
HR=0.76 (0.60–0.95)
Log-rank p<0.0001
Log-rank p=0.0148
Erlotinib (n=204)
Placebo (n=197)
Erlotinib (n=166)
Placebo (n=193)
Time (weeks)
Time (weeks)

20. Zd1839-Iressa in refractary lung cancer
IDEAL 1 (Europe) - GEM/CDDP
RR Median OS
250 mg 18. 4% 7.6 mo R
500 mg 19.0% 8.1 mo
IDEAL 2 (US) - Carbo/Taxol
250 mg 11.8% 6.1 mo
500 mg 8.8% 6.0 mo

21. INTACT Trials GEM/CDDP + Iressa GEM/CDDP + Placebo
CarboCDDP/Paclitaxel + Iressa
CarboCDDP/Paclitaxel + Placebo
1200 patients
No differences (October 2002)

23. IPASS Study Design Up to six 3-wk cycles Gefitinib 250 mg/day PO
Previously untreated NSCLC patients
(N = 1217)
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:

24. Baseline Characteristics
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
93.8
6.1
93.6
6.2
WHO PS, % 1 2
25.8
64.2
10.0
26.5
62.8
10.7
Disease stage at entry, %
IIIB IV
Unknown
24.6
75.4
23.7
76.2
0.2
Mok TS, et al. N Engl J Med. 2009;361:

25. Objective response rate 43% vs 32% p=0.0001
IPASS: PFS e ORR
Probability of PFS
1.0
Carboplatin /
paclitaxel
Gefitinib N
Events
609
453 (74.4%)
608
497 (81.7%)
0.8
HR (95% CI) = (0.651, 0.845) p<0.0001
0.6
Median PFS (months) 4 months progression-free 6 months progression-free 12 months progression-free
5.7 61% 48% 25%
5.8 74% 48% 7%
0.4
Primary objective exceeded: Gefitinib demonstrated superiority relative to carboplatin / paclitaxel in terms of PFS
0.2
However, the hazard ratio was not constant over time, as can be seen from the crossing Kaplan Meier curves and the pattern of the 4, 6 and 12 month progression-free rates, favouring carboplatin/paclitaxel for the first 6 months and gefitinib for the remaining 16 months.
Because of this crossing of the curves, the median progression-free survival is similar on both treatments, 5.7 months for gefitinib and 5.8 months for carboplatin/paclitaxel. Therefore the medians are clearly not a good reflection of the treatment effect in this study.
It is important to note that the hazard ratio, confidence interval and p-value are still valid when interpreted as a representation of the entire study period, i.e. an average. Also, supportive secondary analyses including a log rank test (which does not require curves to be proportional i.e. not crossing) were consistent with the primary analysis.
The crossing of the curves is thought to be driven by differences in progression-free survival outcomes for patients with EGFR mutation positive and negative tumours. This will be explained later in the presentation.
Reference:
Mok et al. ESMO Abstract LBA2.
0.0 4 8 12 16 20 24
Months
At risk :
Gefitinib
609
363
212 76 24 5
Carboplatin / paclitaxel
608
412
118 22 3 1
Objective response rate 43% vs 32% p=0.0001 25 25

26. EGFR mutations: the strongest predictor of response

27. MUTAZIONI DI EGFR
85% circa
di queste mutazioni
delezioni multinucleotidiche
“in-frame” (ESONE 19)
Mutazioni più frequenti: delezione esone 19 o sostituzione L858R dell’esone 21
mutazioni puntiformi (ESONE 21)

28. Stratification of NSCLC according to activating mutations
PFS: 14 mo with erlotinib in pts with EGFR mutations
Sharma, Haber & Settleman. Nat Rev Cancer 2010

29. BR.21 study: EGFR mutation status predicts response…
Response rate (%)
p value
EGFR Mutation status1
Wild-type*
106 8
0.05
Mutant† 10 30
EGFR protein expression (IHC)2
Negative 80 4 NS
Positive 11
EGFR gene copy number (FISH)2
Negative3 41 2
0.03
Positive3 25 20
…but not survival
MS Tsao et al, N Engl J Med 2005

30. IPASS Baseline Characteristics: EGFR Status
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*
21.7
10.8
10.5
0.8
0.5
21.2
12.2
7.7
1.0
1.2
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:

31. 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: ; P < .001)
In EGFR mutation–negative subgroup, significantly shorter PFS with gefitinib (HR: 2.85; 95% CI: ; P < .001)
EGFR Mutation Positive
EGFR Mutation Negative
1.0
Events Gefitinib: 97 (73.5%) Pac/carbo: 111 (86.0%)
1.0
Events Gefitinib: 88 (96.7%) Pac/carbo: 70 (82.4%)
0.8
0.8
0.6
HR: (95% CI: ; P < .001)
0.6
Probability of PFS
Probability of PFS
HR: (95% CI: ; P < .001)
0.4
0.4
Paclitaxel/ carboplatin
Gefitinib
Paclitaxel/ carboplatin
0.2
0.2
Gefitinib 4 8 12 16 20 24 4 8 12 16 20 24
Mos Since Randomization
Mos Since Randomization
Mok TS, et al. N Engl J Med. 2009;361: Reproduced with permission. Copyright © 2009 Massachusetts Medical Society. All rights reserved.

32. 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
EGFR wild type
1.1
23.5
.001
Mok TS, et al. N Engl J Med. 2009;361:

33. IPASS: diversa Risposta Tumorale nei pz EGFR M+ ed EGFR M-
Odds ratio >1 implica una maggior probabilità di risposta con gefitinib
Gefitinib
Carboplatino/ paclitaxel
EGFR M+ odds ratio (IC 95%) = 2.75 ( ), p<0.0001
EGFR M- odds ratio (IC 95%) = 0.04 (0.01 to 0.27), p=0.0001
71,2%
Risposta
tumorale
(%)
47,31%
23,5%
1,1%
(n=132)
(n=129)
(n=91)
(n=85)
Mok T NEJM 2009 33 33

34. IPASS: Superior quality of life and symptom improvement rates for gefitinib in EGFR mutation positive patients
p<0.0001
p<0.0001
p=0.0003
% patients with sustained clinically relevant improvement
Quality of life was assessed using the FACT-L total score and the FACT-L Trial Outcome Index. Symptoms were assessed using the FACT-L Lung Cancer Subscale (LCS).
Clinically relevant improvement was pre-defined as a 6-point improvement for FACT-L and TOI; 2-point improvement for LCS, maintained for at least 21 days.
This graph shows statistically significant increased outcomes for gefitinib compared with carboplatin/paclitaxel doublet chemotherapy in clinically relevant and validated measures of QoL and symptom improvement: Lung Cancer Subscale, Trial Outcome Index and Total FACT-L.
In summary, the data presented demonstrate that patients should be assessed for a tumour biomarker to clearly identify those patients that will have a better outcome with gefitinib compared with carboplatin/paclitaxel.
Reference:
Mok et al. ESMO Abstract LBA2.
p-values from logistic regression with covariates. Post-hoc analysis, EFQ population Clinically relevant improvement pre-defined as 6-point improvement for FACT-L and TOI; 2-point improvement for LCS, maintained for at least 21 days.
EFQ, evaluable for quality of life; FACT-L, Functional Assessment of Cancer Therapy-Lung; TOI, Trial Outcome Index; LCS, Lung Cancer Subscale 34 34

37. ESMO 2010
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

38. OPTIMAL study design R 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) R
1:1
Gemcitabine (1,000 mg/m2 d1,8) Carboplatin (AUC5 d1)
q3w, up to 4 cycles
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
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 38 38

39. OPTIMAL PFS: primary analysis (ITT)
1.0
0.8
0.6
0.4
0.2
Erlotinib (n=82)
Gem/carbo (n=72)
HR=0.16 (0.10–0.26)
Log-rank p<0.0001
PFS probability
Time (months)
Patients at risk
Erlotinib
Gem/carbo

40. OPTIMAL PFS: updated analysis (ITT)
1.0
0.8
0.6
0.4
0.2
Erlotinib (n=82)
Gem/carbo (n=72)
HR=0.16 (0.10–0.26)
Log-rank p<0.0001
PFS probability
4.6
13.1
Time (months)
Patients at risk
Erlotinib
Gem/carbo

41. Subgroup analysis of PFS
Overall
Stage IV
Stage IIIB
Female
Male
Age ≥65
Age <65
PS 0–1
PS 2
Never smoker
Current/former smoker
Adenocarcinoma
Non-adenocarcinoma
0.16 (0.10–0.26) 154
0.18 (0.11–0.28) 138
0.27 (0.06–1.16) 16
0.13 (0.07–0.24) 91
0.26 (0.14–0.50) 63
0.17 (0.07–0.43) 38
0.19 (0.11–0.31) 116
0.16 (0.10–0.26) 144
0.21 (0.04–1.28) 10
0.14 (0.08–0.25) 109
0.21 (0.09–0.49) 45
0.17 (0.11–0.28) 134
0.22 (0.06–0.73) 20
HR (95% Cl) n HR
Favours erlotinib
Favours gem/carbo

42. DCR = disease control rate (CR + PR + SD)
Best tumour response*
Erlotinib
[n=82]
n (%)
Gem/carbo
[n=72] CR
2 (2)
0 (0) PR
66 (81)
26 (36)
ORR
68 (83)
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)

43. K-RAS mutations?

44. Mutazioni k-RAS: fattore prognostico negativo e fattore predittivo di resistenza primaria ai TKI

45. Resistance to EGFR TK inhibitors

46. 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:
Amplificazione MET responsabile del 10-20% delle resistenze ai TKI per attivazione attraverso HER3 di PI3K e AKT (indipendente da EGFR)

47. ARQ-197=oral c-met inhibitor
Dual EGFR-MET inhibition for overcoming MET-mediated resistance to EGFRinhibitors
ARQ-197=oral c-met inhibitor

50. Tumor cell proliferation
ALK Pathway Or
Inversion
Translocation
ALK
ALK fusion protein*
Cell survival
PI3K
BAD
AKT
STAT3/5
mTOR
S6K
RAS
MEK
ErK
PLC-Y
PIP2
IP3
Tumor cell proliferation
*Subcellular localization of the ALK fusion gene, while likely to occur in the cytoplasm, is not confirmed.1,2
1. Inamura K et al. J Thorac Oncol 2008;3:13– Soda M et al. Proc Natl Acad Sci U S A 2008;105:19893–19897 Figure 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. 50

52. Clinical Activity of the Oral ALK Inhibitor, Crizotinib (PF ), 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 3
ASCO Annual Meeting 2010

53. Patients with ALK-positive NSCLC Do not Appear to Respond to EGFR TKIs
Platinum-based chemotherapy
EGFR TKI
TTP for EGFR TKI1
TTP for chemotherapy1
Months 12 24 36 48 60
100 80 40 20
EML4–ALK
EGFR
WT/WT %
*WT/WT = wild type: no ALK fusion or EGFR mutation
1Shaw AT et al. J Clin Oncol 2009;27:4247–4253

54. Crizotinib Selectivity Profile
Upstate 102 kinase
Cellular selectivity on 10 of 13 relevant hits
Kinase
IC50 (nM)
mean*
Selectivity ratio
c-MET 8 –
ALK 20 2X
RON
298
34X
189
22X
Axl
294
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
PDGFR
Crizotinib (PF )
13 kinase “hits” <100X selective for c-MET
Crizotinib: inhibits ALK and c-met
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
*The cellular kinase activities were measured using ELISA capture method

55. Clinical and Demographic Features of Patients with ALK-positive NSCLC
Mean (range) age, years
51 (25–78)
Gender, male/female
43/39
Performance status,* n (%)
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
Histology, n (%)
Adenocarcinoma
79 (96)
Squamous
Other
2 (2)
Prior treatment regimens, n (%)
5 (6)
27 (33)
15 (18) ≥3
34 (41)
Not reported
*Performance status = Eastern Cooperative Oncology Group

56. Tumor Responses to Crizotinib for Patients with ALK-positive NSCLC60 40 20
–20
–40
–60
–80
–100
Progressive disease
Stable disease
Confirmed partial response
Confirmed complete response
Maximum change in tumor size (%)
–30% *
*Partial response patients with 100% change have non-target disease present

57. PFS probability at 6 months: 72%
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% 57

58. Median PFS has Not been Reached 70% of Patients in Follow-up for PFS
1.00
0.75
0.50
0.25
0.00
Progression-free survival probability
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

59. Treatment-related Grade 3/4 Adverse Events in ALK-positive NSCLC
Grade 3 n (%)
Grade 4
n (%)
Any adverse event
10 (12)
1 (1)
ALT elevation*
4 (5)
AST elevation
5 (6)
Lymphopenia
2 (2)
Hypophosphatemia
Neutropenia
Hypoxia
Dyspnea
Pulmonary embolism
*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

61. A-NSCLC Clinical Practice 1st-Line Options in 2010
EGFR Mut+
PTS
Gefitinib
P-based Doublets:
Cis+Gemcitabine
Cis+Docetaxel
better than
Cis+Vin or Cb+Pac
P-based CT+Cetuximab(*)
SQUAMOUS
& NOS PTS
P-based Doublets:
Cis+Pemetrexed
better than
Cis+ Gemcitabine
P-based CT (**)+
Bevacizumab
in selected patients
(**) Cb+Pac > Cis+Gem
NON SQUAMOUS
LC PTS
P-based CT+Cetuximab (*)
(*) According to registration for
EGFR status and CT
Courtesy Dr De Marinis 61

62. Progressi nel 2010?

63. We will need strategies…

64. GREAT (Group REsearch And Trials)
MD Oncologists: Azzurra Onofri Data Managers: Alessandra Lucarelli
Chiara Pierantoni Michela Burattini
Research Nurse: Fabiana Marcucci Chest Surgeons: Armando Sabbatini
Pathologist: Alfredo Santinelli Alessandro Brunelli
Pharmacists: Celestino Bufarini Radiologist: Gianluca Valeri
Andrea Marinozzi