Evolution of knowledge in NSCLC
Pao and Girard, Lancet Oncology 2011
Fattori da considerare nella
scelta terapeutica del NSCLC nel 2012








Stadio di malattia
PS
Età
Comorbidità
Compliance e desiderio del paziente
Istologia
g (squamoso
(q
vs nonnon-squamoso)
q
)
Mutazioni di EGFR
Riarrangiamento di ALK (EML(EML-4ALK)
EGFR gene mutations
Ex 19
Ex 21
Paez et al, Science 2004
EGFR gene mutations







Activating mutations with ligand independent receptor
activity
90% in exons 19 (deletion) and 21 (LB58R)
Global incidence: 10% caucasians
caucasians;; 3030-40% Asiatic pts
++ nevernever-smoker or light
light--smoker
More frequent in female sex
++ adenocarcinoma (in particular BAC non mucinous
mucinous))
Predictive factor of EGFREGFR-TKIs,, g
gefitinib and
erlotinib (in retrospective and prospective studies)
Tiseo et al, Drug Des Devel Ther 2011
IPASS: Study design
Endpoints
Patients
• Chemonaïve
• Age
≥18 years
• Adenocarcinoma
Primary
Gefitinib
(250 mg / day)
histology
• Never
or light exsmokers*
• Life
expectancy
≥12 weeks
• PS
0-2
• Measurable
IV disease
stage IIIB /
1:1 randomisation
Carboplatin
(AUC 5 or 6) /
paclitaxel
(200 mg / m2)
3 weekly#
• Progression-free survival
(non-inferiority)
Secondary
• Objective response rate
• Overall survival
y of life
• Quality
• Disease-related symptoms
• Safety and tolerability
E l
Exploratory
t
• Biomarkers
• EGFR mutation
• EGFR-gene-copy number
protein expression
p
• EGFR p
•
Mok et al, NEJM 2009
Progression-free survival in EGFR
Progressionmutation positive and negative patients
EGFR mutation negative
Gefitinib (n=132)
Carboplatin / paclitaxel (n=129)
1.0
0.8
HR (95% CI) = 0.48 (0.36, 0.64)
p<0 0001
p<0.0001
0.6
No. events gefitinib, 97 (73.5%)
No. events C / P, 111 (86.0%)
0.4
0.2
0.0
0
At risk :
Gefitinib 132
C/P
129
4
8
12
16
20
24
Probability of progression-free
e survival
Probability of progression-free
e survival
EGFR mutation positive
Gefitinib (n=91)
Carboplatin / paclitaxel (n=85)
1.0
0.8
HR (95% CI) = 2.85 (2.05, 3.98)
p<0 0001
p<0.0001
0.6
No. events gefitinib , 88 (96.7%)
No. events C / P, 70 (82.4%)
0.4
0.2
0.0
0
4
8
Months
108
103
71
37
31
7
12
16
20
24
1
0
0
0
0
0
Months
11
2
3
1
0
0
91
85
21
58
4
14
2
1
Treatment by subgroup interaction test, p<0.0001
Mok et al, NEJM 2009
IPASS: Response Rates and
Quality of life
Mutation Positive
80
Gefitinib
Carboplatin/paclitaxel
71.2%
70
M+ HR: 2.75;
2 75; P=0.0001
P=0 0001
ORR
60
50
47.3%
M– HR: 0.04; P=0.0013
40
30
23 5%
23.5%
20
10
0
1.1%
N=132 N=129
Mutation Positive
N=91
N=85
Mutation Negative
Mok et al, NEJM 2009
Thongprasert et al, JTO 2011
Mutation Negative
Randomized studies of
EGFR TKIs
TKI vs CT in
i firstfirst
fi t-line
li therapy
th
Author
Study
N
(EGFR +)
RR, %
(TKI vs CT)
PFS, months
(HR, 95%CI)
OS, months
Mok et al,
2009
IPASS
CT vs Gefitinib
261
71.2 vs 47.3
9.5 vs 6.4
0.48 (0.36-0.64)
21.6 vs 21.9
Lee et al,
al
2009
First-SIGNAL
PG vs Gefitinib
42
84 6 vs 37
84.6
37.5
5
88.44 vs 66.7
7
0.61 (0.31-1.22)
30 6 vs 26
30.6
26.5
5
Mitsudomi et al, WJTOG 3405
2009
PD vs Gefitinib
172
62.1 vs 32.2
9.2 vs 6.3
0 49 (0.34
0.49
(0 34-00.71)
71)
36 vs 39
(ASCO 12)
Maemondo et
al, 2010
NEJGSG002
CT vs Gefitinib
230
74.5 vs 29
10.8 vs 5.4
0.32 (0.24-0.44)
27.7 vs 26.6
Zhou et al,
2011
OPTIMAL
CG vs Erlotinib
154
83 vs 36
13.7 vs 4.6
0.16 (0.10-0.26)
22.7 vs 28.6
(ASCO 12)
Rosell et al,
2012
EURTAC
P-bas vs Erlotinib
174
58.1 vs 14.9
9.7 vs 5.2
0.37 (0.25-0.44)
19.3 vs 19.5
Yang et al,
ASCO 2012
LUX-LUNG 8
PA vs Afatinib
345
56.1 vs 22.6
11.1 vs 6.9
0.58 (0.43-0.78)
NR vs NR
Meccanismi di resistenza
a EGFR
EGFR--TKIs
Sequist et al , Sci Transl Med. 2011
FISH Assay for ALK Rearrangement
p25.2
p25.2
p24.3
p24.1
p23.2
p22.3
p22.1
p16.3
ALK 29.3
Telomere
2p23 region
t(2;5) ALK gene
b
breakpoint
k i t region
i
p24.1
p23.2
p22.3
p22.1
EML4 42.3
Centromere
p24.3
p16.3
p16.1
p16.1
p14
p13.2
p14
p13.2
p12
p12
3’
5’
~250
250 kb
q12.1
q12.3
q12.1
q12.3
q14.1
q14.1
q14.3
q21.2
q14.3
q21.2
q22.1
q22.2
q23 2
q23.2
q22.1
q
q22.2
q23.2
23 2
q24.1
q24.1
q24.3
q24.3
q31.3
q31.3
q32.1
q32.1
q32.3
q32.3
q33.2
q
q33.2
q34
q34
q36.1
q36.3
q37.2
q36.1
q36.3
q37.2
~300
300 kb
Break-apart FISH assay
for ALK-fusion genes1
N
Non-split
lit signal
i
l
Split signal
ALK b
break-apart
ea apa t FISH
S assay
[Courtesy John Iafrate, Massachusetts General Hospital]
Assay is positive if rearrangements can be detected in ≥15% of cells
FISH = fluorescence in situ hybridization
Shaw AT et al. J Clin Oncol 2009
ALK rearrangements:
clinico--pathologic characteristics
clinico
 Global
incidence: ~ 5%; + EML4-ALK translocation
 Determination with FISH; ongoing studies with IHC
 ++ never-smoker or light-smoker; ++ young pts
 Similar incidence in Caucasians and Asiatic pts
 ++ adenocarcinoma with acinar o solid patterns (in
particular
ti l signet
i
t ring-type
i t
cells)
ll )
 In general mutually exclusive with EGFR and K-ras
mutations
 Factor of EGFR-TKI resistance; preliminary data of
g
response
p
to p
pemetrexed
higher
Tiseo et al, Expert Rev Anticancer Ther 2011
Tumor Responses to Crizotinib for
Patients with ALKALK-p
positive NSCLC
Maxim
mum chang
ge in tumorr size (%)
60
Progressive disease
Stable disease
40
Confirmed partial response
Confirmed complete response
20
0
–20
–30%
–40
–60
–80
–100
No. prior
ORR
regimens* % (n/N)
regimens
0
80 (4/5)
1
52 (14/27)
2
67 (10/15)
≥3
56 (19/34)
Objective
j
response
p
rate (ORR):
(
)
57% (95% CI: 46, 68%)
*Partial response patients with 100% change have non-target disease present
*
Bang Y et al, NEJM 2010
Responses to Crizotinib
Crizotinib::
update
p
PROFILE trial 1001 ((149 p
pts))
pts
133 pts with measurable disease
39 pts treated beyond PD
RR: 60.8%
DCR: 82.5% at week
8
70.6% at week
16
RR: similar regardless age, sex, PS, line
PFS: 9.7 months (7.7-12.8 months)
I line 18.3 months
II line or later 9.2 months
mOS: NR, 6-12 ms 87.9%-74.8%
Camidge et al, Lancet Oncol 2012
Crizotinib PROFILE Program
PROFILE 1007 (N=318)
 ALK‐positive by central laboratory
 1 prior chemotherapy
(platinum‐based)
R
A
N
D
O
M
I
S
E
Pemetrexed 500 mg/m2 or
docetaxel 75 mg/m2 (n=159)
infused on day 1 of a 21
21‐day
day cycle
Crossover on PD
PROFILE 1005 (N=400)
 ALK‐positive by central laboratory
 ≥1 p
prior chemotherapy
for
py and not eligible
g
1007
PROFILE 1014 (N=334)
(N 334)
 ALK‐positive locally advanced / metastatic non‐
squamous NSCLC
 No prior treatment for advanced disease
Crizotinib 250 mg b.i.d. (n=159)
[continuous]
Crizotinib 250 mg b.i.d. (N=400)
[continuous]
R
A
N
D
O
M
I
S
E
Crizotinib 250 mg b.i.d. (n=167)
[[continuous]]
Crossover on PD
Pemetrexed/cisplatin or
pemetrexed/carboplatin (n=167)
i f d on day
infused
d 1 off a 21‐day
21 d cycle
l
Clinicaltrials.gov
PROFILE 1007: PFS by independent
radiological review (ITT)
PROFILE 1007: ORR by independent
radiological
g
review (ITT)
(
)
Resistenza a Crizotinib
Doebele et al, Clin Cancer Res 2012
EGFR e ALK e relativi
inibitori a confronto
Variable
EGFR and TKI
ALK and TKI
notes
Pts characteristics
ADK, NS o Light-S
ADK, NS o Light-S
Ex 20 vs 35%, S 5%
Prognostic factor
Yes (good)
Y/N
RR and PFS
70% and 9-12 months
60% and 7-9 months
Resp and mutation type
> Del 19 than L858R
< atypical mut
Probably diff according to variants
Toxicity and outcome
Skin (60%), early
outcome correlation
Visual (60%), early (14 days)
?
Flare at stop (%)
Yes (23%)
Yes (?)
Res mechanisms
1st T790M and others
1st C1156Y, L1196M and others
T790M intratorax PD
Brain PD in Crizo
Overcome Res
Many strategies
Many strategies
Hsp90, Beyond PD and local
therapy
Resp to CT
> than EGFR wt
Resp to PEM > than ALK neg
From target to therapy
approved
20-30 years
4 years
Regardless line