Aprile
2011
New targets in NSCLC
Piano Generale di Emergenza
Presidio Ospedaliero di Livorno
Viale Alfieri 36 Federico Cappuzzo
Istituto Toscano Tumori
Ospedale Civile
Livorno-Italy
D.Lgs del 9 aprile 2008 n. 81 – Titolo I – Sezione VI
Gestione delle emergenze
Istituto Toscano Tumori –Livorno, Italy
Molecular events in lung cancer
Adenocarcinoma
Squamous-cell carcinoma
EGFR resistance mutations
0.8%
HER2
0.9%
EGFR
9.5%
Unknown
53.8%
KRAS
27%
ALK
3.7%
Barlesi F, ASCO 2013
BRAF
1.7%
PI3K
2.6%
Paik PK et al, ASCO 2012
Istituto Toscano Tumori – Livorno, Italy
ROS1 Translocations in NSCLC
Patients with ROS1 rearrangements share many features in common with ALKpositive patients (adenocarcinoma histology, younger age at diagnosis,
never or light smokers)
Mutually exclusive with EGFR, HER2, KRAS, BRAF mutations and with ALK or
translocation
Prognostic role is not defined
SDC4 exon 2
SDC4 exon 2
ROS1 exon 32
ROS1 exon 34
Istituto Toscano Tumori – Livorno, Italy
ROS1 fusion partners in NSCLC
Stumpfova and Janne PA, CCR 2013
Istituto Toscano Tumori – Livorno, Italy
Crizotinib: selective inhibitor of ALK, MET and ROS
Upstate 102
kinase panel
Kinase
Met(h)
Tie2(h)
TrkA(h)
ALK(h)
TrkB(h)
Abl(T315I)(h)
Yes(h)
Lck(h)
Rse(h) [SKY]
Axl(h)
Fes(h)
Lyn(h)
Arg(m)
Ros(h)
CDK2/cyclinE(h)
Fms(h)
EphB4(h)
Bmx(h)
EphB2(h)
Fgr(h)
Fyn(h)
IR(h)
CDK7/cyclinH/MAT1(h)
cSRC(h)
IGF-1R(h)
Aurora-A(h)
Syk(h)
FGFR3(h)
PKCµ(h)
BTK(h)
CDK1/cyclinB(h)
p70S6K(h)
PRK2(h)
PAR-1Bα(h)
PKBß(h)
Ret(h)
GSK3ß(h)
Flt3(h)
MAPK1(h)
ZAP-70(h)
Abl(h)
c-RAF(h)
PKD2(h)
ROCK-II(h)
Rsk3(h)
GSK3α(h)
CDK5/p35(h)
PDGFRα(h)
Rsk1(h)
SGK(h)
CHK1(h)
ErbB4(h)
Rsk2(h)
JNK1α1(h)
PKBα(h)
Blk(m)
CDK3/cyclinE(h)
PKCι(h)
PKCθ(h)
CDK2/cyclinA(h)
PAK2(h)
PKCßI(h)
Pim-1(h)
PKCη(h)
SAPK4(h)
CaMKII(r)
MKK7ß(h)
CaMKIV(h)
CHK2(h)
CK2(h)
JNK2α2(h)
MKK6(h)
CK1δ(h)
PKCα(h)
MAPK2(h)
MEK1(h)
PKCδ(h)
PKCε(h)
Plk3(h)
PKCßII(h)
MSK1(h)
PDGFRß(h)
PKCζ(h)
SAPK3(h)
MAPKAP-K2(h)
PKA(h)
AMPK(r)
CDK6/cyclinD3(h)
CSK(h)
SAPK2a(h)
JNK3(h)
PKBγ(h)
IKKα(h)
NEK2(h)
% Inhibition
94
103
102
100
100
98
96
95
94
93
93
93
91
90
87
84
80
79
77
73
68
64
58
58
56
54
52
50
50
35
25
24
22
21
21
21
18
17
17
17
16
16
15
14
14
11
10
10
7
6
5
5
5
4
4
3
3
3
3
2
2
2
1
1
1
0
0
-1
-1
-1
-1
-1
-2
-2
-3
-3
-3
-3
-3
-5
-6
-6
-6
-6
-7
-7
-9
-9
-9
-9
-10
-10
-11
-11
Cellular selectivity on
10 of 13 relevant hits
Kinase
13 ‘hits’
<100X
selective
for Met
*Measured using ELISA capture method
IC50 (nM) Selectivity
mean*
ratio
Met
8
–
ALK
40–60
5–8X
ROS
55
7X
RON
80
10X
294
34X
322
37X
Tie2
448
52X
Abl
1,159
166X
IRK
2,887
334X
Lck
2,741
283X
Sky
>10,000
>1000X
VEGFR2
>10,000
>1000X
PDGFRβ
>10,000
>1000X
Axl
High probability of
ALK, MET
and ROS inhibition at
clinically
relevant doses
Bang Y, et al. ASCO 2010
Istituto Toscano Tumori – Livorno, Italy
Activity of crizotinib in ROS1+ NSCLC
ORR 72%; DCR 90%
Shaw AT, et al. NEJM 2014
Istituto Toscano Tumori – Livorno, Italy
Median DOR of Crizotinib in ROS1+ NSCLC
Median DOR 17.6 mos (95%CI,14.5 – NR)
Shaw AT, et al. NEJM 2014
Istituto Toscano Tumori – Livorno, Italy
Crizotinib in ROS1+ NSCLC: PFS
Median PFS: 19.2 months
Shaw A et al, NEJM 2014
Istituto Toscano Tumori – Livorno, Italy
Acquired resistance to crizotinib in ROS1 NSCLC
Awad MM, et al. NEJM 2013
Istituto Toscano Tumori – Livorno, Italy
Second generation ROS1 inhibitors
Istituto Toscano Tumori – Livorno, Italy
Crizotinib in MET amplified or ROS1 translocated
NSCLC: The METROS trial
Istituto Toscano Tumori – Livorno, Italy
Clinical characteristics of MET amplified NSCLC
Characteristic
N
%
Total amplified (ratio ≥2.2)
16
100
Squamous
5
31.2
Non-squamous
11
68.8
Never smokers
0
0
Current/former
15
93.7
Smoking unknown
1
6.3
Cappuzzo F et al., J Clin Oncol 2009
Istituto Toscano Tumori – Livorno, Italy
1,0
1,0
,8
,8
≥4 - <5 copies/cell
,6
<2 copies/cell
≥3 - <4 copies/cell
,4
≥2 - <3 copies/cell
≥6 copies/cell
≥5 - <6 copies/cell
,2
CUMULATIVE SURVIVAL
CUMULATIVE SURVIVAL
Survival of Resected NSCLC According to MET Copy
Number
p=0.0045
,6
MET <5 copies/cell(N=383)
,4
MET ≥5 copies/cell (N=48)
,2
0,0
Median survival:
MET FISH-:47.5 months
MET FISH+: 25.8 months
0,0
0
20
40
60
MONTHS
80
100
0
20
40
60
80
100
120
MONTHS
Cappuzzo et al., JCO 2009
Istituto Toscano Tumori – Livorno, Italy
High levels of MET amplification drive
resistance to EGFR-TKIs
Gefitinib Resistant
MET amplification in HCC827 GR6
Ratio MET/centromere >5
Gefitinib Sensitive
NO MET amplification in HCC827
Ratio MET/centromere <2
Modified from Cappuzzo F, et al. Ann Oncol 2008
Istituto Toscano Tumori – Livorno, Italy
Sensitivity to anti-Met agents only in presence
of high levels of MET amplification
Smolen GA et al., PNAS 2006, Tanizaki J et al., JTO 2011
Garcia L, University of Colorado, personal communication
Istituto Toscano Tumori – Livorno, Italy
Tumor Shrinkage Seen in Intermediate
and High MET Cohorts
Best percent change from baseline in target tumor lesionsa by patient
% Change From Baseline
Low MET
n=2
Intermediate MET
n=6
High MET
n=6
100
100
100
80
80
80
60
60
60
40
40
40
20
20
20
0
0
0
–20
–20
–20
–40
–40
–60
–60
–80
–80
–80
–100
–100
–100
c
–40
c
Disease progression
Stable disease
Partial responseb
Complete responseb
Threshold
for partial
response
–60
aConfirmed objective
responses.
investigator assessment.
cTwo patients in the intermediate MET group had an unconfirmed PR that was not confirmed in a second assessment.
bBased on
Garcia L, University of Colorado, personal communication
Istituto Toscano Tumori – Livorno, Italy
RET rearrangements in lung adenocarcinoma
•
•
•
11,294,741-bp
pericentric
inversion on chromosome 10
generating a new gene fusion
joining exons 1-15 of KIF5B to
exons 12-20 of RET
Mutually exclusive with EGFR,
HER2, KRAS, BRAF mutations
and with ALK or ROS1
translocation
Exclusively
identified
in
moderately
to
poorly
differentiated adenocarcinomas
with
solid
predominant
subtype, younger age never or
light smokers and with a
particular pattern of metastatic
spread (lymph nodes)
Istituto Toscano Tumori – Livorno, Italy
RET translocation and sensitivity to anti-RET drugs
Lipson et al. Nature Med. 2012
Istituto Toscano Tumori – Livorno, Italy
RET FISH+ve NSCLC succesfully treated with
vandetanib
• 58 y-o man, past smoker (5 pck/yr)
• ADC, stage IV for supraclavicular,
mediastinal, retroperitoneal and
inguinal nodes abdominal,
• Pre-treated with standard
carboplatin-pemetrexed for 2 cycles
with evidence of progression
• Second-line* Vandetanib 300 mg
daily
* Patient unsuitable for standard chemotherapy
due to recent myocardial infarction
Gautschi O, J Thor Oncol 2013
Istituto Toscano Tumori – Livorno, Italy
Activity of cabozantinib in RET + NSCLC
Drilon et al, Cancer Discov 2013
Istituto Toscano Tumori – Livorno, Italy
HER2 dysregulation in lung cancer
Overexpression
<10%
Amplification
<10%
Mutation
<3%
Istituto Toscano Tumori – Livorno, Italy
HER2 amplification is not prognostic in
resected NSCLC
Cappuzzo et al., JTO 2012
Istituto Toscano Tumori – Livorno, Italy
High levels of HER2 amplification are
responsible for acquired resistance to EGFRTKIs in absence of T790M
Takezawa et al., Cancer Discovery 2012
Istituto Toscano Tumori – Livorno, Italy
High levels of HER2 amplification are responsible
for acquired resistance to cetuximab in colorectal
cancer
Yonesaka et al Science Transl Med 2011
Istituto Toscano Tumori – Livorno, Italy
HER2 mutation
exon19
exon20
exon21
YVMA776-779ins GSP781-783ins
E A Y V M A G V G S P Y V S R L
770
I A K
785
831
G776V,Cins
Istituto Toscano Tumori – Livorno, Italy
HER2 Mutations in NSCLC
Reference
N
Race
%
Never Smoker
(%)
Female (%)
Sasaki
95
Japan
1.0
2.7
3.3
Marchetti
403
Caucasian
2.2
3.1
4.1
Shigematsu
671
All
1.6
3.2
3.6
Stephens
120
Caucasian
4.0
-
-
Arcila
560
All
5.0*
5.0
2.0
* In EGFR and KRAS wild-type population
Istituto Toscano Tumori – Livorno, Italy
Trastuzumab efficacy in pretreatred NSCLC
patients harboring HER2 mutation
Patient #
Therapy
Best Response
1
Vinorelbine-trastuzumab
Partial response
2
Carboplatin-paclitaxel-trastuzumab
Stable disease
3
Docetaxel-masatinib
Progression
4
Vinorelbine-trastuzumab
Partial response
5
Carboplatin-paclitaxel-trastuzumab
Partial response
6
Vinorelbine-trastuzumab
Partial response
7
Vinorelbine-trastuzumab
Stable disease
8
Lapatinib
Progression
9
Vinorelbine-trastuzumab
Partial response
10
Lapatinib
Progression
11
Vinorelbine-trastuzumab
Progression
12
Docetaxel-trastuzumab
Partial response
13
Vinorelbine-trastuzumab
Partial response
14
Vinorelbine-trastuzumab
Partial response
15
Vinorelbine-trastuzumab
Stable disease
16
Trastuzumab
RR: 56.2%
Partial response
Modified from Mazieres et al. ESMO 2012
Istituto Toscano Tumori – Livorno, Italy
BRAF mutations in NSCLC
• Detectable in up to 5% of lung adenocarcinomas
using high sensitive methods
• V600E is the most frequent mutation (up to 60% of
all BRAF mutations)
• V600E more frequent in female and in
micropapillary features
• Non-V600E mutations associate with smoking
exposure with no prognostic effect
Marchetti et al, JCO 2011
Istituto Toscano Tumori – Livorno, Italy
Dabrafenib inhibits BRAF V600E Kinase
Mode of Action
• Reversible, small molecule
BRAF inhibitor
• ATP competitive
RTKs
Dabrafenib
P P
SOS
P P
Grb2
SHC
P P
RAS
BRAF
V600
PI3K/AKT/mTOR
pathway
BRAF
Molecular Activity:
• BRAF V600E: IC50 0.65 nM
• BRAF WT: IC50 3.2 nM
CRAF
MEK
ERK1/2
Selectivity:
• IC50 of 10-100 nM against 8 of
282 human kinases
p90RSK
MSK1
Proliferation, Growth, Survival
Data not registered for darafenib
Davies H, et al. Nature. 2002;417:949-954; Platz A, et al. Mol Oncol. 2008;1:395405; Karasarides M, et al. Oncogene. 2004;23:6292-6298; Curtin JA, et al. N Engl J
Med. 2005;353:2135-2147; Flaherty K, et al. J Clin Oncol. 2009;27 [abstract 9000];
Kefford R, et al. J Clin Oncol. 2010;28 [abstract 8503].
Istituto Toscano Tumori – Livorno, Italy
Maximum Percent Reduction at Time of Best Disease Assessment
Dabrafenib in V600E BRAF mutated NSCLC:
results of a phase II study
50
40
***
30
20
10
0
***
***
−10
*
−20
** ** **
−30
−40
**
−50
−60
Best Confirmed Response
−70
Partial response
−80
Stable disease
−90
Progressive disease
Smoking History
* Smoker, ≤ 40 pack years
**
***Smoker, > 40 pack years
Nonsmoker
*
**
*
**
*
**
**
*
−100
Planchard et al. ASCO 2013
Istituto Toscano Tumori – Livorno, Italy
Dabrafenib in BRAF mutated NSCLC: 2014 update
• BRAF V600E mutations 1.5% of NSCLC, mutually exclusive to other driver
alterations
• Phase II dabrafenib in NSCLC p harboring V600E mut
o 78 previously treated p; median age 66 yrs, 50% female, 15% ECOG 2,
37% never-smoker
o 32% PR / 24% SD > 12 weeks / 29% PD / 14% NE
o Disease control rate: 51% independent review vs 56% investigator
o Median duration of response 11.8 mo
o PFS 5.5 mo
o Safety profile manageable
Planchard et alesmo 2014
Istituto Toscano Tumori – Livorno, Italy
Conclusions
• Crizotinib is an emerging effective treatment in ROS1+ or MET
amplified NSCLC
• MET amplification could be detected in NSCLC generally not
considered for biomarker assessment
• RET translocation is a rare event but already druggable with
available agents
• Strategies against HER2 mutations should be extensively
investigated
• Drugs available for metastatic melanoma could represent a new
option for BRAF mutated NSCLC
Istituto Toscano Tumori – Livorno, Italy