ALK and Other Evolving Targets in
Advanced NSCLC
Mark A. Socinski, MD
Professor of Medicine and Thoracic Surgery
Director, Lung Cancer Section, Division of Hematology/Oncology
Clinical Associate Director, Lung SPORE
Co-Director, UPMC Lung Cancer Center of Excellence and Lung and
Thoracic Malignancies Program
University of Pittsburgh
The Targets
•
•
•
•
•
•
ALK
ROS1
BRAF
C-Met
RET
PI3KCA
ALK
ALK Rearrangement in Cancer
ALK-POSITIVE CANCERS:
Inversion
Or
Translocation
• NSCLC – EML4-ALK, KIF5B- ALK,
TFG-ALK (3-5%)
• Anaplastic large cell lymphoma
– NPM-ALK
• Inflammatory myo-fibroblastic
tumor – TPM3-ALK, TPM4-ALK
• Other solid tumors
Demographics of ALK Population
Shaw et
al.1
(n=19)
Rodig et
al. 2
(n=20)
Yoshida et
al. 3
(n=10)
Inamura et
al. 4
(n=11)
Zhang
et al. 5
(n=12)
Wong et
al. 6
(n=13)
Kwak et
al. 7
(n=82)
Age
(Median)
52 yrs
51 yrs
58 yrs
56 yrs
<61
yrs*
59 yrs
51 yrs
Gender
(% Male)
58
55
50
45
58
38.5
52
Never
smoker (%)
74
70
50
55
83
92.3
76
Histology
( % adeno)
84
Only
Only
adeno adeno
studied studied
Only
adeno
studied
83
84.6
96
56%
show
signet
ring
cells
55%
acinar
histology
Histology
(other
features)
1.Shaw AT et al, J Clin Oncol :27:4247-53, 2009
2.Rodig SJ et al, Clin Cancer Res;15:5216-23, 2009
3.Yoshida A et al, Lung Cancer:72:309-15, 2011
4.Inamura K et al, Mod Pathol:22:508-15, 2009
5.Zhang X et al, Mol Cancer:9:188, 2010
6. Wong DW et al, Cancer:115:1723-33, 2009
7. Kwak EL et al, N Engl J Med:363:1693-703, 2010
Diagnostic features of EML4-ALK–positive
NSCLC
Break-apart FISH
(split of red and green probes)
Shaw A T et al. JCO 2009;27:4247-4253
©2009 by American Society of Clinical Oncology
ALK IHC
H&E
(arrows denote signet ring cells)
Crizotinib: A Small Molecule Tyrosine Kinase
Inhibitor of c-MET, ALK and ROS1
Kinase
IC50 (nM)
mean*
Selectivity
ratio
c-MET
8
–
ALK
40-60
5-8X
ROS1
60
7X
RON
80
10X
294
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
Axl
Co-crystal structure of crizotinib
(PF-02341066) bound to c-MET
Cui et al. J Med Chem 54: 6342-63, 2011 and Pfizer data on file
Updated Phase I Results: Crizotinib in ALK+
NSCLC
Med PFS 9.7 mos
Est OS at - 6 mos – 87.9%
- 12 mos – 74.8%
ORR – 60.8%
Camidge DR et al Lancet Oncology 13:1011-19, 2012
Tumor Responses to Crizotinib for Patients with
ALK-positive NSCLC – Phase II (PROFILE 1005)
100
% Decrease or Increase From Baseline
BOR
80
PD
60
SD
PR
40
CR
20
0
–20
–40
–60
–80
*
–100
Response Evaluable population, N=123 (excludes patients with early death and indeterminate response).
CR = complete response; PD = progressive disease; PR = partial response; SD = stable disease.
*Per RECIST v1.1, percent change from baseline for subjects with best overall response of CR can be <100%
when lymph nodes are included as target lesions.
Crino ASCO 2011
Crizotinib in Patients With ALK-Positive NSCLC
PROFILE 1014
Treatment-naïve,
advanced
ALK-positive NSCLC;
Nonsquamous
N=334
Primary endpoint: PFS
PROFILE 1007
ALK-positive NSCLC;
Progressed on 1 prior
platinum-containing
chemotherapy
N=318
Primary endpoint: PFS
R
A
N
D
O
M
I
Z
E
R
A
N
D
O
M
I
Z
E
Crizotinib 250 mg bid
Pemetrexed 500 mg/m2 d1 +
investigator’s choice of
Cisplatin 75 mg/m2 d1 q3w
OR
Carboplatin AUC 5 or 6 d1 q3w
Crizotinib 250 mg bid
Pemetrexed 500 mg/m2 d1 q3w
OR
Docetaxel 75 mg/m2 d1 q3w
•
Crizotinib recently gained accelerated approval by the US Food and Drug Administration
concurrent with a companion break-apart FISH diagnostic
• Patients with an ALK mutation tend to have adenocarcinoma, are never- or light formersmokers, and are
resistant
to EGFR-TKI therapy
FISH=fluorescence
in situ
hybridization.
US National Institutes of Health website. http://clinicaltrials.gov/ct2/show/NCT01154140. Accessed
9/13/11; US National Institutes of Health website. http://clinicaltrials.gov/ct2/show/NCT00932893.
Accessed 9/13/11; Xalkori [package insert]. New York, NY: Pfizer Inc; 2011.
First and Second Generation ALK TKIs in
Clinical Development
Name
Company
Status
Comments
Crizotinib
Pfizer
1st and 2nd line registration
trials are ongoing. 2nd line
trial is >75% accrued
Accelerated approval granted
August 26, 2011
LDK378
Novartis
Phase 1 dose escalation
Activity observed at 400 mg.
Enrolling in the US and
Europe
AF802
Chugai
Phase 1/2 in Japan and
starting in US
Activity observed in
crizotinib-naïve pts
AP26113
Ariad
Phase 1 starting this fall
Some activity against EGFR
T790M. Enrolling in the US
ASP3026
Astellos
Phase 1
Similar to TAE684. Enrolling
in Japan
CEP-28122
Cephalon
Preclinical
NMS-E628
Nerviano
Preclinical
X276/396
Xcovery
Preclinical
[TITLE]
[TITLE]
Clinical Activity of Hsp90 Agents in
Advanced NSCLC
# pts
IPI-5041
AUY9222
Ganetespib3
76
120
99
ORR (%)
7
14
4
ORR/DCR (%) by genotype
EGFR mt
KRAS mt
ALK +
4/21
20/57
0/13
0/42
0/39
0/6
67/100
29/57
50/87
1. Sequist LV et al. J Clin Oncol 28:4953-4960, 2010
2. Garon EB et al. J Clin Oncol 30: ASCO 2012, abstr # 7543
3. Wong K et al. J Clin Oncol 29: ASCO 2011, abstr # 7500
ROS1
ROS Rearrangement in Cancer
ROS-POSITIVE CANCERS:
• NSCLC – SLC34A2-ROS, CD74-ROS
(1-2%)
Translocation
• Glioblastoma multiforme – FIGROS
• Cholangiocarcinoma– FIG-ROS
• Other solid tumors ?
ROS1 Encodes a Receptor Tyrosine Kinase
Brock TG, Receptors and Tyrosine Kinases
http://www.caymanchem.com/app/template/Article.vm/article/2187
Crizotinib: A Small Molecule Tyrosine Kinase
Inhibitor of c-MET, ALK and ROS1
Kinase
IC50 (nM)
mean*
Selectivity
ratio
c-MET
8
–
ALK
40-60
5-8X
ROS1
60
7X
RON
80
10X
294
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
Axl
Co-crystal structure of crizotinib
(PF-02341066) bound to c-MET
Cui et al. J Med Chem 54: 6342-63, 2011 and Pfizer data on file
Summary of Tumor Responses in Patients with
Advanced ROS1+ NSCLC (N=14*)
Decrease or Increase From Baseline (%)
100
PD
80
SD
PR
CR
60
40
20
‡
†
0
15+
–20
16+
18+
–40
–60
4+
12+
8+
22+
18
44+
–80
–100
dose to last available on treatment
20+
35+
48+
*Response-evaluable population. †Tumor ROS1 FISH-positive, but negative for ROS1 fusion gene expression.
‡Crizotinib held for >6 wks prior to first scans which showed PD. +, Treatment ongoing.
Data in the database as of April 19, 2012.
Crizotinib Response in ROS1-positive
Non-squamous – 4th Line
2/1/2012
On O2, wheelchair-bound, PS 3
3/19/2012
Fully ambulatory, PS 1
BRAF
Overview of the MAPK signaling pathway
• 2002 – Cancer Genome Project
identified BRAF mutations
• Occur in ~50% of melanomas
(90% V600E)
• Serine/threonine kinase
• RAF family member (ARAF,
BRAF and CRAF)
• RAF kinases located downstream
of RAS GTPases and upstream of
MEK and ERK in MAPK signaling
pathway
• Mutated BRAF constitutively
activates the MAPK pathway
Giroux S et al. BMCL Digest 2012
BRAF in NSCLC (Adeno)
• Paik PK et J Clin Oncol 29:2046-51, 2011
 697 adenos tested for BRAF mutations: 18 found (3%)
 All were current or former smokers (median pack yrs, 38, range
14-75)
 Mutually exclusive of EGFR, KRAS and EML4-ALK
 50% V600E (6/10 advanced vs 3/8 early)
• Marchetti A et al. J Clin Oncol 29:3574-79, 2011
 1046 NSCLC tested – 36 (4.9%) adeno, 1 (0.3%) squamous
 57% were V600E (more common in females)
 Mostly smokers (particularly non-V600E)
Genotypes Identified in the LCMC Analysis of
~1000 Adenocarcinomas
Relative frequency of BRAF mutations in (A) lung adenocarcinoma versus (B) melanoma.
Paik P K et al. JCO 2011;29:2046-2051
©2011 by American Society of Clinical Oncology
Figure 8 (A) Representative chemical structures of BRAF inhibitors; (B) Combination therapies involving MEK and HSP90 inhibitors
given in combination with BRAF inhibitors in clinical trials for melanomas.
Simon Giroux
Overcoming acquired resistance to kinase inhibition: The cases of EGFR, ALK and BRAF
Bioorganic &amp; Medicinal Chemistry Letters Volume 23, Issue 2 2013 394 - 401
http://dx.doi.org/10.1016/j.bmcl.2012.11.037
ASCO 2013
Figure 8 (A) Representative chemical structures of BRAF inhibitors; (B) Combination therapies involving MEK and HSP90 inhibitors
given in combination with BRAF inhibitors in clinical trials for melanomas.
Simon Giroux
Overcoming acquired resistance to kinase inhibition: The cases of EGFR, ALK and BRAF
Bioorganic &amp; Medicinal Chemistry Letters Volume 23, Issue 2 2013 394 - 401
http://dx.doi.org/10.1016/j.bmcl.2012.11.037
73 year old women with stage IV adenocarcinoma
(BRAF V600E mutation)
Rec’d 6 cycles of Carbo/pemetrexed/bevacizumab followed
by 9 cycles of maintenance pemetrexed → Dabrafenib
Baseline
8 weeks later
C-MET
c-MET Receptor Tyrosine Kinase
• Implicated in tumor cell
migration, invasion,
proliferation, and angiogenesis1
• The only known high-affinity
receptor for hepatocyte
growth factor (HGF)1
• Amplification is assoc. with:
• Poor prognosis in NSCLC2
• Resistance to EGFR kinase inhibitors in EGFR mutation-positive
NSCLC3,4
1.
2.
3.
4.
Birchmeier C and Gherardi E. Trends Cell Biol 1998;8:404–10
Cappuzzo F et al. JCO 2009;27:1667–74
Engelman JA et al. Science 2007;316:1039–43
Bean J et al. PNAS 2007;104:20932–7
Activation of Met in Cancer
• High Met expression corresponds with higher Met activity
MUTANT MET
Paracrine HGF
LUNG
HCC (Childhood)
PAPIL. RENAL
(Hereditary
& Sporadic)
3
7
INCREASED MET
AUTOCRINE HGF
Paracrine HGF
Other
Focal Amp
BREAST
GASTRIC
COLORECTAL
LUNG
ESOPHAGEAL Met CRC
GASTRIC
GLIOMA
HNSCC
LUNG
MELANOMA
MESOTHELIOMA
OVARIAN
PANCREATIC
RENAL
GLIOMA
OSTEOSARCOMA
PANCREATIC
GASTRIC
HGF/MET Pathway Inhibitors
MET
HGF
Compound
Company
Target(s)
Mechanism
Phase
MetMAb
Genentech
MET
One-Arm Antibody
II
ARQ197
ArQule
MET
Small molecule inhibitor
III
BMS-777607
BMS
MET
Small molecule inhibitor
I/II
INCB-28060
Incyte/Novartis
MET
Small molecule inhibitor
I/II
JNJ-38877605
J&J
MET
Small molecule inhibitor
I
MGCD-265
Methylgene
MET, VEGFRs, Flt3,
TIE-2
Small molecule inhibitor
I
MK-2461
Merck
MET
Small molecule inhibitor
I/II
PF02341066)
Pfizer
MET, ALK
Small molecule inhibitor
III
PF4217903
Pfizer
MET
Small molecule inhibitor
I
SGX523
SGX
MET
Small molecule inhibitor
Discontinued
XL184
Exelixis
MET, VEGFR2, C-kit,
Flt-3, TIE-2
Small molecule inhibitor
III
XL880,
(GSK1363089)
Exelixis / GSK
MET, VEGFR2, C-kit,
Flt-3, TIE-2
Small molecule inhibitor
II
AMG102
Amgen
HGF
Monoclonal antibody
II
AV-299
AVEO
HGF
Monoclonal antibody
I/II
Antibody
TKI
Tivantinib: Phase III NSCLC Study
MARQUEE Study
• Inoperable locally adv or
metastatic NSCLC
• Non-squamous histology
• 1-2 regimens prior
chemo (no prior EGFR
TKI)
• Prior adjuvant/
maintenance therapy
allowed
R
A
N
D
O
M
I
Z
E
• 1˚Endpoint OS (ITT population)
• 2˚/Exploratory Endpoints include:
•
•
•
•
•
PFS (ITT population)
OS and PFS in EGFR WT patients
Safety and toxicity
QOL/FACT-L
Biologic sub-groups
39ESMO 2010
Reference: Sequist et al.
Erlotinib 150 mg PO QD
+ARQ 197 360 mg PO BID
28-day cycle
Erlotinib 150 mg PO QD
+ Placebo
28-day cycle
• 988 patients (~ 120 pts enrolled, Aug 2011)*
• Stratify by EGFR and KRAS mutation status
• Interim analysis performed at 50% of events
Tivantinib: Phase III NSCLC Study
MARQUEE Study
• Inoperable locally adv or
metastatic NSCLC
• Non-squamous histology
• 1-2 regimens prior
chemo (no prior EGFR
TKI)
• Prior adjuvant/
maintenance therapy
allowed
R
A
N
D
O
M
I
Z
E
Erlotinib 150 mg PO QD
+ARQ 197 360 mg PO BID
28-day cycle
Negative
• 1˚Endpoint OS (ITT population)
• 2˚/Exploratory Endpoints include:
•
•
•
•
•
PFS (ITT population)
OS and PFS in EGFR WT patients
Safety and toxicity
QOL/FACT-L
Biologic sub-groups
40ESMO 2010
Reference: Sequist et al.
Erlotinib 150 mg PO QD
+ Placebo
28-day cycle
• 988 patients (~ 120 pts enrolled, Aug 2011)*
• Stratify by EGFR and KRAS mutation status
• Interim analysis performed at 50% of events
Phase II: Erlotinib +/- MetMAb in
2nd/3rd-line NSCLC
MetMAb
Arm A
1:1
Key eligibility:
• Stage IIIB/IV NSCLC
• 2nd/3rd-line NSCLC
• Tissue required
• PS 0–2
n=137*
R
A
N
D
O
M
I
Z
A
T
I
O
N
Stratification factors:
• Tobacco history
• Performance status
• Histology
(15 mg/kg IV Q3W)
+
n=69
erlotinib
(150 mg daily)
Placebo
(IV Q3W)
+
Arm B
n=68
erlotinib
(150 mg daily)
Co-primary objectives:
• PFS in ‘Met Diagnostic
Positive’ patients (est. 50%)
• PFS in overall ITT population
Other key objectives:
• OS in ‘Met Diagnostic Positive’ pts
• OS in overall ITT patients
• Overall response rate
• Safety/tolerability
PD
Add MetMAb
n=27
Must be eligible to be treated
with MetMAb
*128 NSCLC patients enrolled from 3/2009 to 3/2010 plus 9 SCC patients enrolled through 8/2010
Data presented includes >5 additional months of follow-up
5
Met IHC as a companion diagnostic
‘Met Diagnostic Positive’ was defined as majority (≥50%) of tumor cells with
moderate or strong staining intensity
Moderate
Weak
Strong
Ventana’s CONFIRM (SP44 mAb clone)
MET mRNA (2-Dct)
Negative
1000
Met Dx
Negative
Met Dx
Positive
0
2
100
10
1
0
1
3
MET IHC score
•
•
•
Met diagnostic status was assessed after randomization and prior to unblinding
93% of patients had adequate tissue for evaluation of Met by IHC
52% patients with evaluable tissue were “Met Diagnostic Positive”
IHC: immunohistochemistry
Additional biomarker data are discussed in abstract # 7529
6
MetMAb plus erlotinib in Met Dx+ patients
PFS: HR=0.53
OS: HR=0.37
Placebo + MetMAb +
erlotinib erlotinib
Probability of progression free
0.8
1.5
2.9
1.0
0.53
(0.28–0.99)
0.04
27
20
0.8
Probability of survival
Median (mo)
HR
(95% CI)
Log-rank p-value
No. of events
1.0
Placebo + MetMAb +
erlotinib
erlotinib
0.6
0.4
0.2
0.0
3.8
12.6
Median (mo)
0.37
HR
(0.19–0.72)
(95% CI)
0.002
Log-rank p-value
No. of events
26
16
0.6
0.4
0.2
0.0
0
3
6
9
12
15
Time to progression (months)
18
0
3
6
9
12
15
18
21
Overall survival (months)
9
OAM4971g
Global Phase III Clinical Trial
NSCLC
• Inoperable locally
adv/metastatic dz.
• MET diagnostic
positive
• 1-2 regimens prior
chemo (no prior
EGFR TKI)
• Prior adjuvant/
maintenance therapy
allowed
• 1° Endpoint OS
• 2°/Exploratory Endpoints incl:
- PFS
- OS
- Safety and toxicity
- QOL/PRO
- PK and immunogenicity
R
A
N
D
O
M
I
Z
E
Erlotinib 150 mg PO QD
+MetMab 15 mg/kg D1
21-day cycle
Erlotinib 150 mg PO QD
+ Placebo
21-day cycle
• 480 patients
• Stratify by MET score,
prior rx, histology, and
EGFRmutation status
• Interim analysis at 67%
of events
44
RET
RET ASSOCIATED DISEASES
PAPILLARY THYROID CARCINOMA
Multiple RET fusion genes
Gain of function
MULTIPLE ENDOCRINE NEOPLASIA
MEN 2A & 2B
Familial Medullary Thyroid Cancer
Gain of function
HIRSHPRUNG’S DISEASE
Loss of function
KIF5B
EXON 1 2 3 4 5 6 7 8 9 10 11 12 13 14
15 16 17 18 19 202122 23
1 KINESIN MOTOR
2
24
COILED-COIL
25
TAIL
328 329
914 915
963
RET
3
1213 14 15 16 17 18 19
4
CADHERIN
168
TYROSINE KINASE
724
272
1016
1114
KIF5B-RET
1 2 3 4 5 6 7 8 9 10 11 12 13 14
KINESIN MOTOR
2
15
12 13 14 1516 17 18 19
COILED-COIL
328 329
TYROSINE KINASE
575 587
879
978
RET Fusions in NSCLC
• Surgical series of 936 patients examined by
PCR (with IHC and FISH validation)
• 13 cases found (1.4%)
- 11 adenos, 2 adenosquamous
- 7 women, 6 men
- 9 KIF5B-RET, 3 CCDC6-RET, 1 NCOA4-RET
- More often poorly differentiated, young (<60 yrs),
never smokers (82%), solid subtype
Wang R et al. J Clin Oncol 30:4352-59, 2012
Tyrosine kinase inhibitors in current clinical trials,
their targets and adverse effects
Gild, M. L. et al. (2011) Multikinase inhibitors: a new option for the treatment of thyroid cancer
Nat. Rev. Endocrinol. doi:10.1038/nrendo.2011.141
PI3CKA
The PI3K/AKT/mTOR pathway
Papadimitrakopoulou, V. Journal of Thoracic Oncology. 7(8):1315-1326, August 2012.
© 2012International Association for the Study of Lung Cancer. Published by Lippincott Williams & Wilkins, Inc.
2
PI3K- introduction
• PI3K is a member of the class IA Phosphatidyl inositol 3 -kinases (PI3Ks), which transduce signals from growth factor
receptors and GPCRs, via the generation of the lipid second messenger PIP3.
• The opposite reaction is catalysed by a lipid phosphatase called PTEN (phosphate and tensin homolog deleted on
chromosome 10).
PI3K
PI3K
a

PI3K
d
PI3K
g
Expression
Broad
Broad
Leukocytes
Leukocytes
Primary
Physiological
Role
RTK signalling
Insulin
signalling
Platelet
function
B-cell receptor
signalling
Neutrophil and
T cell function
Frequency of Mutations Affecting the PI3K/AKT/mTOR Pathway
Papadimitrakopoulou, V. Journal of Thoracic Oncology. 7(8):1315-1326, August 2012
© 2012International Association for the Study of Lung Cancer. Published by Lippincott Williams & Wilkins, Inc.
2
Energy stress
GF
GRs
PI3K inhibitors
(e.g., wortmannin,
BKM120, BEZ235,
PX-866, GDC 0941)
GF
GRs
IRS
LKB
RAS
PI3K
Raf
PIP3
AMPK
AKT inhibitors
(e.g., perifosine,
PHT427, MK2206)
Akt
TORC1 and TORC2
inhibitors
(e.g., OSI-027, AZD8055,
BEZ235)
MEK
PDK1
SIN1
Rictor
TSC2
Rheb
ERK
RSK
mTORC2
mLST8
PRAS40
Rapalogs
(e.g., rapamycin,
everolimus, temsirolimus,
deferolimus)
Raptor
mTORC1
mLST8
4EBP1
elF4E
P70S6K
S6
Protein synthesis
(Cyclin D, c-Myc, etc.)
Non-selective PI3K inhibitors, including
PI3K 
Agent
Spectrum
DLTs
Activity
PD/other
Perifosine
Pan PI3K
N, V, D, fatigue
SD
CoV – 16%
GDC-0941
PI3Kα =3nm IC50
“ = 28nm IC50
mTOR
N, D, Rash,
hypergylycemia
Ph II
activity in
PTEN-
 pAKT, pS6K
SF1126
Pan PI3K
N,V,D, pruritus,
↑LFTs
SD
IV, BIW
XL-765
Class I PI3K
TORC1 & 2
N,V, ↑ LFTs
SD
Pathway
inhibition at PII
doses
XL-147
Class I PI3Ks
Rash, ↑ LFTs,
hyperglycemia
SD
Pathway
inhibition at PII
doses
BKM 120
Class I PI3Ks
CNS, rash, N, D,
hypergycemia
PR & SD
 pS6K, 18FDG
PET, ↑glucose
Alkyl Phospholipid
Rash & CNS DLT
Conclusions
• Beyond EGFR, there are several other “actionable”
genotypes
• Crizotinib – active in ALK/ROS1 translocated patients,
? met amplification/mutated
• BRAF mutations – vemurafenib, dabrafenib
• Studies ongoing with specifically targeted agents in
molecularly defined populations
• Obtaining tissue for genotyping should be a priority
• Whether more (NGS) or less (tailored IHC/FISH
mutation panels) testing should be done is evolving