Molecular Management of Advanced NSCLC

Report
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

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