MET inhibitors against NSCLC

1
MET inhibitors against NSCLC
Istituto Toscano Tumori-Livorno-Italy

• Federico Cappuzzo
• Istituto Toscano Tumori
• Ospedale Civile
• Livorno-Italy

2
MET Structure and Function

• MET is a receptor tyrosine kinase
• MET gene located on chromosome 7 (7q21q31)
• Produces HGF receptor
• Single precursor protein
• Extracellular a-chain and transmembrane ß-chain,
  linked by disulfide bonds
• MET normally activated via ligation with its
  natural ligand HGF
• Normal MET activation facilitates cell processes
  for embryonic development, wound healing, and
  tissue regeneration

Istituto Toscano Tumori-Livorno-Italy
3
MET dysregulation in NSCLC

• MET abnormalities leading to dysregulated
  activation of MET/HGF pathway
• Protein overexpression
• Increased gene copy number (amplification)
• Mutations
• Aberrant splicing
• Negative biologic effects result in malignancy
  and metastasis

Istituto Toscano Tumori-Livorno-Italy
4
MET expression in solid tumors
MET
p-MET
100
3 2 1 0
90
80
70
Istituto Toscano Tumori-Livorno-Italy
60
50
40
30
20
10
0
Lung
Ovary
Breast
Renal
Colon
Lung Cancer expresses highest pMET among common
solid cancers
Human Cancers
5
MET amplification in NSCLC
Total evaluated 435
Istituto Toscano Tumori-Livorno-Italy
Gene amplification 18 (4.1)
High polysomy 30 (7.0)
Low copy number 383 (88.9)
Cappuzzo et al. J Clin Oncol 200927166774.
6
High MET Copy Number Poor Prognosis in
Surgically Resected/Early Stage NSCLC
1.0
1.0
0.9
0.9
0.8
0.8
0.7
0.7
4 to lt 5 copies/cell
Istituto Toscano Tumori-Livorno-Italy
0.6
0.6
MET lt 5 copies/cell(n 383)
Cumulative Survival (proportion)
lt 2 copies/cell
0.5
0.5
3 to lt 4 copies/cell
0.4
0.4
2 to lt 3 copies/cell
0.3
0.3
6 copies/cell
0.2
0.2
MET 5 copies/cell(n 48)
5 to lt 6 copies/cell
0.1
0.1
P .0045
0
0
0
20
40
60
80
100
0
20
40
60
80
120
100
Time (months)
Time (months)
Cappuzzo et al. J Clin Oncol 200927166774.
7
Anti-MET agents in development in patients with
NSCLC
Agent Target Type Development phase
Ligand antagonists
Ficlatuzumab (AV-299) HGF Monoclonal antibody I and II
Rilotumumab (AMG-102) HGF Monoclonal antibody II
TAK-701 HGF Monoclonal antibody I
Receptor inhibitors
Onartuzumab (OA5D5) MET Monoclonal antibody III completed
Receptor TKIs
Tivantinib (ARQ-197) MET Non-ATP competitive TKI III completed
Cabozantinib (XL-184) MET, RET, VEGFR1-3, KIT, FLT3, TIE2 ATP competitive TKI II
Foretinib (XL-880) MET, RON, VEGFR1-3, PDGFR, KIT, FLT3, TIE2 ATP competitive TKI II
Crizotinib (PF-02341066) MET, ALK ATP competitive TKI II and III
MGCD-265 MET, RON, VEGFR1-2, PDGFR, KIT, FLT3, TIE2 ATP competitive TKI II
Istituto Toscano Tumori-Livorno-Italy
8
Co-inhibition of Met and EGF Receptors is More
Potent than Inhibiting Either Alone in an EGFR WT
NSCLC Model
In Vitro
NSCLC Lines Erlotinib IC50 (µM) Erlotinib IC50 (µM)
NSCLC Lines TGFa TGFaHGF
H596 0.508 gt10
H596MetMAb 0.997
Istituto Toscano Tumori-Livorno-Italy
H596 WT EGFR cell line
9
Onartuzumab (MetMAb) Randomized Phase II Trial

• Onartuzumab (MetMAb) monovalent (single-arm)
  antibody to MET, prevents MET activation by HGF
• Primary endpoint PFS in Met-positive and ITT
  population
• Secondary endpoints OS, ORR, safety

Previously treated advanced-stage NSCLC
patientsN 137 Stratified byHistory of
tabacco use,ECOG PS, histology
MetMAb (15 mg/kg IV every 3 weeks) Erlotinib
(150 mg daily) (n 69)
Istituto Toscano Tumori-Livorno-Italy
PD
Placebo (IV every 3 weeks) Erlotinib (150 mg
daily) (n 68)
Includes 9 patients with squamous cell
histologyPatients in placebo arm allowed to
cross-over to receive MetMAb (n 27)
Spigel, et al. ASCO 2011. Abstract 7505.
10
Onartuzumab (MetMAb) MET Diagnostic IHC
-
Istituto Toscano Tumori-Livorno-Italy

Spigel D, et al. ASCO 2011. Abstract 7505.
11
Onartuzumab (MetMAb) PFS and OS in MET Dx
(High-Positive) Population
PFS HR 0.53
OS HR 0.37
Placebo erlotinib Placebo erlotinib MetMAb erlotinib
Median (mo) 1.5 1.5 2.9
HR 0.53 0.53 0.53
(95 CI) (0.28-0.99) (0.28-0.99) (0.28-0.99)
Log-rank p-value 0.04 0.04 0.04
No. of events 27 20 20
Placebo erlotinib Placebo erlotinib MetMAb erlotinib
Median (mo) 3.8 3.8 12.6
HR 0.37 0.37 0.37
(95 CI) (0.19-0.72) (0.19-0.72) (0.19-0.72)
Log-rank p-value 0.002 0.002 0.002
No. of events 26 16 16
1.0
1.0
Istituto Toscano Tumori-Livorno-Italy
0.8
0.8
0.6
0.6
Probability of progression free
Probability of survival
0.4
0.4
0.2
0.2
0.0
0.0
0
3
6
9
12
15
18
0
3
6
9
12
15
21
18
Time to progression (months)
Overall survival (months)
Spigel D, et al. ASCO 2011. Abstract 7505.
12
The prevalence of MET expression by
immunohistochemistry (IHC) in the METLung
(OAM4971g) trial a randomized,
placebo-controlled Phase III study with erlotinib
placebo vs. erlotinib onartuzumab (MetMAb) in
patients with previously treated NSCLC.
Istituto Toscano Tumori-Livorno-Italy

• Martin J. Edelman1, David Spigel2, Kenneth
  OByrne3, Tony Mok4, Wei Yu5, Simonetta Mocci5,
  Virginia Paton5, Luis Paz-Ares Rodriguez6
• 1Univeristy of New Mexico Health Sciences Center,
  Albuquerque, NM USA 2Sarah Cannon Research
  Institute and Tennessee Oncology PLLC, Nashville,
  TN USA 3Princess Alexandra Hospital, Brisbane,
  Australia 4The Chinese University of Hong Kong,
  Hong Kong 5Genentech, Inc. South San Francisco,
  CA USA 6Instituto de Biomedicina de Sevilla
  (HUVR, US and CSIC) and Hospital Universitario
  Virgen del Rocio, Seville, Spain

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Onartuzumab (MetMAb) Phase III2L/3L MET-positive
NSCLC
Treat until PD
erlotinib onartuzumab
Randomise 11

• 2L and 3L NSCLC pts(1 prior Pt-based line)
• Central testing for
• MET status
• EGFR mutation status

• Treatments
• Tarceva 150 mg PO qd
• onartuzumab/placebo 15 mg/kg IV q3wk

N 490
erlotinib placebo
Istituto Toscano Tumori-Livorno-Italy
No crossover tx

• Stratification criteria
• EGFR mut status
• MET 2 or 3 score
• of prior lines of tx
• Histology

• Key eligibility criteria
• Stage IIIB or IV Met diagnostic positive NSCLC
• 1-2 prior lines of tx
• No prior EGFR inhibitor
• ECOG PS 0 or 1

• Primary endpoint
• Overall survival (OS)
• Secondary endpoints
• Progression-free survival (PFS)
• Overall response rate (ORR)
• Quality of life (QoL)
• Safety

PRE-SCREENING Patients could submit tumor
samples for testing prior to requiring treatment
with 2L or 3L therapy
14
Patient Characteristics
Overall MET Status
    Screened
Age (n1580) Age (n1580) Age (n1580)
  Median (yrs) 63.0
Race (n1580) Race (n1580) Race (n1580)
  White 1290 (82)
  Asian 179 (11)
Other 111 ( 7)
Sex (n1580) Sex (n1580) Sex (n1580)
  Male 991 (63)
Histology (n1552) Histology (n1552) Histology (n1552)
  Non-Squamous 1183 (76)
  Squamous 369 (24)
EGFR Activating Mutation (n1531) EGFR Activating Mutation (n1531) EGFR Activating Mutation (n1531)
  Yes 122 ( 8)
  No 1409 (92)
    Screened
MET IHC Status (n1587) MET IHC Status (n1587) MET IHC Status (n1587)
  MET-positive 782 (49)
MET-negative 805 (51)

MET IHC Score (n1587) MET IHC Score (n1587) MET IHC Score (n1587)
3 175 (11)
  2 607 (38)
  1 666 (42)
  0 139 ( 9)
Patients with valid MET results were summarized.
15
MET prevalence by Histology
MET prevalence by EGFR status
 n1552  n1552 Non-Squamous Squamous
MET IHC Status MET IHC Status n1183 n369
  MET-positive 655 (55) 114 (31)
Plt0.0001
 n1531  n1531 EGFR mut Non EGFR mut
MET IHC Status MET IHC Status n122 n1409
  MET-positive 74 (61) 696 (49)
P0.02
MET prevalence by Smoking History
 n1575  n1575 Never Previous Current
MET IHC Status MET IHC Status n260 n997 n318
  MET-positive 142 (55) 496 (50) 133 (42)
P0.002 (vs Never)
P0.01 (vs Previous)
MET prevalence by Asian vs. ROW
 n1580  n1580 Asian White Other
Met IHC Status Met IHC Status n179 n1290 n111
  MET-positive 94 (53) 611 (47) 71 (64)
P0.2 (vs Asian)
Chi square test
16
Tivantinib (ARQ 197) a Novel and Selective
Tyrosine Kinase Inhibitor

• Non-ATP competitive inhibitor of c-MET
• Novel mechanism of binding stabilizes inactive
  conformation of c-MET

Istituto Toscano Tumori-Livorno-Italy

• Compound demonstrates broad-spectrum, anti-tumor
  activity in a number of tumor xenograft models
  (including NSCLC)
• In vivo anti-tumor activity of ARQ 197 EGFR
  inhibitor greater than either drug alone
• Demonstration of safety and linear PK in phase I
  combination with EGFR inhibitor erlotinib

17
Tivantinib Study DesignRandomized,
placebo-controlled, double-blind clinical trial

R A N D O M I Z E
Erlotinib 150 mg PO QD ARQ 197 360 mg PO BID
28-day cycle

• NSCLC
• Inoperable locally adv/ metastatic dz.
• 1 prior chemo (no prior EGFR TKI)

PD
Erlotinib 150 mg PO QD Placebo 28-day cycle
Istituto Toscano Tumori-Livorno-Italy

• Endpoints
• 1 PFS
• 2 ORR, OS
• Subset analyses
• Crossover ORR

• 33 sites in 6 countries
• Study accrual over 11 months (10/08-9/09)
• Randomization stratified by prognostic factors
  incl. sex, age, smoking, histology, performance
  status, prior therapy and best response, and
  geography (U.S. vs. ex-U.S.)

18
Tivantinib PFS in Histologic and Molecular
Subgroups
ARQ197/erlotinib ARQ197/erlotinib Placebo/erlotinib Placebo/erlotinib Unadjusted HR (95 CI)
N Median PFS (95 CI, weeks) Median PFS (95 CI, weeks) Median PFS (95 CI, weeks) Median PFS (95 CI, weeks) Unadjusted HR (95 CI)
Squamous Cell 26 / 24 26 / 24 26 / 24 13.7 (8.0?18.1) 13.7 (8.0?18.1) 8.4 (7.9?21.0)
Non-Squamous Cell 58 / 59 58 / 59 58 / 59 18.9 (15.0?31.1) 18.9 (15.0?31.1) 9.7 (8.0?16.0)
c-MET FISH gt4 19 / 18 19 / 18 19 / 18 15.4 (8.1?24.4) 15.4 (8.1?24.4) 15.3 (7.1?16.3)
c-MET FISH gt5 8 / 11 8 / 11 8 / 11 24.1 (16.3?NE) 24.1 (16.3?NE) 15.6 (7.9?31.4)
EGFR mutant 6 / 11 6 / 11 6 / 11 24.1 (8.0?32.1) 24.1 (8.0?32.1) 21.0 (8.1?36.0)
EGFR wt 51 / 48 51 / 48 51 / 48 13.7 (8.1?18.1) 13.7 (8.1?18.1) 8.1 (7.9?9.9)
KRAS mutant 10 / 5 10 / 5 10 / 5 9.7 (7.9?NE) 9.7 (7.9?NE) 4.3 (1.1?8.0)
KRAS wt 49 / 45 49 / 45 49 / 45 15.4 (8.1?18.1) 15.4 (8.1?18.1) 9.9 (8.0?16.0)
HR1.05
HR0.71
Istituto Toscano Tumori-Livorno-Italy
HR0.71
HR0.45
HR1.23
HR0.70
HR0.18
HR1.01
5.0
2.0
1.0
0
0.5
1.5
Favors ARQ 197/Erlotinib
Favors Erlotinib/placebo
19
MARQUEE phase III study design
Istituto Toscano Tumori-Livorno-Italy
Primary end-point OS
20
MARQUEE study biomarkers
Istituto Toscano Tumori-Livorno-Italy
21
MARQUEE PFS in the study population
Istituto Toscano Tumori-Livorno-Italy
22
MARQUEE OS in the study population
Istituto Toscano Tumori-Livorno-Italy
23
MARQUEE PFS and OS in MET-
Istituto Toscano Tumori-Livorno-Italy
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MARQUEE PFS and OS in MET
Istituto Toscano Tumori-Livorno-Italy
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MARQUEE Forest plot for OS in key subgroups
Istituto Toscano Tumori-Livorno-Italy
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Foretinib (EXEL-2880) A MET and VEGFR2 Tyrosine
Kinase Inhibitor

• Pre-clinical evidence of efficacy1
• Phase I/II (phase II is randomized erlotinib /-
  foretinib) trial currently ongoing2

Istituto Toscano Tumori-Livorno-Italy
1. Reprinted from Qian F, et al. Cancer Res.
2009698009-8016, with permission from the AACR.
2. ClinicalTrials.gov. NCT01068587.
27
Biomarker Analysis of NCIC Clinical Trials Group
IND.196 a Phase I Study of Erlotinib plus
Foretinib in patients with Advanced Pretreated
NSCLC Patients

• NB Leighl, MS Tsao, G Liu, D Tu, Z Chen, S
  Sakashita, C Ho, FA Shepherd, N Murray, J Goffin,
  G Nicholas, L Kim, S Kamel-Reid, J Ho, T
  Zhang, NA Pham, M Sukhai, L Seymour, G Goss, PA
  Bradbury
• NCIC Clinical Trials Group, Kingston, Canada

Istituto Toscano Tumori-Livorno-Italy
NCIC CTG received trial support from GSK
presenter and co-authors report no other
conflicts
28
Erlotinib plus Foretinib responses observed in
EGFR mut and in MET IHC
MET
Istituto Toscano Tumori-Livorno-Italy
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Conclusions

• MET is a negative prognostic factor in NSCLC
• Several agents are under investigation
• MET overexpressing patients seem more sensitive
  to anti-MET agents
• Efficacy in MET amplified/mutated patients is
  unknown
• Anti-MET strategies should be investigated in
  individuals with EGFR mutations with acquired
  resistance to anti-EGFR agents

Istituto Toscano Tumori-Livorno-Italy