MET inhibitors against NSCLC

Federico CappuzzoIstituto Toscano Tumori

Ospedale CivileLivorno-Italy

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MET Structure and Function

• MET is a receptor tyrosine kinase• MET gene located on chromosome 7 (7q21–q31)• Produces HGF receptor

– Single precursor protein– Extracellular α-chain and transmembrane β-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 regenerationIsti

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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

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MET expression in solid tumors

MET p-MET

Lung Cancer expresses highest pMET among

common solid cancers

100%90%80%70%60%50%40%30%20%10%

0%Lung Ovary Breast Renal Colon

Human Cancers

3210

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MET amplification in NSCLC

Low copy number: 383 (88.9%)

Gene amplification: 18 (4.1%)

High polysomy: 30 (7.0%)

Total evaluated: 435

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Cappuzzo et al. J Clin Oncol 2009;27:1667–74.

High MET Copy Number: Poor Prognosis in Surgically Resected/Early Stage NSCLC

Cappuzzo et al. J Clin Oncol 2009;27:1667–74.

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0 20 40 60 80 100Time (months)

≥ 4 to < 5 copies/cell

< 2 copies/cell≥ 3 to < 4 copies/cell

≥ 2 to < 3 copies/cell≥ 6 copies/cell

≥ 5 to < 6 copies/cell

1.00.90.80.70.60.50.40.30.20.1

00 20 40 60 80 120

Time (months)

MET < 5 copies/cell(n = 383)

MET ≥ 5 copies/cell(n = 48)

100

P = .0045

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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

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Met activation by HGF decreases sensitivity to erlotinib. MetMAb restores sensitivity. Combination of erlotinib+MetMAb exhibits robust activity.

Co-inhibition of Met and EGF Receptors is More Potent than Inhibiting Either Alone in an EGFR WT

NSCLC Model

H596: WT EGFR cell line

In Vivo

Control

In Vitro

NSCLC LinesErlotinib IC50 (μM)

TGFα TGFα+HGF

H596 0.508 >10

H596+MetMAb 0.997

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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

Onartuzumab (MetMAb): Randomized Phase II Trial

Spigel, et al. ASCO 2011. Abstract 7505.

*Includes 9 patients with squamous cell histology†Patients in placebo arm allowed to cross-over to receive MetMAb (n = 27)

MetMAb (15 mg/kg IV every 3 weeks) + Erlotinib (150 mg daily)

(n = 69)

Placebo (IV every 3 weeks) + Erlotinib (150 mg daily)

(n = 68)

PD*

Previously treated advanced-stage

NSCLC patientsN = 137*

Stratified by:History of tabacco use,

ECOG PS, histology

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Onartuzumab (MetMAb): MET Diagnostic IHC

Spigel D, et al. ASCO 2011. Abstract 7505.

Negative Weak

StrongModerate

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Onartuzumab (MetMAb): PFS and OS in MET Dx+ (High-Positive) Population

Spigel D, et al. ASCO 2011. Abstract 7505.

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Time to progression (months)0 3 6 9 12 15 18

PFS: HR = 0.53Placebo + erlotinib

MetMAb + erlotinib

Median (mo) 1.5 2.9HR 0.53(95% CI) (0.28-0.99)Log-rank p-value 0.04No. of events 27 20

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Overall survival (months)0 3 6 9 12 15 21

OS: HR = 0.37Placebo + erlotinib

MetMAb + erlotinib

Median (mo) 3.8 12.6HR 0.37(95% CI) (0.19-0.72)Log-rank p-value 0.002No. of events 26 16

18

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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.

Martin J. Edelman1, David Spigel2, Kenneth O’Byrne3, 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, SpainIs

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Onartuzumab (MetMAb) Phase III2L/3L MET-positive NSCLC

Treat until PD

Randomise

1:1

No crossover tx

N = 490

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

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

erlotinib + onartuzumab

erlotinib + placebo

*PRE-SCREENING: Patients could submit tumor samples for testing prior to requiring treatment with 2L or 3L therapy

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Screened*Age (n=1580)

Median (yrs) 63.0

Race (n=1580)

White 1290 (82%)

Asian 179 (11%)

Other 111 ( 7%)

Sex (n=1580)

Male 991 (63%)

Histology (n=1552)

Non-Squamous 1183 (76%)

Squamous 369 (24%)

EGFR Activating Mutation (n=1531)

Yes 122 ( 8%)

No 1409 (92%)

Screened*MET IHC Status (n=1587)

MET-positive 782 (49%)

MET-negative 805 (51%)

MET IHC Score (n=1587)

3+ 175 (11%)

2+ 607 (38%)

1+ 666 (42%)

0 139 ( 9%)

Patient Characteristics Overall MET Status

* Patients with valid MET results were summarized.

n=1552 Non-Squamous SquamousMET IHC Status n=1183 n=369

MET-positive 655 (55%) 114 (31%)

*P<0.0001

n=1575 Never Previous CurrentMET IHC Status n=260 n=997 n=318 MET-positive 142 (55%) 496 (50%) 133 (42%)

*P=0.002 (vs Never)*P=0.01 (vs Previous)

n=1531 EGFR mut Non EGFR mutMET IHC Status n=122 n=1409

MET-positive 74 (61%) 696 (49%)

*P=0.02

MET+ prevalence by Smoking History

MET+ prevalence by Histology MET+ prevalence by EGFR status

n=1580 Asian White OtherMet IHC Status n=179 n=1290 n=111

MET-positive 94 (53%) 611 (47%) 71 (64%)*P=0.2 (vs Asian)

MET+ prevalence by Asian vs. ROW

*Chi square test

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

HN

H H

O O

HN N

• 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

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

RANDOMIZE

Erlotinib 150 mg PO QD+ Placebo

28-day cycle

Erlotinib 150 mg PO QD+ Placebo

28-day cycle

Erlotinib 150 mg PO QD+ ARQ 197 360 mg PO BID

28-day cycle

Erlotinib 150 mg PO QD+ ARQ 197 360 mg PO BID

28-day cycle

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

NSCLC• Inoperable locally adv/

metastatic dz.• ≥1 prior chemo

(no prior EGFR TKI)

• 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.)

PD

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5.02.0

Tivantinib: PFS in Histologic and Molecular Subgroups

ARQ197/erlotinib Placebo/erlotinib

Unadjusted HR (95% CI)N Median PFS (95% CI, weeks)

Squamous Cell 26 / 24 13.7 (8.0‒18.1) 8.4 (7.9‒21.0)

Non-Squamous Cell 58 / 59 18.9 (15.0‒31.1) 9.7 (8.0‒16.0)

c-MET FISH >4 19 / 18 15.4 (8.1‒24.4) 15.3 (7.1‒16.3)

c-MET FISH >5 8 / 11 24.1 (16.3‒NE) 15.6 (7.9‒31.4)

EGFR mutant 6 / 11 24.1 (8.0‒32.1) 21.0 (8.1‒36.0)

EGFR wt 51 / 48 13.7 (8.1‒18.1) 8.1 (7.9‒9.9)

KRAS mutant 10 / 5 9.7 (7.9‒NE) 4.3 (1.1‒8.0)

KRAS wt 49 / 45 15.4 (8.1‒18.1) 9.9 (8.0‒16.0)

1.00

Favors ARQ 197/Erlotinib

Favors Erlotinib/placebo

HR=0.70

HR=0.18

0.5 1.5

HR=1.01

HR=1.23

HR=0.45

HR=0.71

HR=1.05

HR=0.71

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MARQUEE phase III study design

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Primary end-point: OS

MARQUEE study biomarkers

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MARQUEE: PFS in the study population

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MARQUEE: OS in the study population

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MARQUEE: PFS and OS in MET-

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MARQUEE: PFS and OS in MET+

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MARQUEE: Forest plot for OS in key subgroups

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Foretinib (EXEL-2880): A MET and VEGFR2 Tyrosine Kinase Inhibitor

Pre-clinical evidence of efficacy[1]

Phase I/II (phase II is randomized erlotinib +/- foretinib) trial currently ongoing[2]

1. Reprinted from Qian F, et al. Cancer Res. 2009;69:8009-8016, with permission from the AACR. 2. ClinicalTrials.gov. NCT01068587.

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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

NCIC CTG received trial support from GSK; presenter and co-authors report no other conflicts

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Erlotinib plus Foretinib: responses observed in EGFR mut+ and in MET IHC+ I196

(n = 27 evaluable patients)

Met: P AXL: PMet: P AXL: NMet: N AXL: PMet: N AXL: NMet: N AXL: NAMet: NA AXL: PMet: NA AXL: NA

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-100

-80

-60

-40

-20

0

20

40

60

80

100

E:MutE:Mut

E:WT E:Mut

E:WT

E:WTE:WT

E:WT E:WT

E:WT

E:WT

K:WTK:WT

K:WT K:WT

K:Mut

K:WT

K:WT

K:Mut K:Mut

K:Mut

K:WT

*

##

#

##

* No FORET # PR

MET+

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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

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