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MET as a New Therapeutic Target in Lung Cancer: Current Status & Future Directions David R. Gandara, MD University of California Davis Comprehensive Cancer Center

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MET as a New Therapeutic Target in Lung Cancer:

Current Status & Future Directions

David R. Gandara, MD University of California Davis

Comprehensive Cancer Center

Alex A. Adjei Roswell Park Cancer Institute

Buffalo, NY USA

Apologies from Alex

Complexity of MET Signaling

Hepatocyte Growth Factor

MET is Expressed in a Variety of Tumor Types

Non-neoplastic and human solid tumor tissue arrays with c-MET IHC stain

Ma PC, et al. Genes Chromosomes Cancer. 2008;

100%

80%

60%

40%

20%

0% TM

A S

pec

imen

s W

ith

ME

T

Colon Renal Breast Lung Ovary Non-

neoplastic

3

2

1

0

TM

A S

pec

imen

s W

ith

Ph

osp

ho

-ME

T

100%

80%

60%

40%

20%

0% Lung Ovary Breast Renal Colon

3

2

1

0

Tumor Tissue Normal Tissue

Kid

ney

Ova

ry

Co

lon

L

un

g

Negative (0)

or Weak (1)

Negative

(0)

Weak

(1)

Moderate

(2)

Strong

(3)

MET as a Therapeutic Target in NSCLC

• MET Mutation • Uncommon (2-4%)

• MET Amplification • Definition? • Uncommon (5%)

• MET Expression

• Protein (IHC): H Score • mRNA Expression

HGF Plasma Levels in Erlotinib-treated Patients with WT EGFR (UCD #128)

HGF plasma levels (ng,mL) p=0.01

Disease Control Rate

PD all others

0

1000

2000 PD

all others

Farneth, Mack, Gandara et al: IASLC WCLC, 2009

Co-Expression of c-MET/EGFR & Synergistic Growth Stimulation by HGF/EGF

Puri & Salgia: J Carcinogenesis, 2008

A549 H1838 SKMES

MET Inhibitors: Modes of Pathway Inhibition

Anti-HGF Ab • Ficlatuzumab • Rilotumumab • TAK701

Non-selective MET inhibitors • Crizotinib • Cabozantinib • Foretinib • E7050 • ANG707 • MGCD265

Anti-METAb • Onartuzumab

Selective MET inhibitors • Tivantinib • PF04217903 • AMG337 • EMD12144063 • INCB028060

Onartuzumab is an Anti-MET Monovalent Antibody that Inhibits HGF-Mediated Activation

• Rationale for targeting MET:

– MET is amplified, mutated, overexpressed in many tumors

– MET expression is associated with a worse prognosis in many cancers including NSCLC

– MET activation is implicated in resistance to erlotinib/gefitinib in pts with activating EGFR mutations

• METMAb:

– One-armed format designed to prevent HGF-mediated stimulation of pathway

– Preclinical activity across multiple tumor models

METMAb

MET

HGF HGF

MET

Growth, Migration, Survival No 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

In Vitro

NSCLC lines Erlotinib IC50 (μM)

TGFα TGFα+HGF

H596 0.508 >10

H596+MetMAb 0.997

• Met activation by HGF decreases sensitivity to erlotinib

• MetMAb restores sensitivity

• Combination of MetMAb+erlotinib exhibits robust activity

Day

0 14 21 28 35 49 56 63 M

ean

tu

mo

r vo

l.

0

600

900

1200

1500

1800

Placebo

Erlotinib

MetMAb

MetMAb+erlotinib

300

7

HGF-Tg-C3H-SCID H596

150 mg/kg 30 mg/kg

Arm A Erlotinib (150 mg QD oral) + METMAb (15 mg/kg IV q3w)

Addition of METMAb*

PD

*If eligible

Co-Primary Objectives:

• PFS in ‘MET High’ patients

• PFS in overall ITT population

Other Key Objectives:

• OS in ‘MET High’ patients

• OS in Overall ITT patients

• Overall Response Rate

• Safety/Tolerability

Study Design: Global Double-Blind, Placebo-Controlled Phase II Study

Arm B Erlotinib (150 mg QD oral) + Placebo (IV q3w)

Key Eligibility:

• Stage IIIB/IV NSCLC

• 2nd/3rd-line NSCLC

• Tissue Required

• PS 0-2

R A N D O M I Z A T I O N

1:1

n=128

n=64

n=64

n=23

- Enrollment from 3/2009 to 3/2010 - Data cut off: June 8 2010

Stratification Factors:

• Tobacco History

• Performance Status

• Histology

Spigel et al: WCLC 2011

Development of Met IHC for use as a companion diagnostic

• Technical metrics – Tissue was obtained from 100% of patients.

– 93% of patients had adequate tissue for evaluation of Met by IHC

• Intensity of Met IHC staining on NSCLC tumor cells scored in 4 categories

• Met diagnostic status was assessed after randomization and prior to unblinding – ‘Met Diagnostic Positive’ was defined as majority (≥50%) of tumor cells with moderate or strong

staining intensity

Negative (0) Weak (1+)

Moderate (2+) Strong (3+)

Met Dx

Negative

Met Dx

Positive

MET IHC score

52% patients enrolled were ‘Met Diagnostic Positive’

Spigel et al: WCLC 2011

PFS and OS: ITT Population

PFS, HR=1.09 OS, HR=1.09

PFS and OS show no benefit from adding Onartuzumab to Erlotinib

Spigel et al: WCLC 2011

PFS and OS: MET High Population

PFS, HR=0.56 OS, HR=0.55

Onartuzumab + Erlotinib improves both PFS and OS in MET High NSCLC patients

Spigel et al: WCLC 2011

PFS and OS: MET Low Population

PFS, HR=2.01 OS, HR=3.02

MET Low NSCLC Patients do worse with Onartuzumab + Erlotinib

Spigel et al: WCLC 2011

Phase III: Erlotinib +/- Onartuzumab in 2nd/3rd-line NSCLC

16

Placebo +

Erlotinib (150 mg daily)

Onartuzumab

(15 mg/kg IV Q3W)

+

Erlotinib (150 mg daily)

R

1:1

(N=480)

Study Population

Key eligibility:

• Stage IIIB/IV NSCLC

• MET Dx Positive*

• 2nd/3rd-line NSCLC

• Tissue required

• PS 0–1

• No prior EGFR inhib.

Primary objective:

• OS

Secondary Objectives:

PFS QoL

ORR Safety

Stratification factors:

• EGFR Mut Status

• MET IHC 2+ v. 3+

• No. of prior therapies

• Histology

*Central Testing for MET and EGFR

GO27820: Randomized Phase II study NSCLC Squamous Cell Histology (SC Consortium*)

Treat until PD

Carbo/Paclitaxel + MetMAb

Carbo/Paclitaxel + placebo

Randomise 1:1

Stage IV NSCLC squamous histology

Stratification: • Met Dx status

Maintenance

CR

PR

SD

4 cycles

MetMAb

Placebo N = 110

(50% Met+)

Assumptions: median PFS in control arm is ~4 months, and target HR is 0.67 Primary analysis at: 44 PFS events in Met+, and 88 PFS events in ITT population.

SC Consortium:

Squamous Cell Consortium, SPECS award: Hirsch, Govindan, Gandara

Tivantinib (ARQ 197): a Selective MET TKI

• Non-ATP competitive inhibitor of MET

– 356nM IC50

• Novel mechanism of binding stabilizes inactive conformation of MET

• Demonstrates broad-spectrum, anti-tumor activity in xenograft models (including NSCLC)

• In vivo anti-tumor activity of tivantinib + EGFR inhibitor greater than either drug alone

• Demonstration of safety and linear PK in phase I combination with EGFR inhibitor erlotinib

Munshi N, et al. Mol Cancer Ther 2010;9:1544-53 Unpublished; courtesy of ArQule, Inc. and Kyowa Hakko Kirin Co., Ltd

Laux I, et al. ASCO 2009 Goldman J, et al. IASLC 2009

Tivantinib (ARQ 197)-209: Erlotinib +/- Tivantinib in EGFR TKI-Naïve NSCLC

Randomized, placebo-controlled, double-blind clinical trial

NSCLC

Inoperable locally adv/metastatic dz.

≥1 prior chemo (no prior EGFR TKI)

Endpoints

1° PFS

2° ORR, OS

Subset analyses

Crossover: ORR

R A N D O M I Z E

Randomization stratified by prognostic factors incl. sex, age, smoking, histology, performance status, prior therapy and best response, and geography (US vs. ex-US)

Erlotinib 150 mg PO QD + Tivantinib 360 mg PO BID

28-day cycle

Erlotinib 150 mg PO QD + Placebo PO BID

28-day cycle

PD

Tivantinib (ARQ 197)-209: PFS & OS in ITT Population (n=84)

*Cox regression model

PFS OS

Tivantinib (ARQ 197)-209: PFS and OS in Non-Squamous Cell Patients (n=117)

*Cox regression model

Tivantinib (ARQ 197)-209: PFS in Histologic & Molecular Subgroups

Tivantinib (ARQ 197) Phase III Clinical Trial

• 1° Endpoint OS (ITT population)

• 2°/Exploratory Endpoints incl:

– PFS (ITT population)

– OS and PFS in EGFR WT patients

– Safety and toxicity

– QOL/FACT-L

– Biologic sub-groups

• NSCLC

• Inoperable locally adv/metastatic

• Non-squamous histology

• 1-2 regimens prior chemo (no prior EGFR TKI)

• Prior adjuvant/ maintenance therapy allowed

RANDOMIZE

• 988 patients

• Stratify by EGFR and KRAS mutation status

• Interim analysis performed at 50% of events

Erlotinib 150 mg PO QD + Tivantinib 360 mg PO BID

28-day cycle

Erlotinib 150 mg PO QD + Placebo

28-day cycle

www.clinicaltrials.gov

Cabozantinib (XL184) Target Profile

ATP competitive, reversible

RTK Cellular IC50 (nM) autophosphorylation

MET 8

VEGFR2 4

Kinase IC50 (nM)

MET 1.8

VEGFR2 0.035

RET 5.2

KIT 4.6

AXL 7.0

TIE2 14

FLT3 14

S/T Ks (47) >200

XL184 Randomized Discontinuation Study Design

Tumor Types

Breast cancer

Gastric/GEJ cancer

HCC Melanoma NSCLC Ovarian cancer

Pancreatic cancer

Prostate cancer

SCLC

Cabozantinib (XL184) given orally QD at 100 mg (125 mg salt equivalent)

Broad Anti-tumor Activity Across Multiple Tumor Types

Effects in bone

(N=269)

39 PARTIAL RESPONSES IN 269 PATIENTS WITH ≥1 POST-BASELINE ASSESSMENT

Interim RDT data presented at 2010 EORTC-NCI-AACR Symposium

Cabozantinib (XL184) Shows Promising Activity in Previously Treated NSCLC Patients

Best Radiologic Time Point Response of Patients with >1 Post-baseline Tumor Assessment

Interim RDT data presented at 2010 EORTC-NCI-AACR Symposium

NSCLC: Dramatic Response in Tumor with Cabozantinib (XL184)

Radiographic Images from a 72-Year-Old Male with Metastatic NSCLC

Radiographic Images from a 88-Year-Old Female with Metastatic NSCLC

PATIENT WITH ADENOCARCINOMA WITH 61% REDUCTION IN THE SUM OF TARGET LESIONS PRIOR ANTICANCER TREATMENT: SUNITINIB (SD AS BEST RESPONSE)

PATIENT WITH ADENOCARCINOMA WITH 36% REDUCTION IN THE SUM OF TARGET LESIONS PRIOR ANTICANCER TREATMENT: PACLITAXEL/CARBOPLATIN, ERLOTINIB, INVESTIGATIONAL AGENT (SD AS BEST RESPONSE)

Screening Week 12

Screening Week 12

Interim RDT data presented at 2010 EORTC-NCI-AACR Symposium

Phase II Trial of XL184 +/- Erlotinib in Advanced EGFR MT+ & Erlotinib Resistant NSCLC (California N01)

R

A

N

D

O

M

I

Z

E

XL184 Advanced EGFR MT+

NSCLC

Progressed on Erlotinib

after prior response

Tumor Tissue Available

PI: Reckamp

Erlotinib + XL184

XL184:

Erlotinib: 150 mg/d

Summary and Conclusions

HGF & MET are good targets for cancer therapy:

• MET is (over)expressed in multiple tumor types

• HGF & MET control multiple biologic functions of cancer cells including proliferation, survival, and angiogenesis

• MET activation confers resistance to chemo- & radiotherapy

• HGF & MET mediate resistance to target therapies against other receptors including EGFR and VEGFR

• Targeted agents against METPredictive biomarkers need to be defined

• Rational Combinations are being explored