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