MET as a New Therapeutic Target in Lung Cancer: Current Status & Future Directions
David R. Gandara, MD University of California Davis Comprehensive Cancer Center
Apologies from Alex
Alex A. Adjei Roswell Park Cancer Institute Buffalo, NY USA
Complexity of MET Signaling Hepatocyte Growth Factor
80% 60%
3 2 1 0
Lung
Normal Tissue
100%
3 2 1 0
Kidney
Colon
40% 20% 0%
Colon Renal Breast Lung Ovary Nonneoplastic
100% 80% 60% 40%
Negative (0) or Weak (1)
20% 0%
Tumor Tissue
Ovary
TMA Specimens With Phospho-MET
TMA Specimens With MET
MET is Expressed in a Variety of Tumor Types
Lung
Ovary
Breast
Renal
Colon
Ma PC, et al. Genes Chromosomes Cancer. 2008;
Negative (0)
Weak (1)
Moderate Strong (2) (3)
Non-neoplastic and human solid tumor tissue arrays with c-MET IHC stain
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) Disease Control Rate 2000
PD all others
p=0.01 1000
0 PD
all others
Farneth, Mack, Gandara et al: IASLC WCLC, 2009
Co-Expression of c-MET/EGFR & Synergistic Growth Stimulation by HGF/EGF
A549
H1838
SKMES
Puri & Salgia: J Carcinogenesis, 2008
MET Inhibitors: Modes of Pathway Inhibition Anti-METAb
Anti-HGF Ab
• Onartuzumab
• Ficlatuzumab • Rilotumumab • TAK701
Selective MET inhibitors • • • • •
Tivantinib PF04217903 AMG337 EMD12144063 INCB028060
Non-selective MET inhibitors • • • • • •
Crizotinib Cabozantinib Foretinib E7050 ANG707 MGCD265
Onartuzumab is an Anti-MET Monovalent Antibody that Inhibits HGF-Mediated Activation HGF
• Rationale for targeting MET:
HGF
– 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
MET
MET
Growth, Migration, Survival
No Activity
• METMAb: – One-armed format designed to prevent HGF-mediated stimulation of pathway – Preclinical activity across multiple tumor models
Co-inhibition of Met and EGF receptors is more potent than inhibiting either alone in an EGFR Wt NSCLC model Placebo Erlotinib MetMAb MetMAb+erlotinib
In Vivo 1800
In Vitro NSCLC lines
TGFα
TGFα+HGF
0.508
>10
H596+MetMAb
0.997
Mean tumor vol.
1500
Erlotinib IC50 (μM)
H596
1200 900
600 300 0
H596: WT EGFR cell line 150 mg/kg 30 mg/kg
• • •
HGF-Tg-C3H-SCID H596
0
7
14
21
28 Day
Met activation by HGF decreases sensitivity to erlotinib MetMAb restores sensitivity Combination of MetMAb+erlotinib exhibits robust activity
35
49
56
63
Study Design: Global Double-Blind, Placebo-Controlled Phase II Study n=64
n=128 Key Eligibility: • Stage IIIB/IV NSCLC • 2nd/3rd-line NSCLC • Tissue Required • PS 0-2
1:1 R A N D O M I Z A T I O N
Arm A Erlotinib (150 mg QD oral) + METMAb (15 mg/kg IV q3w) Stratification Factors: • Tobacco History
n=64
• Performance Status • Histology
Arm B Erlotinib (150 mg QD oral) + Placebo (IV q3w)
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
PD Addition of METMAb*
n=23
*If eligible
- Enrollment from 3/2009 to 3/2010 - Data cut off: June 8 2010
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 Negative (0)
Weak (1+)
Met Dx Negative
Moderate (2+)
Strong (3+)
Met Dx Positive MET IHC score
•
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 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 (N=480) Onartuzumab (15 mg/kg IV Q3W) +
Study Population Key eligibility: • Stage IIIB/IV NSCLC • MET Dx Positive* • 2nd/3rd-line NSCLC • Tissue required • PS 0–1 • No prior EGFR inhib.
Erlotinib (150 mg daily) R 1:1
Placebo +
Erlotinib (150 mg daily)
Stratification factors: • EGFR Mut Status • MET IHC 2+ v. 3+ • No. of prior therapies • Histology
*Central Testing for MET and EGFR
Primary objective: • OS Secondary Objectives: PFS QoL ORR Safety 16
GO27820: Randomized Phase II study NSCLC Squamous Cell Histology (SC Consortium*)
4 cycles
Stage IV NSCLC squamous histology
Randomise 1:1
Maintenance
Carbo/Paclitaxel + MetMAb
MetMAb Treat until PD
CR PR SD
Stratification: • Met Dx status
N = 110 (50% Met+)
Carbo/Paclitaxel + placebo
Placebo
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
Erlotinib 150 mg PO QD + Tivantinib 360 mg PO BID 28-day cycle
PD Erlotinib 150 mg PO QD + Placebo PO BID 28-day cycle
Randomization stratified by prognostic factors incl. sex, age, smoking, histology, performance status, prior therapy and best response, and geography (US vs. ex-US)
Tivantinib (ARQ 197)-209: PFS & OS in ITT Population (n=84) PFS
*Cox regression model
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 • NSCLC • Inoperable locally adv/metastatic • Non-squamous histology • 1-2 regimens prior chemo (no prior EGFR TKI) • Prior adjuvant/ maintenance therapy allowed
• •
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
R A N D O M IZ E
Erlotinib 150 mg PO QD + Tivantinib 360 mg PO BID 28-day cycle Erlotinib 150 mg PO QD + Placebo 28-day cycle
• 988 patients • Stratify by EGFR and KRAS mutation status • Interim analysis performed at 50% of events
www.clinicaltrials.gov
Cabozantinib (XL184) Target Profile Kinase
IC50 (nM)
RTK
Cellular IC50 (nM) autophosphorylation
MET
1.8
MET
8
VEGFR2
4
VEGFR2
0.035
RET
5.2
KIT
4.6
AXL
7.0
TIE2
14
FLT3
14
S/T Ks (47)
>200
ATP competitive, reversible
XL184 Randomized Discontinuation Study Design
Cabozantinib (XL184) given orally QD at 100 mg (125 mg salt equivalent) Tumor Types
Breast cancer
Gastric/GEJ cancer
HCC
Melanoma
NSCLC
Ovarian cancer
Pancreatic cancer
Prostate cancer
SCLC
Broad Anti-tumor Activity Across Multiple Tumor Types
(N=269)
Effects in bone
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 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)
Screening
Week 12
Radiographic Images from a 72-Year-Old Male with Metastatic NSCLC 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
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) Advanced EGFR MT+ NSCLC Progressed on Erlotinib after prior response Tumor Tissue Available
R A N D O M I Z E
XL184
Erlotinib + XL184
XL184: Erlotinib: 150 mg/d
PI: Reckamp
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