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MET inhibitors against NSCLC

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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 (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 regeneration Istituto Toscano Tumori-Livorno-Italy HGF, hepatocyte growth factor; NSCLC, non-small-cell lung cancer. MET is a receptor tyrosine kinase with the gene located on chromosome 7 (7q21-7q31); it encodes the receptor for hepatocyte growth factor (HGF), and it’s also called HGFR or HGF receptor. MET is produced first as a precursor protein composed of the extracellular alpha chain and transmembrane beta chain, linked by disulfide bonds. MET is normally activated via ligation or binding with its natural ligand HGF, which is also called scatter factor. Normal or physiologic MET activation facilitates cell processes for embryonic development, wound healing, and tissue regeneration. Figure source: Faria C, Smith C, Rutka J. The Role of HGF/c-Met Pathway Signaling in Human Medulloblastoma, Molecular Targets of CNS Tumors. In: Garami (Ed.). InTech Publications. Available from:

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
p-MET 100% 3 2 1 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 Istituto Toscano Tumori-Livorno-Italy
Total evaluated: 435 Istituto Toscano Tumori-Livorno-Italy Low copy number: 383 (88.9%) High polysomy: 30 (7.0%) Gene amplification: 18 (4.1%) Cappuzzo et al. J Clin Oncol 2009;27:1667–74.

6 Istituto Toscano Tumori-Livorno-Italy Cumulative Survival (proportion)
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 Istituto Toscano Tumori-Livorno-Italy ≥ 4 to < 5 copies/cell 0.6 0.6 MET < 5 copies/cell (n = 383) Cumulative Survival (proportion) < 2 copies/cell 0.5 0.5 ≥ 3 to < 4 copies/cell 0.4 0.4 ≥ 2 to < 3 copies/cell 0.3 ≥ 6 copies/cell 0.3 NSCLC, non-small-cell lung cancer. Cappuzzo et al has recently reported that high MET copy number, as shown in this survival analysis here, leads to poor prognosis in surgically resected early stage non-small-cell lung cancer. 0.2 ≥ 5 to < 6 copies/cell 0.2 MET ≥ 5 copies/cell (n = 48) 0.1 0.1 P = .0045 20 40 60 80 100 20 40 60 80 100 120 Time (months) Time (months) Cappuzzo et al. J Clin Oncol 2009;27:1667–74.

7 Anti-MET agents in development in patients with NSCLC
Target Type Development phase Ligand antagonists Ficlatuzumab (AV-299) HGF Monoclonal antibody I and II Rilotumumab (AMG-102) II TAK-701 I Receptor inhibitors Onartuzumab (OA5D5) MET III completed Receptor TKIs Tivantinib (ARQ-197) Non-ATP competitive TKI Cabozantinib (XL-184) MET, RET, VEGFR1-3, KIT, FLT3, TIE2 ATP competitive TKI Foretinib (XL-880) MET, RON, VEGFR1-3, PDGFR, KIT, FLT3, TIE2 Crizotinib (PF ) MET, ALK II and III MGCD-265 MET, RON, VEGFR1-2, PDGFR, KIT, FLT3, TIE2 Istituto Toscano Tumori-Livorno-Italy

8 Istituto Toscano Tumori-Livorno-Italy
Co-inhibition of Met and EGF Receptors is More Potent than Inhibiting Either Alone in an EGFR WT NSCLC Model In Vitro In Vivo Control NSCLC Lines Erlotinib IC50 (μM) TGFα TGFα+HGF H596 0.508 >10 H596+MetMAb 0.997 Istituto Toscano Tumori-Livorno-Italy H596: WT EGFR cell line -Co-inhibition of Met and EGFR results in more robust activity, relative to either alone – including in an EGFR WT preclinical model. -In vitro, growth of a WT EGFR NSCLC line H596 is inhibited by erlotinib. In the presence of HGF, the cells are no longer sensitive to single-agent erlotinib; rather a combination of MetMAb and erlotinib is required to inhibit growth. -Similarly, in mouse models that express human HGF, growth of H596 is not inhibited by erlotinib; There is modest single-agent MetMAb activity, and sustained inhibition with the combination of MetMAb and erlotinib Met activation by HGF decreases sensitivity to erlotinib. MetMAb restores sensitivity. Combination of erlotinib+MetMAb exhibits robust activity.

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 patients N = 137* Stratified by: History 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) ECOG PS, Eastern Cooperative Oncology Group Performance Score; HGF, hepatocyte growth factor; ITT, intent-to-treat; IV, intravenous; NSCLC, non-small cell lung cancer; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; q3w, every 3 weeks. This slide represents MetMAb, or onartuzumab, in the initial Phase 2 clinical trial that was performed. The Phase I clinical trial was performed at the University of Chicago; it showed very good toxicity profile[1] and therefore a Phase II clinical trial was instituted by Dr. Spiegel and colleagues. That was presented in 2011 and this was a randomized study looking at onartuzumab, which is also known as MetMAb, plus erlotinib or placebo plus erlotinib, as one can appreciate here. This was for previously-treated advanced stage non-small cell lung cancer patients, with 137 patients, and it was stratified by a history of tobacco use, ECOG performance status, as well as histology. Reference: 1. Surati M, Patel P, Peterson A, Salgia R. Role of MetMAb (OA-5D5) in c-MET active lung malignancies. Expert Opin Biol Ther Dec;11(12): *Includes 9 patients with squamous cell histology †Patients in placebo arm allowed to cross-over to receive MetMAb (n = 27) Spigel, et al. ASCO Abstract 7505.

10 Onartuzumab (MetMAb): MET Diagnostic IHC
Negative Weak Strong Moderate - Istituto Toscano Tumori-Livorno-Italy IHC, immunohistochemistry. The slide here shows the immunohistochemical pattern for MET, and the MET receptor tyrosine kinase can be stained by the SP44 monoclonal antibody clone. And, as one can appreciate, it can be negative in certain tumors or weak in other tumors, or moderate as well as strong; this will be important as we select out the patient population that could potentially respond to this kind of therapeutic. + Spigel D, et al. ASCO Abstract 7505.

11 Onartuzumab (MetMAb): PFS and OS in MET Dx+ (High-Positive) Population
PFS: HR = 0.53 OS: HR = 0.37 Placebo + erlotinib MetMAb + erlotinib Median (mo) 1.5 2.9 HR 0.53 (95% CI) ( ) Log-rank p-value 0.04 No. of events 27 20 Placebo + erlotinib MetMAb + erlotinib Median (mo) 3.8 12.6 HR 0.37 (95% CI) ( ) Log-rank p-value 0.002 No. of events 26 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 CI, confidence interval; HR, hazard ratio; PFS, progression free survival; OS, overall survival. As the data that was presented for onartuzumab phase II trial for survival, and this was for MET high-positive population, on the left one can see the 2 curves, and the curves are separating out very nicely in the sense that the MetMAb and erlotinib have better progression-free survival (PFS) as compared to placebo and erlotinib. Also, as you can see on the curve on the right, the overall survival (OS) for placebo/erlotinib is actually worse as compared to MetMAb plus erlotinib itself. Now, the molecular mechanism of this needs to be understood even further, but these are quite exciting findings. 0.4 0.2 0.2 0.0 0.0 3 6 9 12 15 18 3 6 9 12 15 18 21 Time to progression (months) Overall survival (months) Spigel D, et al. ASCO Abstract 7505.

12 Istituto Toscano Tumori-Livorno-Italy
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 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, Spain

13 Onartuzumab (MetMAb) Phase III 2L/3L MET-positive NSCLC
erlotinib + onartuzumab Treat until PD Randomise 1:1 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 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 Stratification criteria: EGFR mut status MET 2+ or 3+ score # of prior lines of tx Histology 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 13

14 Patient Characteristics Overall MET Status
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%) 139 ( 9%) * Patients with valid MET results were summarized.

15 MET+ prevalence by Histology MET+ prevalence by EGFR status
Non-Squamous Squamous MET IHC Status n=1183 n=369 MET-positive 655 (55%) 114 (31%) *P<0.0001  n=1531 EGFR mut Non EGFR mut MET IHC Status n=122 n=1409 MET-positive 74 (61%) 696 (49%) *P=0.02 MET+ prevalence by Smoking History  n=1575 Never Previous Current MET 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) MET+ prevalence by Asian vs. ROW  n=1580 Asian White Other Met IHC Status n=179 n=1290 n=111 MET-positive 94 (53%) 611 (47%) 71 (64%) *P=0.2 (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 EGFR inhibitor greater than either drug alone Demonstration of safety and linear PK in phase I combination with EGFR inhibitor erlotinib

17 Istituto Toscano Tumori-Livorno-Italy
Tivantinib: Study Design Randomized, placebo-controlled, double-blind clinical trial R A N D O M I Z E Erlotinib 150 mg PO QD + ARQ 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 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) HR=1.05 HR=0.71 Istituto Toscano Tumori-Livorno-Italy HR=0.71 HR=0.45 HR=1.23 HR=0.70 HR=0.18 HR=1.01 0.5 1.0 1.5 2.0 5.0 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

24 MARQUEE: PFS and OS in MET+
Istituto Toscano Tumori-Livorno-Italy

25 MARQUEE: Forest plot for OS in key subgroups
Istituto Toscano Tumori-Livorno-Italy

26 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] Istituto Toscano Tumori-Livorno-Italy HGF, hepatocyte growth factor; VEGFR2, vascular endothelial growth factor receptor 2. Foretinib is a MET and VEGF receptor tyrosine kinase inhibitor, there is preclinical evidence of efficacy as can be appreciated from these diagrams here. A phase I/II clinical trial is currently enrolling patients, and this is actually erlotinib plus or minus foretinib. 1. Reprinted from Qian F, et al. Cancer Res. 2009;69: , with permission from the AACR NCT

27 Biomarker Analysis of NCIC Clinical Trials Group IND
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 Istituto Toscano Tumori-Livorno-Italy
Erlotinib plus Foretinib: responses observed in EGFR mut+ and in MET IHC+ MET+ Istituto Toscano Tumori-Livorno-Italy

29 Istituto Toscano Tumori-Livorno-Italy
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

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