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MET inhibitors against NSCLC Federico Cappuzzo Istituto Toscano Tumori Ospedale Civile Livorno-Italy Istituto Toscano Tumori-Livorno-Italy.

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Presentation on theme: "MET inhibitors against NSCLC Federico Cappuzzo Istituto Toscano Tumori Ospedale Civile Livorno-Italy Istituto Toscano Tumori-Livorno-Italy."— Presentation transcript:

1 MET inhibitors against NSCLC Federico Cappuzzo Istituto Toscano Tumori Ospedale Civile Livorno-Italy Istituto Toscano Tumori-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

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 MET p-MET Lung Cancer expresses highest pMET among common solid cancers 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% LungOvaryBreastRenalColon Human Cancers Istituto Toscano Tumori-Livorno-Italy

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

6 High MET Copy Number: Poor Prognosis in Surgically Resected/Early Stage NSCLC Cappuzzo et al. J Clin Oncol 2009;27:1667– Cumulative Survival (proportion) Time (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 Time (months) MET < 5 copies/cell (n = 383) MET 5 copies/cell (n = 48) 100 P =.0045 Istituto Toscano Tumori-Livorno-Italy

7 Anti-MET agents in development in patients with NSCLC AgentTargetTypeDevelopment phase Ligand antagonists Ficlatuzumab (AV-299)HGFMonoclonal antibodyI and II Rilotumumab (AMG-102)HGFMonoclonal antibodyII TAK-701HGFMonoclonal antibodyI Receptor inhibitors Onartuzumab (OA5D5)METMonoclonal antibodyIII completed Receptor TKIs Tivantinib (ARQ-197)METNon-ATP competitive TKIIII completed Cabozantinib (XL-184)MET, RET, VEGFR1-3, KIT, FLT3, TIE2 ATP competitive TKIII Foretinib (XL-880)MET, RON, VEGFR1-3, PDGFR, KIT, FLT3, TIE2 ATP competitive TKIII Crizotinib (PF )MET, ALKATP competitive TKIII and III MGCD-265MET, RON, VEGFR1-2, PDGFR, KIT, FLT3, TIE2 ATP competitive TKIII Istituto Toscano Tumori-Livorno-Italy

8 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 Lines Erlotinib IC50 ( μ M) TGF α TGF α +HGF H >10 H596+MetMAb0.997 Istituto Toscano Tumori-Livorno-Italy

9 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 Abstract *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 patients N = 137* Stratified by: History of tabacco use, ECOG PS, histology Istituto Toscano Tumori-Livorno-Italy

10 Onartuzumab (MetMAb): MET Diagnostic IHC Spigel D, et al. ASCO Abstract Negative Weak StrongModerate Istituto Toscano Tumori-Livorno-Italy - +

11 Onartuzumab (MetMAb): PFS and OS in MET Dx+ (High-Positive) Population Spigel D, et al. ASCO Abstract Probability of progression free Time to progression (months) PFS: HR = 0.53 Placebo + erlotinib MetMAb + erlotinib Median (mo) HR0.53 (95% CI)( ) Log-rank p-value0.04 No. of events Probability of survival Overall survival (months) OS: HR = 0.37 Placebo + erlotinib MetMAb + erlotinib Median (mo) HR0.37 (95% CI)( ) Log-rank p-value0.002 No. of events Istituto Toscano Tumori-Livorno-Italy

12 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. Edelman 1, David Spigel 2, Kenneth OByrne 3, Tony Mok 4, Wei Yu 5, Simonetta Mocci 5, Virginia Paton 5, Luis Paz-Ares Rodriguez 6 1 Univeristy of New Mexico Health Sciences Center, Albuquerque, NM USA; 2 Sarah Cannon Research Institute and Tennessee Oncology PLLC, Nashville, TN USA; 3 Princess Alexandra Hospital, Brisbane, Australia; 4 The Chinese University of Hong Kong, Hong Kong; 5 Genentech, Inc. South San Francisco, CA USA; 6 Instituto de Biomedicina de Sevilla (HUVR, US and CSIC) and Hospital Universitario Virgen del Rocio, Seville, Spain Istituto Toscano Tumori-Livorno-Italy

13 Onartuzumab (MetMAb) Phase III 2L/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 Istituto Toscano Tumori-Livorno-Italy

14 Screened* Age (n=1580) Median (yrs)63.0 Race (n=1580) White1290 (82%) Asian 179 (11%) Other111 ( 7%) Sex (n=1580) Male991 (63%) Histology (n=1552) Non-Squamous1183 (76%) Squamous 369 (24%) EGFR Activating Mutation (n=1531) Yes 122 ( 8%) No1409 (92%) Screened* MET IHC Status (n=1587) MET-positive782 (49%) MET-negative805 (51%) MET IHC Score (n=1587) (11%) (38%) (42%) 0139 ( 9%) Patient Characteristics Overall MET Status * Patients with valid MET results were summarized.

15 n=1552Non-SquamousSquamous MET IHC Status n=1183n=369 MET-positive655 (55%)114 (31%) *P< n=1575NeverPrevious Current MET IHC Status n=260n=997 n=318 MET-positive142 (55%)496 (50%) 133 (42%) *P=0.002 (vs Never) *P=0.01 (vs Previous) n=1531EGFR mutNon EGFR mut MET IHC Status n=122n=1409 MET-positive74 (61%)696 (49%) *P=0.02 MET+ prevalence by Smoking History MET+ prevalence by Histology MET+ prevalence by EGFR status n=1580AsianWhite Other Met IHC Status n=179n=1290 n=111 MET-positive94 (53%)611 (47%) 71 (64%) *P=0.2 (vs Asian) MET+ prevalence by Asian vs. ROW *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 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 Istituto Toscano Tumori-Livorno-Italy

17 Tivantinib: Study Design Randomized, placebo-controlled, double-blind clinical trial RANDOMIZERANDOMIZE Erlotinib 150 mg PO QD + Placebo 28-day cycle Erlotinib 150 mg PO QD + Placebo 28-day cycle Erlotinib 150 mg PO QD + ARQ mg PO BID 28-day cycle Erlotinib 150 mg PO QD + ARQ 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 Istituto Toscano Tumori-Livorno-Italy

18 Tivantinib: PFS in Histologic and Molecular Subgroups ARQ197/erlotinibPlacebo/erlotinib Unadjusted HR (95% CI) NMedian PFS (95% CI, weeks) Squamous Cell26 / ( )8.4 ( ) Non-Squamous Cell58 / ( )9.7 ( ) c-MET FISH >419 / ( )15.3 ( ) c-MET FISH >58 / (16.3NE)15.6 ( ) EGFR mutant6 / ( )21.0 ( ) EGFR wt51 / ( )8.1 (7.99.9) KRAS mutant10 / 59.7 (7.9NE)4.3 (1.18.0) KRAS wt49 / ( )9.9 ( ) 1.00 Favors ARQ 197/Erlotinib Favors Erlotinib/placebo HR=0.70 HR= HR=1.01 HR=1.23 HR=0.45 HR=0.71 HR=1.05 HR=0.71 Istituto Toscano Tumori-Livorno-Italy

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] 1. Reprinted from Qian F, et al. Cancer Res. 2009;69: , with permission from the AACR. 2. NCT Istituto Toscano Tumori-Livorno-Italy

27 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 Istituto Toscano Tumori-Livorno-Italy

28 Erlotinib plus Foretinib: responses observed in EGFR mut+ and in MET IHC+ MET+ Istituto Toscano Tumori-Livorno-Italy

29 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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