Presentation on theme: "MET inhibitors against NSCLC"— Presentation transcript:
1 MET inhibitors against NSCLC Istituto Toscano Tumori-Livorno-ItalyFederico CappuzzoIstituto Toscano TumoriOspedale CivileLivorno-Italy
2 MET Structure and Function MET is a receptor tyrosine kinaseMET gene located on chromosome 7 (7q21–q31)Produces HGF receptorSingle precursor proteinExtracellular α-chain and transmembrane β-chain, linked by disulfide bondsMET normally activated via ligation with its natural ligand HGFNormal MET activation facilitates cell processes for embryonic development, wound healing, and tissue regenerationIstituto Toscano Tumori-Livorno-ItalyHGF, 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 overexpressionIncreased gene copy number (amplification)MutationsAberrant splicingNegative biologic effects result in malignancy and metastasisIstituto Toscano Tumori-Livorno-Italy
4 MET expression in solid tumors p-MET100%32190%80%70%Istituto Toscano Tumori-Livorno-Italy60%50%40%30%20%10%0%LungOvaryBreastRenalColonLung Cancer expresses highest pMET among common solid cancersHuman Cancers
5 MET amplification in NSCLC Istituto Toscano Tumori-Livorno-Italy Total evaluated: 435Istituto Toscano Tumori-Livorno-ItalyLow 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 NSCLC1.01.00.90.188.8.131.52.7Istituto Toscano Tumori-Livorno-Italy≥ 4 to < 5 copies/cell0.60.6MET < 5 copies/cell (n = 383)Cumulative Survival (proportion)< 2 copies/cell0.50.5≥ 3 to < 4 copies/cell0.40.4≥ 2 to < 3 copies/cell0.3≥ 6 copies/cell0.3NSCLC, 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/cell0.2MET ≥ 5 copies/cell (n = 48)0.10.1P = .00452040608010020406080100120Time (months)Time (months)Cappuzzo et al. J Clin Oncol 2009;27:1667–74.
7 Anti-MET agents in development in patients with NSCLC TargetTypeDevelopment phaseLigand antagonistsFiclatuzumab (AV-299)HGFMonoclonal antibodyI and IIRilotumumab (AMG-102)IITAK-701IReceptor inhibitorsOnartuzumab (OA5D5)METIII completedReceptor TKIsTivantinib (ARQ-197)Non-ATP competitive TKICabozantinib (XL-184)MET, RET, VEGFR1-3, KIT, FLT3, TIE2ATP competitive TKIForetinib (XL-880)MET, RON, VEGFR1-3, PDGFR, KIT, FLT3, TIE2Crizotinib (PF )MET, ALKII and IIIMGCD-265MET, RON, VEGFR1-2, PDGFR, KIT, FLT3, TIE2Istituto 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 ModelIn VitroIn VivoControlNSCLC LinesErlotinib IC50 (μM)TGFαTGFα+HGFH5960.508>10H596+MetMAb0.997Istituto Toscano Tumori-Livorno-ItalyH596: 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 erlotinibMet 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 HGFPrimary endpoint: PFS in Met-positive and ITT populationSecondary endpoints: OS, ORR, safetyPreviously treated advanced-stage NSCLC patients N = 137*Stratified by: History of tabacco use, ECOG PS, histologyMetMAb (15 mg/kg IV every 3 weeks) + Erlotinib (150 mg daily)(n = 69)Istituto Toscano Tumori-Livorno-ItalyPD*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 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 NegativeWeakStrongModerate-Istituto Toscano Tumori-Livorno-ItalyIHC, 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 = 0.53OS: HR = 0.37Placebo + erlotinibMetMAb + erlotinibMedian (mo)1.52.9HR0.53(95% CI)( )Log-rank p-value0.04No. of events2720Placebo + erlotinibMetMAb + erlotinibMedian (mo)3.812.6HR0.37(95% CI)( )Log-rank p-value0.002No. of events26161.01.0Istituto Toscano Tumori-Livorno-Italy0.80.80.60.6Probability of progression freeProbability of survival0.4CI, 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.0.40.20.20.00.036912151836912151821Time 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-ItalyMartin J. Edelman1, David Spigel2, Kenneth O’Byrne3, Tony Mok4, Wei Yu5, Simonetta Mocci5, Virginia Paton5, Luis Paz-Ares Rodriguez61Univeristy 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 + onartuzumabTreat until PDRandomise1:12L and 3L NSCLC pts (1 prior Pt-based line)Central testing for*:MET statusEGFR mutation statusTreatments:Tarceva 150 mg PO qdonartuzumab/placebo 15 mg/kg IV q3wkN = 490erlotinib + placeboIstituto Toscano Tumori-Livorno-ItalyNo crossover txKey eligibility criteria:Stage IIIB or IV Met diagnostic positive NSCLC1-2 prior lines of txNo prior EGFR inhibitorECOG PS 0 or 1Stratification criteria:EGFR mut statusMET 2+ or 3+ score# of prior lines of txHistologyPrimary 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 therapy13
14 Patient Characteristics Overall MET Status Screened*Age (n=1580)Median (yrs)63.0Race (n=1580)White1290 (82%)Asian179 (11%)Other111 ( 7%)Sex (n=1580)Male991 (63%)Histology (n=1552)Non-Squamous1183 (76%)Squamous369 (24%)EGFR Activating Mutation (n=1531)Yes122 ( 8%)No1409 (92%)Screened*MET IHC Status (n=1587)MET-positive782 (49%)MET-negative805 (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-SquamousSquamousMET IHC Statusn=1183n=369MET-positive655 (55%)114 (31%)*P<0.0001 n=1531EGFR mutNon EGFR mutMET IHC Statusn=122n=1409MET-positive74 (61%)696 (49%)*P=0.02MET+ prevalence by Smoking History n=1575NeverPreviousCurrentMET IHC Statusn=260n=997n=318MET-positive142 (55%)496 (50%)133 (42%)*P=0.002 (vs Never)*P=0.01 (vs Previous)MET+ prevalence by Asian vs. ROW n=1580AsianWhiteOtherMet IHC Statusn=179n=1290n=111MET-positive94 (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-METNovel mechanism of binding stabilizes inactive conformation of c-METIstituto Toscano Tumori-Livorno-ItalyCompound 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 aloneDemonstration 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 trialRANDOMIZEErlotinib 150 mg PO QD+ ARQ mg PO BID28-day cycleNSCLCInoperable locally adv/ metastatic dz.≥1 prior chemo (no prior EGFR TKI)PDErlotinib 150 mg PO QD+ Placebo28-day cycleIstituto Toscano Tumori-Livorno-ItalyEndpoints1° PFS2° ORR, OSSubset analysesCrossover: ORR33 sites in 6 countriesStudy 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.)
19 MARQUEE phase III study design Istituto Toscano Tumori-Livorno-ItalyPrimary 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 efficacyPhase I/II (phase II is randomized erlotinib +/- foretinib) trial currently ongoingIstituto Toscano Tumori-Livorno-ItalyHGF, 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 ClinicalTrials.gov. 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 PatientsNB 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 BradburyNCIC Clinical Trials Group, Kingston, CanadaIstituto Toscano Tumori-Livorno-ItalyNCIC 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 ConclusionsMET is a negative prognostic factor in NSCLCSeveral agents are under investigationMET overexpressing patients seem more sensitive to anti- MET agentsEfficacy in MET amplified/mutated patients is unknownAnti-MET strategies should be investigated in individuals with EGFR mutations with acquired resistance to anti-EGFR agentsIstituto Toscano Tumori-Livorno-Italy