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Targeting MET in NSCLC John Heymach, MD, PhD Associate Professor

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Targeting MET in NSCLC John Heymach, MD, PhD Associate Professor

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  1. Please note, these are the actual video-recorded proceedings from the live CME event and may include the use of trade names and other raw, unedited content. Select slides from the original presentation are omitted where Research To Practice was unable to obtain permission from the publication source and/or author. Links to view the actual reference materials have been provided for your use in place of any omitted slides.

  2. Targeting MET in NSCLC John Heymach, MD, PhD Associate Professor Thoracic/Head and Neck Medical Oncology and Cancer Biology 9th Annual Winter Lung Cancer Conference Hollywood, FL Feb. 11, 2012

  3. The hepatocyte growth factor/c-Met signaling pathway in cancer • Met Small Molecule Inhibitors • XL184 • ARQ197 • PF-02341066/Crizotinib • BMS-777607 • Met/HGF Antibodies • MetMAb • AMG102 Interacting proteins(e.g., RON, EGFRs, 6ß4 integrin, plexin B1, CD44, and FAS) Therapeutic antibodies(e.g., AMG102, MetMAb, TAK-701 and SCH900105) C-MET kinase inhibitors(e.g., ARQ197, PF2341066. PF4217903, JNJ38877606, INCB028060, XL880, XL184, MP470, MK2461, MGCD265, BMS777607, and AMG208) TRENDS in Molecular Medicine Adapted from Liu, Trends Mol Med, 2010; Mayor, Lancet Oncology, 2011

  4. c-MET as a Therapeutic Target in NSCLC • HGF/MET axis is associated with invasiveness and is regulated in part by the HIF and EGFR pathways • MET amplifications are associated with EGFR inhibitor resistance • HGF/MET may promote resistance to VEGF inhibitors Xu L, et al. Oncogene. 2010;29:2616-2627. Engelman JA, et al. Science. 2007;316:1039-1043. Cascone, et al. ASCO 2010.

  5. c-Met receptor tyrosine kinase inhibitors – promising therapeutic target in NSCLC • ARQ-197, a novel and selective non-ATP competitive inhibitor of c-MET • ARQ 209 enrolled 167 advanced NSCLC patients Randomized, placebo-controlled, double-blind clinical trial R A N D O M I Z E • NSCLC • Inoperable locally adv/metastatic dz. • 1 prior chemo (no prior EGFR TKI) Erlotinib 150 mg PO QD + ARQ 197 360 mg PO BID 28-day cycle PD Erlotinib 150 mg PO QD + Placebo 28-day cycle • Endpoints • Primary: PFS • Secondary: 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 including sex, age, smoking, histology, performance status, prior therapy, best response, and geography (US vs ex-US) Schiller JH, et al. J Clin Oncol 2010;28:18s (abstr LBA7502 and oral presentation)

  6. ARQ-197 plus erlotinib was associated with improvements in PFS and OS compared with erlotinib alone *Cox regression model. Schiller JH, et al. J Clin Oncol 2010;28:18s (abstr LBA7502 and oral presentation)

  7. PFS and OS benefits most pronounced in patients with non-squamous cell carcinoma *Cox regression model. Schiller JH, et al. J Clin Oncol 2010;28:18s (abstr LBA7502 and oral presentation)

  8. PFS in histologic and molecular subgroups c-MET FISH >5, HR = 0.45 KRAS mutant, HR = 0.18 Schiller JH, et al. J Clin Oncol 2010;28:18s (abstr LBA7502 and oral presentation)

  9. 1:1 RANDO M IZ A T I O N OAM4558g study design: randomized Phase II study of erlotinib +/- MetMAb n = 128 Arm A (n = 64) Erlotinib (150 qd-oral) + MetMAb (15 mg/kg IV q3w) • Key eligibility: • Stage IIIB/IV NSCLC • 2nd/3rd-line NSCLC • Tissue required • PS 0–2 • Stratification factors: • Tobacco history • Performance status • Histology Arm B (n = 64) Erlotinib (150 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 • Enrollment from 3/2009 to 3/2010 • Data cut-off: 8 June 2010 Addition of MetMAb* n = 23 * If eligible Spigel et al, J Clin Oncol 29: 2011 (suppl; abstr 7505)

  10. PFS and OS: ITT population • Objective response rates: Erlotinib + Placebo n = 3 (4.7%), Erlotinib + MetMAb n = 4 (6.3%) • 23 patients from the Erlotinib + Placebo arm crossed over to MetMAb mPFS and mOS are consistent with previously reported findings in a similar disease setting Spigel et al, J Clin Oncol 29: 2011 (suppl; abstr 7505)

  11. PFS and OS: Met high population • MetMAb + Erlotinib improves both PFS and OS in • Met high NSCLC patients Spigel et al, J Clin Oncol 29: 2011 (suppl; abstr 7505)

  12. PFS and OS: Met low population • Met low NSCLC patients do worse with • MetMAb + Erlotinib Spigel et al, J Clin Oncol 29: 2011 (suppl; abstr 7505)

  13. HGF/MET axis and resistance to VEGF inhibitors

  14. Stromal and tumor MET expression is increased in VEGFR TKI resistant H1975 xenografts Cascone, Proc AACR 2011

  15. Ectopic HGF overexpression induces relative resistance to VEGF/R inhibition in NSCLC xenografts

  16. Dual MET/VEGFR targeting is more effective than VEGFR or MET targeting alone

  17. Patterns of tumor revascularization associated with VEGF inhibitor resistance: Normalized vs sprouting revascularization Long-term Anti-VEGF Acquired Resistance: Normalized Revascularization Short-term Anti-VEGF HGF Sensitive phase Reduced MVD Baseline Tumor cells Primary Resistance: Sprouting Vascularization Tumor endothelium Pericytes Adapted from Cascone T et al. 2010

  18. Elevations in bFGF and HGF Develop Prior to Progression on Bevacizumab and Chemotherapy "Several proangiogenic cytokines were elevated before progression, notably basic fibroblast growth factor (bFGF), PlGF, and HGF." Kopetz et al, JCO 2010

  19. Summary • MET and its ligand HGF are overexpressed in cancers and are associated with metastatic spread • MET may contribute to resistance to EGFR, VEGF inhibitors • Amplification of MET gene seen in some cases of acquired resistance to EGFR TKIs in NSCLC • MET inhibition shows promise in MET+ tumors in combination with erlotinib • Phase III trials in progress in NSCLC • Erlotinib +/- MetMAb • Erlotinib +/- ARQ197

  20. Saturday, February 11, 2012Hollywood, Florida Co-Chairs Rogerio C Lilenbaum, MD Mark A Socinski, MD Co-Chair and Moderator Neil Love, MD Faculty Chandra P Belani, MD John Heymach, MD, PhD Pasi A Jänne, MD, PhD Thomas J Lynch Jr, MD Heather Wakelee, MD

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