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.

3. 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

4. The hepatocyte growth factor/c-Met signaling pathway in cancer Adapted from Liu, Trends Mol Med, 2010; Mayor, Lancet Oncology, 2011 Met Small Molecule Inhibitors –XL184 –ARQ197 –PF-02341066/Crizotinib –BMS-777607 Met/HGF Antibodies –MetMAb –AMG102 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) Interacting proteins (e.g., RON, EGFRs,  6ß4 integrin, plexin B1, CD44, and FAS) TRENDS in Molecular Medicine

5. 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.

6. c-Met receptor tyrosine kinase inhibitors – promising therapeutic target in NSCLC Schiller JH, et al. J Clin Oncol 2010;28:18s (abstr LBA7502 and oral presentation) ARQ-197, a novel and selective non-ATP competitive inhibitor of c-MET ARQ 209 enrolled 167 advanced NSCLC patients Endpoints Primary: PFS Secondary: ORR, OS Subset analyses Crossover: ORR RANDOMIZERANDOMIZE Erlotinib 150 mg PO QD + ARQ 197 360 mg PO BID 28-day cycle Erlotinib 150 mg PO QD + Placebo 28-day cycle PD 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) Randomized, placebo-controlled, double-blind clinical trial NSCLC Inoperable locally adv/metastatic dz.  1 prior chemo (no prior EGFR TKI)

7. 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) E + A (n = 84) E + placebo (n = 83) Hazard ratiop-value PFS16.1 weeks9.7 weeks0.68<0.05 OS36.6 weeks 29.4 weeks0.680.52*

8. 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) E + A (n = 84) E + placebo (n = 59) Hazard ratiop-value PFS18.9 weeks9.7 weeks0.61<0.05* OS43.1 weeks 29.4 weeks0.58<0.05*

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

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

11. 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) Erlotinib + placebo (n = 64) Erlotinib + MetMAb (n = 64) HR (95% CI) Log-rank p-value Median PFS (wk) 11.1 9.61.09 (0.71-1.67)0.6988 Median OS (mo) 8.27.11.09 (0.62-1.91)0.7642

12. 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) Erlotinib + placebo (n = 30) Erlotinib + MetMAb (n = 35) HR (95% CI) Log-rank p-value Median PFS (wk) 6.4 12.40.56 (0.31-1.02)0.0547 Median OS (mo) 7.47.70.55 (0.26-1.16)0.1113

13. 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) Erlotinib + placebo (n = 29) Erlotinib + MetMAb (n = 27) HR (95% CI) Log-rank p-value Median PFS (wk) 11.4 6.02.01 (1.04-3.91)0.0354 Median OS (mo) 9.25.53.02 (1.13-8.11)0.0212

14. HGF/MET axis and resistance to VEGF inhibitors

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

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

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

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

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

20. 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

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