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GlaxoSmithKline Oncology

GlaxoSmithKline Oncology. Luca Marini MD Italy and SEE Oncology Medical Director. GlaxoSmithKline Pipeline . Submitted. Phase 1. Phase 2. Phase 3. Marketed/ Approved. Iboctadekin † + rituximab NHL iboctadekin † + doxil ovarian 1120212 † MEK inh totrombopag † thrombocytopenia

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GlaxoSmithKline Oncology

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  1. GlaxoSmithKline Oncology Luca Marini MD Italy and SEE Oncology Medical Director

  2. GlaxoSmithKline Pipeline Submitted Phase 1 Phase 2 Phase 3 Marketed/ Approved Iboctadekin† + rituximab NHL iboctadekin† + doxil ovarian 1120212 † MEK inh totrombopag† thrombocytopenia AKT P13K BRaf ofatumumab DLBCL (relapsed and frontline) Votrient (pazopanib) NSCLC Votrient (pazopanib) ovarian Votrient (pazopanib) + Tykerb MBC Promacta/Revolade ORT Tyk/verb SCCHN (unresectable) Tyk/verb IBC ofatumumab † DLBCL GSK1363089 † (PRC, SCCHN and GI) MAGE 3 Melanoma Tyk/verb SCCHN (resectable) Tyk/verb 1L BC Tyk/verb adj BC Tyk/verb gastric Votrient (pazopanib) sarcoma Votrient/Tykerb IBC Promacta/Revolade † HepC induced thrombocytopenia Promacta/Revolade † CLD induced thrombocytopenia ofatumumab† follicular lymphona MAGE 3 NSCLC Melanoma Avodart Prostate Ca prevention Votrient (pazopanib) RCC ofatumumab † refractory CLL Tyk/verb 1L HR+ BC Revolade ITP Tyk/verb ref BC Hycamtin SCLC Hycamtin ovarian Hycamtin cervical Hycamtin Oral Arranon/Atriance ALL Bexxar NHL † In-license or other alliance relationship with a third party

  3. Pazopanib: Mechanism of Action

  4. VEGF Pathway Ligando SCF ematopoiesi melanogenesi fertilità cel emapoietiche progenitrici monociti trofoblasto cel mesangiali cel musc liscie CE circolanti cel pancreatiche cel retina megacariociti Sede recettori - funzioni

  5. Pazopanib Clinical Development

  6. Pazopanib: Development Settings Glioblastoma Nasopharyngeal Thyroid Ca. Lung Cancer Breast Ca. Mesothelioma Breast Ca. Lung cancer Ovarian Ca. Cervical Ca. Neuroendocrine ca. RCC Phase II studies Phase III studies Prostate Ca. STS

  7. Pazopanib Renal Cell Carcinoma

  8. Phase III Trial of Pazopanib in Locally Advanced and/or Metastatic Renal Cell Carcinoma Cora N. Sternberg,1 Cezary Szczylik,2 Eun S. Lee,3Pamela Salman,4 Jozef Mardiak,5 Ian D. Davis,6Lini Pandite,7 Mei Chen,8 Lauren McCann,8Robert E. Hawkins9 1San Camillo and Forlanini Hospitals, Rome, Italy; 2Military Institute of Medicine, Warsaw, Poland; 3National Cancer Center, Gyeonggi-do, Korea; 4Fundación Arturo López Pérez, Santiago, Chile; 5National Oncological Institute, Klenová, Bratislava, Slovakia; 6Austin Hospital, Melbourne, Australia; 7GlaxoSmithKline, Inc., Research Triangle Park, NC, USA; 8GlaxoSmithKline, Inc., Collegeville, PA, USA; 9University of Manchester and Christie Hospital NHS Foundation Trust, Manchester, UK

  9. Study Design Patients with advanced RCC(N = 435) • Stratification • ECOG PS 0 vs 1 • Prior nephrectomy • Rx-naive (n = 233) vs 1 cytokine failure (n = 202) Randomization2:1 Pazopanib 800 mg qd(n = 290) Matching Placebo(n = 145) Option to receive pazopanib via an open-label study at progression.

  10. PFS in Overall Study Population 1.0 Hazard Ratio = 0.46 95% CI (0.34, 0.62) P value < 0.0000001 Median PFS Pazopanib: 9.2 mo Placebo: 4.2 mo 0.8 0.6 Proportion Progression-Free 0.4 0.2 Pazopanib Placebo 0.0 0 5 10 15 20 Months Patients at risk Pazopanib 290 159 76 29 6 Placebo 145 38 14 2

  11. PFS in Treatment-Naive Subpopulation 1.0 Hazard Ratio = 0.40 95% CI (0.27, 0.60) P value < 0.0000001 Median PFS Pazopanib: 11.1 mo Placebo: 2.8 mo 0.8 0.6 Proportion Progression-Free 0.4 0.2 Pazopanib Placebo 0.0 0 5 10 15 20 Months Patients at risk Pazopanib 155 34 39 11 1 Placebo 78 22 7 2

  12. PFS in Cytokine-Pretreated Subpopulation 1.0 Hazard Ratio = 0.54 95% CI (0.35, 0.84) P value < 0.001 Median PFS Pazopanib: 7.4 mo Placebo: 4.2 mo 0.8 0.6 Proportion Progression-Free 0.4 0.2 Pazopanib Placebo 0.0 0 5 10 15 20 Months Patients at risk Pazopanib 135 75 37 18 5 Placebo 67 16 7

  13. Tumor Response

  14. Most Common Adverse Events ( 10%) Median exposure: pazopanib7.4 (0 - 23) vs placebo3.8 (0 - 22) months

  15. Pazopanib Summary Significant improvement in PFS and RR compared with placebo in treatment-naive and cytokine-pretreated patients Significant improvement in PFS was observed in all subgroups Acceptable safety profile Interim OS data are not mature

  16. Pazopanib Proof of Concept in Lung Cancer and Biomarkers Research

  17. Phase II Study of Pazopanib (GW786034) Given Preoperativelyin Stage I-II Non-Small CellLung Cancer (NSCLC):A Proof-of-Concept Study NK Altorki,1 JV Heymach,2 MJ Guarino,3 P Lee,4 E Felip,5 TL Bauer,3 S Swann,6 D Roychowdhury,6LH Ottesen,7 D Yankelevitz1 ASCO 2008

  18. Phase II, Non-randomised, Open-label Trial 35 pts with resectable, treatment-naive, early-stage (IA, IB, IIA, or IIB [to T2]) NSCLC Endpoint 1°: Evaluate reductions in tumour volume assessed by HRCT after preoperative treatment

  19. Tumour Volumetric Response Thirty (85.7%) patients achieved reduction in tumour volume after median 16 days treatment Objective response according to RECIST: 3 PRs (ORR: 8.6%) Volumetric reduction from baseline was 86% Tumour volume change from baseline, % Patients

  20. Safety and Tolerability Profile

  21. Conclusions Short-term Pazopanib treatment demonstrated single-agent activity in early-stage NSCLC 86% of patients experienced a reduction in tumour volume Acceptable safety profile The CAF profile demonstrates that potential biomarkers could be predictive for response. Further evaluation in NSCLC trials is needed

  22. Recombinant proteins Standardized manufacturing (GSK’s expertise in Biologicals) Convenient to administer (intra-muscular, outpatient) Combined with GSK’s proprietary immunological Adjuvant Systems Specifically designed for cancer Optimal antigen presentation Induction of anti-tumour T-cells Minimal implementation constraints GSK Approach to The Field : ASCI(1) Part 1

  23. More than targeted – tumour cell specific Anticipated fewer side effects GSK Approach to The Field : ASCI(2) Part 1 • Prevention of relapse • Minimal residual disease • Educate the patient’s immune system to fight cancer • Novel approach involving all immune anti-cancer cells

  24. Getting the Right Antigen (e.g. NSCLC) Cancer testis onlyMAGE-A3 Sienel 2004 Weynant 1994NY-ESO-1 Tajima 2003TRAG-3 Zhu 2003 Expressed in a few normal tissuesWT1 Oji 2002PRAME Ikeda 1997SURVIVIN-2B Ichiki 2005 Part 1 Tumor-specific, shared antigens Over-expressed in cancer • HER-2 Swanton 2006 • MUC 1 Ho 1993 • SURVIVIN Falleni 2003 Mutated, unique • P53 Takanashi 1989 • a-Actinin-4 Echchakir 2001 • Malic enzymes Karanikas 2001

  25. MAGE-A3 tumor antigen Genuine target - identified via screening with anti-tumor killer T-cells Genuine tumor-specific - not expressed in normal cells Easy to detect in patients (RT-PCR on tumor tissue) Present in major tumor types Lung 35-50% Bladder 30-58% Liver 24-78% Melanoma 65% Present in early and advanced stages of a given disease Potentially associated with poor survival prognosis Part 1

  26. 249553/004 Study Design Double-blind, randomized, placebo-controlled phase II study Part 2 • NSCLC • p-stage IB and stage II • MAGE-A3 + by RT-PCR • Complete resection • Recovered (PS 0-1) • No anti-cancer adjuvant therapy • Stratified • Stage IB vs. II • Squamous vs. non-squamous • LN sampling vs. dissection MAGE-A3 ASCI 2 • Induction: q3w x 5 • Maintenance: q3m x 8 • Total 27 months 1 Placebo

  27. Clinical results: Disease-free interval Part 2 MAGE-A3 Placebo Disease Free Interval Distribution Time from surgery (months) HR=0.75 (95% CI = 0.46 - 1.23)one-sided logrank p= 0.122 Median follow-up 44 months DFI: Interval from the date of surgical resection to the date of recurrence HR: Hazard ratio calculated by Cox analysis

  28. Phase III study – MAGRITMAGE-A3 as Adjuvant Non-Small Cell LunGCanceRImmunoTherapy Part 2 Resected MAGE-A3 (+) NSCLC Pathological stage IB, II, IIIA No chemo Chemo Randomization Up to 4 cycles of platinum-based chemo MAGE-A3 ASCI Placebo Randomization Powered for efficacy MAGE-A3 ASCI Placebo Powered for efficacy

  29. Revolade • Small molecule thrombopoietin receptor agonist • First in class, once daily tablet • Induces megakaryocyte proliferation and differentiation • Increases platelet counts in thrombocytopenic patients

  30. Type I anti-CD20 MAb in development for the treatment of CLL, FL, and DLBCL1,2 Unique monoclonal antibody that targets the distinct small loop epitope on CD202 Selected for high functional activity Produces more robust CDC Exhibits enhanced binding to and slow dissociation from CD201,2 Ofatumumab 30 1Teeling JL, et al. Blood. 2004;104(6):1793-1800. 2Teeling JL, et al.J Immunol. 2006;177(1):362-371.

  31. Compounds in the clinic Confidential

  32. Cancer Research: A Change in Strategy To From • Precedented targets • Best in class, differentiation by safety or convenience • Common cancers, all comers • Monotherapy, add-on • Minimal biomarkers, diagnostics, imaging • US/EU centric • Innovative targets: Breakthrough Science • First in class, differentiated by superior efficacy and unmet need • Genetically stratified, smaller populations • Combination, factorial designs • Translational medicine embedded throughout • Increased focus on Asia Confidential

  33. MEK Inhibition in Cancer Therapy Mutated and activated in multiple cancers MEK1&2 ERK1&2 Receptor Tyrosine Kinase RAS-RAF-MEK pathway implicated in many tumors • B-Raf activating mutations 60% melanoma, 50% papillary thyroid, 30% ovarian 15% colorectal • Select patients based on single activating mutation • Pancreatic Cancer (95% K-Ras mutated) N-Ras H-Ras K-Ras A-Raf B-Raf C-Raf Activation of Transcription/Proliferation Confidential

  34. AKT Signaling in Cancer • Many oncogenes/ tumor suppressor genes cause AKT activation (eg. ERBB2, RAS, SRC, PTEN) • AKT activated in approx: • 90% ovarian cancer • 50% melanoma • 40% breast • 40% endometrial • 40% prostate cancer (androgen-independent) Confidential

  35. PI3K PI3K Inhibitors: Rationale and Potential PI3K signaling pathway plays critical role in cancer Frequently activated by genetic mutation in broad array of human malignancies: breast colon ovarian hepatocellular gastric others Modified from Vivanco & Sawyers Nat. Rev. Cancer 2:489 ‘02 Confidential

  36. PI3K-MEK Pathway Combination • MAPK and/or PI3K/AKT signaling activated in most cancers • Strong genetic and preclinical rationale to target both pathways simultaneously Confidential

  37. Marked Synergy of MEK/PI3Ki Combination in Cancer Cell Lines Confidential

  38. BRAF Inhibitor Program Tumor Type BRAF mut frequency Melanoma 60% Colon 12% Papillary thyroid 35-70% Ovarian 30% Cholangiocarcinoma 20% Confidential

  39. Mechanisms of c-MET activation Amplified Gastric GBM Sarcomas Many pRCC HCC SCLC* SCCHN* Meso* Melan* Gastric NSCLC Breast Prostate** CRC** *? SNP vs. mutation ** rare Confidential Figure adapted from Merchant, ICTTO, 2007

  40. Early Clinical Portfolio Strategy • Early use of predictive markers to treat the “right” patients with the “right” drug • Imaging to provide answers to critical early development questions • Expedited development of novel drug combinations based on predictive markers • Adaptive designs to expedite “precision medicine” Confidential

  41. Predictive Biomarker Approach High density genome-wide DNA copy number analysis Compound sensitivity/resistance profiling Selected sequence analysis of cancer and target genes Identification of fixed genetic abnormalities that correlate with sensitivity/resistance mRNA profiling miRNA profiling Phosphoprotein analysis Clinical trials to test predictive value of specific response prediction markers Confidential

  42. Application of Translational MedicineExample: to improve PoS with AKT inhibitor Cell line response to AKT inhibitors Unselected Baseline sensitivity With PTEN or Pi3K mutations To select for in patient populations Number of breast cancer cell lines With Ras or Raf mutations To exclude in patient populatins Sensitive Intermediate Resistant <1mM 1-10mM >10mM Confidential

  43. GSK P13K Inhibitor – breast cancer predictive stratification biomarkers • PIK3CA mutations correlate with sensitivity in breast cancer cell lines • Sensitive lines are those with gIC50’s < overall median WT PIK3CA+ UNK Confidential

  44. GSK P13K Inhibitor – Colorectal cancer predictive stratification biomarkers • Colon Cancers have intermediately sensitive profile • Specific mutations of the KRAS appear to associate with ‘458 resistance (p = 0.025; Fisher’s Exact Test) KRAS WT G12/13 Mutation Other Mutation Confidential

  45. Hypothesis-Driven Adaptive Phase II Patients with Colorectal Carcinoma BRAF + PI3K/PTEN BRAF + KRAS + PI3K/PTEN KRAS + Adaptive Assignment of Arms Phase 2 BRAFi + AKTi Phase 2 BRAFi alone Phase 2 MEKi + AKTi Phase 2 MEKi + PI3Ki Confidential

  46. Discovery Performance Units Smaller, Focused, Empowered, Accountable Signal Transduction Metabolism Biopharmaceutical Stem Cell Epigenetics Confidential

  47. Cancer Metabolism DPU • Cancer cell metabolism is distinct from normal cells • Metabolic differences create unique vulnerabilities, thus the potential for large therapeutic windows • Compelling scientific evidence supports multiple druggable targets • Identify synergies between cancer genetics and unique metabolic defects for target discovery and clinical development • Utilize specific ability of PET or other molecular imaging to identify immediate responses confidential

  48. Cancer Metabolism confidential

  49. Cancer EpigeneticsHistone Methyl Transferases (HMTs) and Histone Demethylases (HDMs) • HMTs and HDMs regulate specific histone site methylation. • In tumors, regulation of histone site methylation is a mechanism to regulate transcription: • expression of oncogenes • suppression of tumor suppressors • The biological role of most HMTs and HDMs is not yet well-characterized.

  50. Emerging Science: Targeting Ub/Ubl modifications • Target DUBs that have been shown to modulate human oncogenes • Identify novel targets • Not to pursuing proteasome inhibition

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