GlaxoSmithKline Oncology

Luca Marini MD

Italy and SEE Oncology Medical Director

GlaxoSmithKline Pipeline

Submitted

Votrient (pazopanib) RCC

ofatumumab † refractory CLL

Tyk/verb 1L HR+ BC

Revolade ITP

Phase 1

Iboctadekin† + rituximab NHL

iboctadekin† + doxil ovarian

1120212 † MEK inh

totrombopag† thrombocytopenia

AKT

P13K

BRaf

Phase 2

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

Phase 3

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 NSCLCMelanoma

Avodart Prostate Ca prevention

Marketed/ Approved

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

Pazopanib: Mechanism of Action

VEGF Pathway

cel emapoietiche progenitrici

monocititrofoblasto

cel mesangiali cel musc liscie

CE circolanti cel pancreatiche

cel retina megacariociti

ematopoiesimelanogenesi

fertilità

Ligando SCF

Sede recettori- funzioni

Pazopanib

Clinical Development

RCC

Lung cancer

STS

Ovarian Ca.

Breast Ca.

Cervical Ca.

Glioblastoma

NasopharyngealThyroid Ca.

Mesothelioma

Lung Cancer

Breast Ca.

Neuroendocrine ca.

Prostate Ca.

Phase II studies

Pazopanib: Development Settings

Phase III studies

Pazopanib

Renal Cell Carcinoma

Phase III Trial of Pazopanib in Locally Advanced and/or Metastatic Renal

Cell Carcinoma Cora N. Sternberg,1 Cezary Szczylik,2 Eun S. Lee,3

Pamela Salman,4 Jozef Mardiak,5 Ian D. Davis,6 Lini Pandite,7 Mei Chen,8 Lauren McCann,8

Robert 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

Study Design

Pazopanib 800 mg qd(n = 290)

Matching Placebo(n = 145)

Option to receive pazopanib via an open-label study at progression.

Stratification• ECOG PS 0 vs 1• Prior nephrectomy• Rx-naive (n = 233) vs 1 cytokine

failure (n = 202)

Patients with advanced RCC(N = 435)

Randomization2:1

PFS in Overall Study Population

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Patients at risk Pazopanib 290 159 76 29 6 Placebo 145 38 14 2

Hazard Ratio = 0.4695% CI (0.34, 0.62)P value < 0.0000001

Median PFSPazopanib: 9.2 moPlacebo: 4.2 mo

PazopanibPlacebo

PFS in Treatment-Naive Subpopulation

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Patients at risk Pazopanib 155 34 39 11 1 Placebo 78 22 7 2

Hazard Ratio = 0.4095% CI (0.27, 0.60)P value < 0.0000001

Median PFSPazopanib: 11.1 moPlacebo: 2.8 mo

PazopanibPlacebo

PFS in Cytokine-Pretreated Subpopulation

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Patients at risk Pazopanib 135 75 37 18 5 Placebo 67 16 7

Hazard Ratio = 0.5495% CI (0.35, 0.84)P value < 0.001

Median PFSPazopanib: 7.4 moPlacebo: 4.2 mo

PazopanibPlacebo

Tumor Response

Pazopanib (n = 290)

Placebo(n = 145)

ORR (CR + PR), % Overall population Treatment-naive Cytokine-pretreated

3032

29

34

3

Duration of response, weeks 59

─

Most Common Adverse Events ( 10%)

Median exposure: pazopanib 7.4 (0 - 23) vs placebo 3.8 (0 - 22) months

Adverse Event

Pazopanib (n = 290) % Placebo (n = 145) %

All Grs Gr 3 Gr 4 All Grs Gr 3 Gr 4

Any eventa 92 33 7 74 14 6

Diarrhea 52 3 < 1 9 < 1 0

Hypertension 40 4 0 10 < 1 0

Hair color changes 38 < 1 0 3 0 0

Nausea 26 < 1 0 9 0 0

Anorexia 22 2 0 10 < 1 0

Vomiting 21 2 < 1 8 2 0

Fatigue 19 2 0 8 1 1

Asthenia 14 3 0 8 0 0

Hemorrhageb 13 1 < 1 5 0 0

Abdominal pain 11 2 0 1 0 0

Headache 10 0 0 5 0 0

a 4% of patients in pazopanib arm and 3% of patients in placebo arm had grade 5 adverse events.b Included hemorrhage from all sites; 1% patients in pazopanib arm had grade 5 events.

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

PazopanibProof of Concept inLung Cancer and Biomarkers Research

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,6

LH Ottesen,7 D Yankelevitz1

ASCO 2008

Phase II, Non-randomised, Open-label Trial

35 pts with resectable, treatment-naive, 35 pts with resectable, treatment-naive,

early-stage (IA, IB, IIA, or IIB [to T2]) NSCLCearly-stage (IA, IB, IIA, or IIB [to T2]) NSCLC

Endpoint 1°: Evaluate reductions in tumour volume assessed by HRCT after preoperative treatment

Tumour Volumetric Response

Thirty (85.7%) patients achieved reduction in tumour volume after median 16 days treatmentObjective response according to RECIST: 3 PRs (ORR: 8.6%)Volumetric reduction from baseline was 86%

Patients

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Safety and Tolerability Profile

Grade Number (%) Event

3 5 (14%) 1 patient each: Rash, dyspnea, increased K+, increased blood pressure, urinary tract infection, pneumonia, lymphopenia

2 patients: Increased ALT

4 1 (3%) Pulmonary embolism 18 days post-therapy

Most Common AEs Pts (%) Grade 1 Grade 2 Grade 3

Hypertension 16 (46) 4 11 1

Diarrhea 13 (37) 13

Fatigue 13 (37) 10 3

Nausea 12 (34) 10 2

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

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

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

Getting the Right Antigen (e.g. NSCLC)

Part 1

Tumor-specific, shared antigens Over-expressed in cancer

Mutated, unique

–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

HER-2 Swanton 2006

MUC 1 Ho 1993SURVIVIN Falleni 2003

P53 Takanashi 1989

-Actinin-4 Echchakir 2001

Malic enzymes Karanikas 2001

MAGE-A3 tumor antigenPart 1

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

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

Placebo

• Induction: q3w x 5• Maintenance: q3m x 8 • Total 27 months

1

2

Clinical results: Disease-free intervalPart 2

MAGE-A3Placebo

Time from surgery (months)

Dis

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Inte

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Dis

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DFI: Interval from the date of surgical resection to the date of recurrenceHR: Hazard ratio calculated by Cox analysis

Median follow-up 44 months

HR=0.75 (95% CI = 0.46 - 1.23)

one-sided logrank p= 0.122

Phase III study – MAGRITMAGE-A3 as Adjuvant Non-Small Cell LunG CanceR ImmunoTherapy

Part 2

Powered for efficacy

MAGE-A3 ASCI Placebo

No chemo

MAGE-A3 ASCI Placebo

Powered for efficacy

Chemo

Resected MAGE-A3 (+) NSCLC

Pathological stage IB, II, IIIA

Randomization

Randomization Up to 4 cycles of platinum-based chemo

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

1Teeling JL, et al. Blood. 2004;104(6):1793-1800.2Teeling JL, et al. J Immunol. 2006;177(1):362-371.

1Teeling JL, et al. Blood. 2004;104(6):1793-1800.2Teeling JL, et al. J Immunol. 2006;177(1):362-371.

Compounds in the clinic

MEK Inhibitor Phase 2 3Q09

AKT Inhibitor (#2, #3) Phase 1

PI3K Inhibitor (#2) Phase 1

BRaf Inhibitor Phase 1

CENPE Inhibitor Phase 1

MET Inhibitor Phase 2

FAK Phase 1 4Q09

Confidential

Cancer Research: A Change in Strategy

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

From To

Confidential

MEK Inhibition in Cancer Therapy

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)

H-Ras K-Ras N-Ras

A-Raf B-Raf C-Raf

MEK1&2

ERK1&2

Receptor Tyrosine Kinase

Mutated and activatedin multiple cancers

Activation of Transcription/Proliferation

Confidential

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

Modified from Vivanco & SawyersNat. Rev. Cancer 2:489 ‘02

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 colonovarian hepatocellular gastricothers

PI3KPI3K

Confidential

PI3K-MEK Pathway Combination

MAPK and/or PI3K/AKT signaling activated in most cancersStrong genetic and preclinical rationale to target both pathways simultaneously

Confidential

Marked Synergy of MEK/PI3Ki Combination in Cancer Cell Lines

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Confidential

BRAF Inhibitor Program

Tumor Type BRAF mut frequencyMelanoma 60%Colon 12%Papillary thyroid 35-70%Ovarian 30%

Cholangiocarcinoma 20%Confidential

Mechanisms of c-MET activation

pRCCHCCSCLC*SCCHN*Meso*Melan*

GastricGBMSarcomas

GastricNSCLCBreastProstate**CRC**

Many

Amplified

Figure adapted from Merchant, ICTTO, 2007

*? SNP vs. mutation** rare

Confidential

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

High density genome-wide DNA copy number analysis

mRNA profilingmiRNA profiling

Compound sensitivity/resistance profiling

Selected sequence analysis of cancer and target genes

Identification of fixed genetic abnormalities that

correlate with sensitivity/resistance

Clinical trials to test predictive value of specific

response prediction markers

Phosphoprotein analysis

Predictive Biomarker Approach

Confidential

Application of Translational MedicineExample: to improve PoS with AKT inhibitor

0

5

10

15

20

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5

10

15

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40

60

80

<1M 110M >10M

Sensitive Intermediate Resistant

Unselected

With PTEN or Pi3K

mutations

With Ras or Raf mutations

Nu

mb

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anc

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es Baseline sensitivity

To select for in patient populations

To exclude in patient populatins

Cell line response to AKT inhibitors

Confidential

• PIK3CA mutations correlate with sensitivity in breast cancer cell lines

• Sensitive lines are those with gIC50’s < overall median

GSK P13K Inhibitor – breast cancer predictive stratification biomarkers

PIK3CA+WT

UNK

Confidential

GSK P13K Inhibitor – Colorectal cancer predictive stratification biomarkers

G12/13 MutationWT

Other Mutation

KRAS

• Colon Cancers have intermediately sensitive profile

• Specific mutations of the KRAS appear to associate with ‘458 resistance (p = 0.025; Fisher’s Exact Test)

Confidential

Hypothesis-Driven Adaptive Phase II

Patients with Colorectal Carcinoma

BRAF +PI3K/PTEN

KRAS +PI3K/PTEN

BRAF + KRAS +

Phase 2BRAFi +

AKTi

Phase 2BRAFi alone

Phase 2MEKi +AKTi

Phase 2MEKi +

PI3Ki

Adaptive Assignment of Arms

Confidential

Discovery Performance Units Smaller, Focused, Empowered, Accountable

Signal Transduction Metabolism

Epigenetics Stem Cell Biopharmaceutical

Confidential

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

Cancer Metabolism

confidential

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.

Emerging Science: Targeting Ub/Ubl modifications

Target DUBs that have been shown to modulate human oncogenes

Identify novel targets Not to pursuing proteasome inhibition

Cancer Stem Cells

Small molecule druggable targets within the known canonical cancer stem cell pathways (wnt, notch, hedgehog)

Novel targets and screens

Committed to building a biologics pipeline and identifying suitable cancer stem cell targets for biopharmaceutical drugs

Overlap with Epigenetics DPU