Immuno-Oncology

Axel Hoos, MD, PhD Senior Vice President, Oncology R&D

February 24, 2016 Oncology R&D strategy Focusing on 3 areas fundamental to oncology

Cancer Epigenetics Long-Term Survival & Reprogram Cancer Cures Cells

Immuno-Oncology Stimulate Anti -Tumour First in Class Medicines

Immunity & Combination Therapy GSK Pipeline GSK

Cancer Stem Cells & Targeted Therapies

2 3 Generations of therapies

Generation 1 Generation 2 Generation 3 Multiple therapies under YERVOY KEYTRUDA Anti-PD-L1 (CTLA-4) (PD-1) development

2010 2011 2012 2013 2014 2015 2016 2017 2018 2019

PROVENGE BLINCYTO sipuleucel-T (BITE) (Cell Therapy) CAR-Ts OPDIVO (PD-1) Key Approved IMLYGIC Under T-Vec (Oncolytic Virus) development 3 Main trends

SOC Immune New replacements profiling technologies Elimination of chemotherapy Patient selection Expansion of the from SOC to predict toolbox regimens response 2016 CURE

Substantial survival Complex improvements combinations Across wide Maximise efficacy populations Improved endpoints Accelerated development 4 3rd Generation opportunities Spectrum of immuno-oncology modalities

Adaptive Immunity Innate Immunity T-Cell Immunity B-Cell Immunity

Cytokines Cellular Therapies - NK Cells Cancer Vaccines T-cell Checkpoint Modulators Checkpoint Modulators “Connector” Bi-specific Abs - Dual-specific Abs Small Molecules Oncolytic Viruses Adjuvants Approved therapies 5 3rd Generation opportunities GSK’s multi-modality pipeline

Adaptive Immunity Innate Immunity T-Cell Immunity B-Cell Immunity

Cytokines Cellular Therapies - NK Cells* Cancer Vaccines T-cell Checkpoint Modulators Checkpoint Modulators “Connector” Bi-specific Abs - Dual-specific Abs Small Molecules Oncolytic Viruses Adjuvants GSK Pipeline * in planning 6 3rd Generation leadership Innovation across novel targets, modalities and combinations (5 in the clinic)

Modality Program Mechanism Pre-clinical Phase 1 Phase 2

GSK3174998 OX40 agonist Solid Tumours, Heme Malignancies GSK3359609 ICOS agonist BCMA -ADC mAbs GSK2857916 Multiple Myeloma Brontictuzumab * Notch1 Solid Tumours, Heme Malignancies Tarextumumab * Notch2/3 SCLC GSK Immune checkpoints

Cell NY-ESO-1* TCR-T Sarcoma, Multiple Myeloma, NSCLC, Ovarian, Melanoma Therapy GSK/Adaptimmune TCR-T

GSK CAR-T

Synthetic / GSK1795091 TLR-4 agonist Small Molecules GSK Novel mechanisms

Bi- GSK/ImmunoCore ImmTacs Specific GSK mAb-dAbs Molecules GSK/AdiMab Dual-specific Abs

* Collaboration with third party NY-ESO T-Cell Therapy

Sarcoma Phase I/II: Individual patient complete response (CR) • TCR T-cell therapy Baseline Day 2: Inflammation Day 100: CR • 50% ORR seen in sarcoma

• Ongoing studies in ovarian and other solid tumours and haematological malignancies

• Planned studies in combination 60 Sarcoma Phase I/II: Best Response in treated patients (N=12)*

with checkpoint modulators 40 Best response Stable disease Confirmed complete or partial response 20 17 15

• Collaboration with Adaptimmune 0 -20 -15 -16 -26 -40

baseline (%) baseline -50 Status: Phase I/II -60 -55 -58 -64 Indications: NY-ESO-1 positive Cancers: -80 -70 Excludes 3 subjects who did not receive a T-Cell Infusion.

Sarcoma, Myeloma, NSCLC, fromtargetlesionin Change -100 Melanoma, Ovarian Cancer One subject with disease progression is excluded because lesion could not be measured -100 *Subjects did not receive the target cell dose Filing strategy to be agreed with Adaptimmune -120 261* 230 206* 207 200 204 202 209 205 208 201 Subject number Note: GSK3377794 subject to exercise of option by GSK GSK, data on file. 8 GSK3174998 OX40 agonist mAb

Survival in animal model (CT26) • GSK3174998 is one of four humanised OX-40s OX-40 + PD-1 100 in clinic 80 • Dual mechanism: enhancing effector T-cell and 60 aOX40 /aPD-1 suppressing T-regs 40

20 aOX40 Percent survival Percent control aPD-1 • Phase I Study started in eight cancers 0 20 30 40 50 60 70 80 90 Time (days) • Combination with Merck PD1 in 2016 Survival in animal model (CT26) OX-40 + TLR-4 100 • Combination with GSK TLR4 in 2017 TLR4a / aOX40 • Collaboration with MD Anderson 50

TLR4a Percent survival Percent Status: Phase I control aOX40 Indications: Solid tumours, Heme Malignancies 0 Planned Filing: 2020 0 50 100 150 Study day GSK, data on file. 9 GSK3359609 first-in-class ICOS agonist antibody

• Universal mechanism across multiple ICOS in ipilimumab-treated patients GSK3359609 cancers CD4 ICOS T cells

80 T cell Activation in-vitro

• Patient selection biomarker L 100 CD69+ CD4 T cells 24hr after stimulation  60 80 • Enhances T-cells associated with 40 60 survival 20 40

Cell count/ Cell 0 20 • Use after CTLA-4 and PD-1 in Baseline W7 W12 W24 0 unresponsive or refractory patients Ipilimumab Responders T CD4 cellsof total % 0.01 0.1 1 10 100 Ipilimumab Non-Responders ICOS Ab (ug/ml) • Possible anchor for use in combinations CD4 ICOS T cells T cell Proliferation in-vitro 100 • Collaboration with INSERM 25 Ki67+ CD4 T cells 48hr after stimulation 80 CD4 ICOS >4 20 60 15

40 OS (%) OS 20 10 CD4 ICOS ≤4 0 5 Status: Phase I start Q1 2016 0 12 24 36 48 60

% of total CD4 T T CD4 cellsof total % 0 Indications: Solid tumours, Heme Malignancies Time (months) 0.01 0.1 1 10 100 Planned Filing: 2020 ICOS Ab (ug/ml) DiGiacomo, Clin Immunol Immunother 2013 10 GSK2857916 BCMA-ADC

Bone Marrow Dissemination Model (SCID Mice) • B Cell Maturation Antigen

• Antibody Drug Conjugate (ADC) with MMAF (auristatin derivative)

• High-expression target in multiple myeloma

• ADCC enhanced

• Immunogenic cell death inducer

• Strong pre-clinical activity

• High potential for combinations

Status: Phase I Indications: Multiple Myeloma Tai et al, Blood (2014), 123(20):3128-38 Planned Filing: Data dependent (post 2020)

11 Immuno-Oncology at GSK Mission: Maximise patient survival Achieve a long-term leadership position in Oncology

Scientific Focus Tactics Goals

• Diversified pipeline • Optimise T-cell Immunity • Across key modalities • Transformational effects for Rationale: has delivered patients transformational medicines • Innovation • Maximise survival • 3rd generation targets, modalities & combinations • Pipeline sustainability • Synergies and transformational effects through combinations • Build world-class discovery • Long-term leadership position and development team in Oncology

• Fully-integrated programs from early discovery through licensure

• Partnerships • Best science • Access to combinations

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