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

1. GSK Oncology
Axel Hoos, MD, PhD
Senior Vice President, Oncology R&D
March 8, 2017

2. Oncology R&D Strategy
Maximizing survival through transformational medicines and combinations
2
Cancer Epigenetics
Cell & Gene Therapy
Immuno-Oncology
Reprogram cancer
cells
Stimulate anti-tumour
immunity
Cells as medicines
First-in-class medicines
Long-term survival &
cures
Combination therapy
GSKpipeline

3. Today CURE
SOC
replacements
Elimination of
chemotherapy
from SOC
regimens
Substantial survival
improvements
Across wide
populations
New
technologies
Expansion of the
toolbox
Complex
combinations
Maximise efficacy
Immune
profiling
Patient selection
to predict
response
Improved endpoints
Accelerated
development
3
Main Trends

4. Oncology – Pipeline Snapshot
4
† Collaboration with a third party.
Notch2/3 (tarextumab)
†
SCLC
BET inhibitor (GSK525762)
LSD-1 inhibitor (GSK2879552)
EZH2 inhibitor (GSK2816126)
Solid tumours, Heme Malignancies
AML, SCLC
Solid tumours, Heme Malignancies
PRMT5 inhibitor (GSK3326595) †
Solid tumours, Lymphoma
Novel small molecule targets
PI3K beta inhibitor (GSK2636771) Prostate cancer
CAR-T and TCR-Ts
NY-ESO-1 TCR-T †
Sarcoma, Multiple Myeloma, NSCLC, Ovarian cancer, Melanoma
BCMA ADC (GSK 2857916)
†
OX40 agonist (GSK3174998)
†
Solid tumours, Heme Malignancies
ICOS agonist (GSK3359609)
†
TLR4 agonist (GSK1795091)
Novel small molecule targets
ImmTacs
†
mAb-dAbs and dual-specific Abs
Solid tumours
Cancer
Multiple Myeloma
Immuno-Oncology
Epigenetics
Cell & gene therapy
Other targeted therapies
Mechanism Pre-clinical Phase I Phase II

5. 5
Immuno-Oncology: 3 Generations of Therapies
Generation 1 Generation 2
PROVENGE
sipuleucel-T
(Cell Therapy)
YERVOY
ipilimumab (CTLA-4)
Generation 3
Multiple therapies
under
development
OPDIVO
nivolumab (PD-1)
2010 2011 2012 20152013 2014 2016 2017 2018 2019
KEYTRUDA
pembrolizumab (PD-1)
BLINCYTO
blinatumomab (BITE)
IMLYGIC
T-Vec (Oncolytic Virus)Under
development
Approved
Hoos A, Nat Rev Drug Discov 2016
TECENTRIQ
atezolizumab (PD-L1)

6. 3rd Generation Opportunities
Spectrum of immuno-oncology modalities
Cancer Vaccines
Cytokines
Cellular Therapies
T-cell Checkpoint Modulators
Oncolytic Viruses
NK Cells
Checkpoint Modulators
-
Adjuvants
“Connector” Bi-specific Abs -
Dual-specific Abs
Small Molecules
6
T-Cell Immunity
Innate Immunity
B-Cell Immunity
Adaptive Immunity
Approved therapies

7. 3rd Generation Opportunities
GSK’s multi-modality pipeline
Cancer Vaccines
T-Cell Immunity
Cytokines
Cellular Therapies
T-cell Checkpoint Modulators
Innate Immunity
B-Cell Immunity
Adaptive Immunity
Oncolytic Viruses
NK Cells*
Checkpoint Modulators
-
Adjuvants
“Connector” Bi-specific Abs -
Dual-specific Abs
Small Molecules
GSK Pipeline 7* in planning

8. B Cell maturation antigen (BCMA)
Antibody drug conjugate (ADC) with MMAF
(auristatin derivative)
High-expression target in multiple myeloma
and some NHL
Immunogenic cell death inducer
Phase I efficacy in refractory population:
~67% RR at > phase II dose
Next steps:
- Rapid development for monotherapy
- Combinations with SOC and novel agents
8
All doses: ORR = 8/30 (27%; 95% CI: 12.3%, 45.9%)
At >Ph2 dose 3.4 mg/kg: ORR= 6/9 (66.7%; 95% CI: 0.29, 0.92%)
Safety observations:
Thrombocytopenia, transient
Corneal toxicity: dry eye, blurry vision, reversible
Phase I data presented at ASH December 2016
ASH: American Society of Hematology.
GSK2857916: First-in-class anti-BCMA-ADC,
proof of concept in multiple myeloma

9. GSK3174998 is one of several OX-40s in clinic
Dual mechanism: enhancing effector T-cell and
suppressing T-regs
Phase I Study under way in eight cancers
Combination with Merck PD1 started 3Q16
Combination with GSK TLR4 expected to start
in 2H2017
Collaboration with MD Anderson
GSK3174998 OX40 agonist mAb
aOX40
TLR4a
TLR4a / aOX40
control
Survival in animal model (CT26)
OX-40 + TLR-4
Percentsurvival
Study day
0 50
0
50
100
100 150
Survival in animal model (CT26)
OX-40 + PD-1
control aPD-1
aOX40
aOX40 /aPD-1
Percentsurvival
Time (days)
20 30 40 50 60
0
20
40
60
80
100
70 80 90
9Source: GSK, data on file.

10. Uniquely engineered IgG4 mAb with agonist
function and no cell depletion
Evolved from patient selection biomarker
Enhances T-cells associated with clinical
benefit
Universal mechanism across multiple cancers:
Phase I ongoing in 8 cancers
Possible use after CTLA-4 and PD-1 in
unresponsive or refractory patients
Possible anchor for combinations: Expected
start in combo with Merck PD-1 in 2Q17
GSK3359609 First-in-class ICOS agonist mAb
10
ICOS in ipilimumab-treated patients GSK3359609
Cellcount/L
Ipilimumab Responders
Ipilimumab Non-Responders
Baseline W7 W12 W24
0
20
40
60
80
CD4 ICOS T cells
12 24 36 48
0
20
40
60
100
CD4 ICOS T cells
OS(%)
80
60
Time (months)
CD4 ICOS >4
0
CD4 ICOS ≤4
T cell Proliferation in-vitro
%oftotalCD4Tcells
ICOS Ab (ug/ml)
Ki67+ CD4 T cells 48hr after stimulation
0.01 0.1 1 10 100
0
5
10
15
20
25
%oftotalCD4Tcells
ICOS Ab (ug/ml)
T cell Activation in-vitro
CD69+ CD4 T cells 24hr after stimulation
0
20
40
60
80
100
0.01 0.1 1 10 100
DiGiacomo, Clin Immunol Immunother 2013

11. GSK1795091: TLR4 agonist
Pre-clinical combination synergy
TLR4 + OX40
TLR4 + ICOS
11
Glycolipid TLR-4 agonist compound
Phase I in healthy volunteers under way to
determine dose and PD effects
Phase I combination with OX-40 in cancer patients
expected to start 2H17
Activates dendritic cells and innate immunity,
positively modulates tumour microenvironment
Strong combination potential with several IO
agents
Potential mechanistic synergies with OX40 and
ICOS agonist mAbs

12. TCR T-cell therapy
50% ORR in synovial sarcoma
Ongoing studies in myeloma, ovarian
cancer and other solid tumours
Planned studies in combination with
checkpoint modulators
FDA Breakthrough designation
EMA PRIME designation
Collaboration with Adaptimmune
NY-ESO-1 TCR-T Cell Therapy
12
Baseline Day 2: Inflammation Day 100: CR
Sarcoma Phase I/II: Best response in treated patients (N=12)*
Sarcoma Phase I/II: Individual patient complete response (CR)
Note: GSK3377794 subject to exercise of option by GSK
Excludes 3 subjects who did not receive a T-Cell Infusion.
One subject with disease progression is excluded because lesion could not be measured
*Subjects did not receive the target cell dose
Stable disease
-15 -16
-26
-50
-55
-64-58
-100
-70
1517
Subject number
Confirmed complete or partial response
261* 230 206* 207 200 204 202 209 205 208 201
Best response
-120
-100
-80
-60
-40
-20
0
20
40
60
Changeintargetlesionfrom
baseline(%)
Source: GSK, data on file.

13. Partnerships
GSK partnerships in Cell Therapy and Clinical Translational Research
13
And others…
Cell Therapy Oncology Clinical & Translational Consortium
13

14. Dhanak et al Nature, 2013
14
Epigenetics clinical programs
LSD1
EZH2
PRMT5
BET

15. ‘762 Blocks binding of BET family proteins (BRD2, 3 and 4) to acetylated histones
causing targeted changes in gene expression including oncogene silencing
Nature 2010;468:1119-1123
Preclinical data: Activity of GSK525762 in many cancer types (gIC50 < 1 M)
0.001
0.01
0.1
1
10
100
gIC50,µM
15
Broad activity across multiple tumor types – preclinical cell line models
GSK525762: BET inhibitor

16. 16
†
•Across all dose cohort (n=17):12% RR
•At 80/100 mg doses (n=9): 22% RR
Preliminary evidence of clinical activity in
NUT midline carcinoma (NMC) (AACR 2016)
•Solid Tumor: CRPC and ER positive BC expansion cohorts
completed; TNBC, SCLC, NMC cohorts ongoing
•Heme: Dose finding in AML completed; dose finding in NHL and
MM ongoing; expansion cohorts commencing April 2017
•Anticipate presenting heme clinical data by YE 2017
Progress in Ph I since AACR 2016
•Pre-clinical data suggest combination synergy
•Combo in ER positive BC with fulvestrant (active)
•Combo in mCRPC with abiraterone or enzalutamide (start ~2Q)
•Other novel combos in 2017 and 2018
Expect start of combination studies in 2017
12 / 17 patients with NMC presented (5 non-evaluable ).
2 mg QD
4 mg QD
80 mg QD #5
80 mg QD #8
X
X
4 mg QD
16 mg QD
100 mg QD #1
80 mg QD #2
60 mg QD #4
100 mg QD #3
80 mg QD #7
80 mg QD #9
Study day
200
-40
100
80
60
40
20
0
-20
-60
-80
-100
Spider plot of % change from baseline in target lesion diameter
X
X XX
150100500
GSK525762: Potential First-in-class BET Inhibitor
Early clinical efficacy in NMC; Progress in many tumour types

17. Scientific Focus
• Optimise T-cell Immunity
• Re-program cancer cells
• Cells as medicines
• Synergies and transformational
effects through combinations
Tactics
• Diversified pipeline
• Across key modalities
• Innovation
• 3rd generation targets,
modalities & combinations
• Build world-class discovery
and development team
• Fully-integrated programs from
early discovery through licensure
• Partnerships
• Best science
• Access to combinations
Goals
• Transformational effects for
patients
• Maximise survival
• Pipeline sustainability
• Long-term leadership position
in Oncology
Mission: Maximise patient survival
Achieve a long-term leadership position in Oncology
Oncology at GSK
17