Table 3. Treatment-related AEs Figure 4. PK and receptor occupancyBackground

Methods

Results

● Inducible T cell co-stimulator (ICOS) is a member of the B7/CD28 immunoglobulin (Ig) receptor superfamily.1

● ICOS expression is highly induced upon T cell receptor engagement with cognate antigen and activation(Figure 1).1

● ICOS provides a co-stimulatory signal augmenting T-cell proliferation, survival, cytokine production,cytotoxic function, and is involved in B cell function.2,3,4

● GSK3359609 alone and in combination with pembrolizumab was well tolerated in patients withadvanced solid tumors at the 0.001–3 mg/kg dose range.● Maximum tolerated dose was not reached; maximum administered dose was

3 mg/kg GSK3359609.● Majority of AEs were Grade 1/2 and not attributed to study treatment.● Treatment-related AEs leading to discontinuation occurred in 1 patient each in monotherapy

(n=62) and combination (n=36) at the highest dose level.● Dose proportional increases in GSK3359609 concentrations were observed.● PK/PD analysis showed ≥75% total ICOS receptor saturation across dosing interval at

GSK33590609 dose levels ≥0.3 mg/kg.● A range of doses (≥0.1–1 mg/kg) have shown biological and clinical activity (including in

patients with prior anti-PD-1/L1 exposure). These doses are being investigated further inexpansion cohorts to establish the recommended GSK3359609 dose.

● Preliminary biological and clinical data support the mechanism of action of a non-depletingICOS agonist as a clinical target.

● Doses over 0.1 mg/kg are being investigated further in expansion cohorts to establish therecommended GSK3359609 dose and assess clinical activity across different patient groups.

● Thank you to patients and families as well as site staff and GlaxoSmithKline (GSK) 204961 study team.● Funding for this study (NCT02723955) was provided by GSK in collaboration with Merck Sharp & Dohme Corp., a

subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Editorial support was provided by Clare Slater, CMPP PhD, ofFishawack Indicia Ltd., and was funded by GSK.

Conclusions

References

Acknowledgments

Table 1. Patient disposition by cohort and dose

GSK335609 Dose mg/kg

MonotherapyDose Escalation

MonotherapyPK/PD

CombinationDose Escalation

0.001 1 Not evaluated Not evaluated

0.003 1 Not evaluated Not evaluated

0.01 2 Not evaluated 5 (n=1 ongoing)

0.03 3 5 5

0.1 5 10 (n=4 ongoing) 5

0.3 3 14 (n=4 ongoing) 5 (n=2 ongoing)

1 4 3 (n=1 ongoing) 8 (n=3 ongoing)

3 3 8 8 (n=5 ongoing)

Total=98 22 40 36

Treatment-related safety● Treatment-related DLTs leading to discontinuation reported at 3 mg/kg GSK3359609 dose level:

● 1 patient in the monotherapy dose escalation group experienced Grade 3/4 elevations in alanineaminotransferase, aspartate aminotransferase, alkaline phosphatase, bilirubin, gamma-glutamyltranspeptidase, impaired liver function (serious) and Grade 1 amylase and Grade 3 lipase.

● 1 patient in the combination group experienced Grade 3 pneumonitis.● Serious AEs (SAEs) in monotherapy group: 1 patient (3 mg/kg) had impaired liver function (Grade 3).

● Confounded by progression in liver metastases and biliary tract obstruction that required stenting.● SAEs in GSK3359609 + pembrolizumab group: 4 patients had SAEs.

● Grade 5 pulmonary hypertension (GSK3359609 0.1 mg/kg + pembrolizumab 200 mg): occurred afterpatient off study treatment for 2 months; patient had comorbidities including hepatitis, pancreatitis andmethemoglobinemia (dapsone related).

● Grade 3 diarrhea (GSK3359609 0.3 mg/kg + pembrolizumab 200 mg): resolved with steroids.● Grade 3 hypotension (GSK3359609 1 mg/kg + pembrolizumab 200 mg): occurred after study

treatment infusion; resolved and did not result in treatment discontinuation.● Grade 3 pneumonitis and Grade 3 lower respiratory infection, which were not concurrent

(GSK3359609 3 mg/kg + pembrolizumab 200 mg): pneumonitis resolved with steroids; lowerrespiratory infection may be a flare due to pneumonitis; resolved with antibiotics and steroids.

Figure 1. ICOS mechanism of action

AE by preferred term

Monotherapy(Dose Escalation and PK/PD)

N=62

Combination Dose Escalation

N=36

All Grades Grade 3/4 All Grades Grade 3/4

Any TR-AEa, n (%) 22 (35) 3 (5) 15 (42) 4 (11)

Fatigue 9 (15) 0 1 (3) 0

AST increased 3 (5) 2 (3) 3 (8) 0

Diarrhea 3 (5) 0 1 (3) 1 (3)

Pyrexia 0 0 3 (8) 0

GSK3359609 monotherapy: melanoma patient

1Princess Margaret Cancer Centre, Toronto, ON, Canada; 2Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN, USA; 3START Madrid-FJD, University Hospital "Fundacion Jimenez Diaz", Madrid, Spain;4University Hospital of Siena, Siena, Italy, 5Netherlands Cancer Institute – Antoni van Leeuwenhoek, Amsterdam, Netherlands, 6Vall d`Hebron Institute of Oncology (VHIO)-Cellex Center, Barcelona, Spain;

7Austin Hospital, Melbourne, Australia, 8Peter MacCallum Cancer Centre and the University of Melbourne, Melbourne, Australia; 9Sir Charles Gairdner Hospital, Nedlands, Australia; 10Fox Chase Cancer Center, PA, USA; 11New York University Langone Medical Center, NY, USA; 12GlaxoSmithKline, Research Triangle Park, NC, USA; 13GlaxoSmithKline, Collegeville, PA USA;

14Merck & Co Inc, North Wales, PA, USA; 15GlaxoSmithKline, Collegeville, PA, USA; 16Gustave Roussy Institut de Cancérologie, Villejuif, France

First in Human Study with GSK3359609, Inducible T cell Co-stimulator Receptor Agonist in Patients with Advanced, Solid Tumors: Preliminary Results from INDUCE-1

Hansen AR1, Bauer TM2, Moreno V3, Maio M4, Groenland S5, Martin-Liberal J6, Gan H7, Rischin D8, Millward M9, Olszanski AJ10, Cho DC11, Paul E12, Ballas M13, Ellis C13, Zhou H13, Yadavilli S13, Shaik JS13, Schmidt EV14, Hoos A15, Angevin E16

No. 1138PD

Presented at the ESMO 2018 Congress, Munich, Germany, 19–23 October 2018

Disclosures

APC, antigen presenting cell; ICOS-L, ICOS ligand; TCR, T cell receptor; MHC, major histocompatibility complex

aOccurring in ≥3 patients; AE, adverse event; AST, aspartate aminotransferase; TR-AE, treatment-related AE

● GSK3359609 is a humanized IgG4 antibody selected for its potent binding, agonist activity againsthuman ICOS and low/no depleting effects5

● Engagement of ICOS to stimulate the agonist function is hypothesized to translate into an optimaltherapeutic effect4,6

● The unique mechanistic profile of GSK3359609 offers an opportunity to investigate the antitumorpotential of targeting a T cell co-stimulator alone and in combination with pembrolizumab.

● INDUCE-1 (204691; NCT02723955) is a first-in-human study evaluating the safety, pharmacokinetics(PK), pharmacodynamics (PD), and antitumor activity of GSK3359609 alone and in combination withpembrolizumab in selected solid tumors.● INDUCE-1 consists of dose escalation and cohort expansion phases; cohort expansion phases are

ongoing in several tumor types.

ObjectivesPrimary● Determine safety, tolerability, and maximum tolerated/administered dose of GSK3359609 as

monotherapy and in combination with pembrolizumab.

Secondary● Determine recommended GSK3359609 dose(s) for further exploration; evaluate preliminary antitumor

activity; characterize PK; evaluate immunogenicity.

Exploratory● Evaluate PD effects; explore associations between antitumor activity, PK and biomarkers in tissue and

blood.

Patients – key inclusion criteria● Histological or cytological documentation of advanced/metastatic or recurrent invasive malignancy.● Disease that has progressed after standard therapy for the specific tumor type, or for which standard

therapy has proven to be ineffective, is intolerable, or is considered inappropriate, or if no furtherstandard therapy exists.● ≤5 prior lines of therapy for advanced disease including both standard of care and investigational therapies.

● Measurable disease according to Response Evaluation Criteria in Solid Tumors v1.1 guidelines;Eastern Cooperative Oncology Group performance status 0–1; adequate organ function.

● Agree to undergo a pre-treatment and on-treatment biopsy and have disease amenable to biopsyrequired in PK/PD dose expansion cohorts.

Patients – key exclusion criteria● Prior anticancer or investigational therapy within 30 days or five half-lives, whichever is shorter.● ≥Grade 3 toxicity related to prior immunotherapy and led to treatment discontinuation.● History of invasive malignancy other than disease under study unless disease-free for ≥2 years.● Central nervous system (CNS) metastasis; exceptions include previously treated CNS metastasis that is

asymptomatic and has no requirement for steroids at least 14 days prior to first dose of study treatment.● Active autoimmune disease that required systemic treatment within the last 2 years.● History of idiopathic pulmonary fibrosis, pneumonitis requiring steroids, interstitial lung disease, or

organizing pneumonia.

Study design (Figure 2)● Accelerated titration design for the first 3 dose levels in Part 1A; 1 patient enrolled at each dose level.● Modified toxicity probability interval method informed subsequent dose escalation decisions in Parts

1A/2A (minimum 3 patients per dose level).● Starting dose of 0.001 mg/kg: the projected human dose based on the minimally anticipated biologic

effect observed in preclinical studies.

1. Hutloff A., et al. Nature 1999; 397: 263-266. 2. Simpson TR, et al. Curr Opin Immunol 2010;22: 326-332.3. Mak T, et al. Nat Immunol 2003; 765-772.

4. Fan X, et al. J Exp Med. 2014; 211:715-725.5. Mayes P, et al. Nat Rev Drug Disc. 2018; 17: 509-527.6. Brett S, et al. ESMO 2018 poster: Abstract 1840P.

Presenting author email address: Aaron.Hansen@uhn.ca

Figure 3. Duration of study treatment: Individual patient data

B. Peak receptor occupancy corresponding to maximum plasma concentration; similar relationship for CD8+ receptor occupancy (data not shown)

Week 9

Figure 2. Study design

Dose escalation

Dose escalation

Part 1A: GSK3359609 monotherapy

GSK3359609 monotherapy PK/PD cohort

● Parts 1A and 2A: escalating doses of GSK3359609 via IV infusion every 3 weeks

● Part 2A: 200 mg pembrolizumab via IV every 3 weeks

● 28-day DLT assessment period● Imaging every 9 weeks for 54 weeks then

12-weekly thereafter● Blood and tumor biopsy (mandatory in

PK/PD cohort) collected at baseline andon-treatment time points for PD analyses; blood collected for PK and immunogenicity

● Safety monitored throughout

Treatment period ≤2 years:Interventions and assessments

● Every 12 weeks● Survival● Subsequent

anti-cancer therapy

Follow-up period ≤2 years: Assessments

Part 2A: GSK3359609/pembrolizumab

1. NSCLC (including targeted mutations)2. Head & Neck (any histology)3. Melanoma (cutaneous/ocular) 4. Esophageal SCC5. Bladder/Urothelial

6. Prostate7. Cervical 8. Colorectal (MSS/MSI-H) 9. Malignant pleural mesothelioma

Tumor types

Table 2. Patient demographics and disease characteristics

Monotherapy Dose Escalation

N=22

Monotherapy PK/PDN=40

Combination Dose Escalation

N=36

Sex, n (%), female / male 12 (55) / 10 (45) 17 (43) / 23 (58) 14 (39) / 22 (61)

Median age, years (min, max) 59 (36, 78) 59 (42, 81) 58 (23, 73)

Primary tumor type, n (%)Colorectal, MSS/MSI-H*CervicalBladder/UrothelialHead/Neck, any histology/locationMelanomaMesotheliomaNSCLCProstate Esophageal, SCC

8 (36)3 (14)2 (9)2 (9)2 (9)2 (9)2 (9)1 (5)

0

10 (25)6 (15)1 (3)6 (15)8 (20)3 (8)2 (5)2 (5)2 (5)

11 (31)6 (17)2 (6)6 (17)3 (8)3 (8)1 (3)3 (8)1 (3)

≥2 target lesions locations, n (%) 15 (68) 25 (63) 16 (44)

≥3 prior systemic regimens in advanced/metastatic setting, n (%) 7 (32) 16 (40) 13 (36)

Prior PD-1/L1 inhibitor, n (%) 8 (36) 15 (38) 7 (19)

Pre-treatment

Day 43 on treatment

Patient case studies

GSK3359609/Pembrolizumab combination therapy: PD changes in a HNSCC patient

Pre-treatment

Day 43 on treatment

PD1+ CD4+ CD8+ GranzymeB+

Ki67+ CD4+ CD8+GranzymeB+

ICOS+ CD4+ CD8+ PDL1+

A. Dose-proportional PK from 0.01 to 3 mg/kg; no PK difference between monotherapy and combination with pembrolizumab

DLT, dose-limiting toxicity; MSS, microsatellite stability; MSI-H, high microsatellite instability; NSCLC, non-small-cell lung carcinoma; SCC, squamous cell carcinoma

History:● 53Y female, Diagnosis: Stage IV KRAS mutant, MSI-H

CRC.

● Prior regimens: FOLFOX; capecitabine;FOLFIRI/bevacizumab; atezolizumab/selicrelumab ~3months, BoR: PD; Anti-CEA ADC ~2 months, BoR:PD; RO695688/obinutuzumab ~2 months, BoR: PD.

● Disease burden: 4 target lesions (liver and lung): sumof diameters = 123 mm.

Study Treatment:● GSK3359609 1 mg/kg + pembrolizumab 200 mg

ongoing.

A. Monotherapy Dose Escalation

B. PK/PD Cohort

C. Combination Dose Escalation

Esophagus

Malignant pleural mesothelioma

Colon/Rectum

Prostate

Head and neck

Melanoma

Non-small-cell lung

Cervix

Bladder/Urothelial

*Monotherapy Dose Escalation & PK/PD: 100% MSS; Combination Dose Escalation: 64% MSS, 36% MSI-HPD-L1, programmed death-ligand 1

Baseline Week 9 Week 36

History:● 53Y male; Stage IIIc nodular melanoma

[BRAF/cKIT mutation negative].● Prior regimens: ipilimumab/nivolumab

~ 2 months; nivolumab ~ 1 year,

● Best overall response (BoR): SD.

● Disease Burden: 5 target lesions (LN, Lung,SubQ): sum of diameters = 225 mm. Multiple non target lesions.

Study treatment: ● GSK3359609 monotherapy to Week 48;

0.1 mg/kg x 3 doses, then 1 mg/kg.

● BoR: PR● Tumor biopsies collected after 43 days on-treatment showed greater number of T cells, granzyme-B

expressing CD8 Tc cells, PD1 expressing T cells and proliferating T cells while fewer proliferating tumor cells.

Ongoing

0 9 18 27 36 45Weeks in Treatment

3.000

1.000

0.300

0.100

0.030

GSK

3359

609

dosa

ge (m

g/kg

)G

SK33

5960

9 do

sage

(mg/

kg)

0 9 18 36Weeks in Treatment

27

3.000

1.000

0.300

0.100

0.030

0.010

0.0010.003

0 9 18 27 36 54 6345Weeks in Treatment

Ongoing

3.000

1.000

0.300

0.100

0.030

0.010

GSK

3359

609

dosa

ge (m

g/kg

)

Part 1A dose (mg/kg) 0.03 0.1 0.3 1 3

Time after first dose (days)

Part 1A dose (mg/kg)Part 2A dose (mg/kg)

0.010.01

0.030.03

0.10.1

0.30.3

11

33

Time after first dose (days)

Mea

n C

D4+

rece

ptor

occ

upan

cy (%

)

00

20

80

120

1 7 14 21

40

100

60

Med

ian

plas

ma

GSK

3359

60

conc

entra

tion

(µg/

mL)

0

0.1

1

10

100

1 2.54.5 7 14 21

Limit of quantification (0.1 µg/mL)

History:• 74Y male, Stage IIIc HPV- HNSCC• Prior regimens: cetuximab ~3 months, BoR: PR

Study treatment:• GSK3359609 0.3 mg/kg + pembrolizumab 200 mg combination therapy• Post treatment sample showed an increase in Granzyme B+ and PD-L1+ cells compared with

pre-treatment samples.

GSK3359609/Pembrolizumab combination therapy: MSI-H CRC patientWeek 9

Week 18 Week 27

Baseline

ARH: Research support – Genentech/Roche, Merck, GSK, Bristol-Myers Squibb (BMS), Novartis, Boston Biomedical, Boehringer-Ingelheim. TMB:Consulting or advisory role – Guardant Health, Loxo, Pfizer, Moderna Therapeutics, Ignyta; Research funding – Daiichi Sankyo, Medpacto, Inc, Incyte, Mirati Therapeutics, MedImmune, Abbvie, AstraZeneca (AZ), Leap Therapeutics, MabVax, Stemline Therapeutics, Merck, Lilly, GSK, Novartis, Pfizer, Principa Biopharma, Genentech/Roche, Deciphera, Merrimack, Immunogen, Millennium, Ignyta, Calithera Biosciences, Koltan Pharmaceuticals, PrincipaBiopharma, Peleton, Innumocore, Roche, Aileron Therapeutics, BMS, Amgen, Moderna Therapeutics, Sanofi, Boehringer-Ingelheim, Astellas Pharma, Five Prime Therapeutics, Jacobio. VM, SG, JML: no conflicts of interest. M.Miao: Advisory Boards and Travel – GSK, BMS, AZ, Roche, Merck Sharp & Dohme (MSD), Incyte. Patient’s fee for subjects enrolled in clinical trials from: BMS, GSK, AZ, Roche, Merck, MSD, Incyte, Novartis. HG: Consulting or advisory role – Abbvie, Merck Serono; Speakers Bureau – Abbvie, BMS, Ignyta; Research funding – Abbvie; Travel, accommodations, expenses –Abbvie, Ignyta, MSD. DR: Advisory Boards/Steering Committees (uncompensated) – Merck, Amgen, Regeneron, BMS; Research funding from Genentech/Roche, Merck, Amgen, Regeneron, BMS, GSK. M.Millward: Advisory boards – MSD, BMS, Roche, AZ. AJO: Consulting or advisory role –BMS; G1 Therapeutics; Kyowa Hakko Kirin; Merck; Takeda; Research funding: Amgen, BMS, EMD Serono, Immunocore, Incyte, Kura, Kyowa Hakko Kirin, Lilly, Pfizer, GSK, Takeda, Checkmate, Boston Biomedical, Astellas, Targovax. DCC: Honoraria – BMS, Exelixis, Genentech; Consulting or advisory role – Pfizer, Prometheus. EA: Consulting or advisory role – MSD, GlaxoSmithKline, Celgene Research; Travel, accommodations, expenses –AbbVie, Roche, Sanofi, Pfizer. EP, MB, CE, HZ, SY JSS, AH: employees of and hold stocks/shares in GSK. EVS: employee of and hold stocks/shares in Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA

ICOS+ CD4+ CD8+ PDL1+ PD1+ CD4+ CD8+ GranzymeB+

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