1Screening -4–0Week

Biopsy* PK/PDmandatory

Q3W dosing from Week 12

*Indicated biopsies are mandatory for PK/PD cohort. Other biopsies are optional but strongly encouraged for all patients

Treatment until progression, death, or 2 years

PK/PDmandatory

Disease progression

2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 105

GSK1795091

IO combination: a, b or c

Study design

1Screening -4–0Week

Biopsy* mandatory

Q3W dosing from Week 13

Treatment until progression, death, or 2 years

mandatory Disease progression

2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 105

GSK1795091

IO combination: a, b, or c

Study design

*Indicated biopsies are mandatory for all expansion cohorts. Other biopsies are optional but strongly encouraged for all patients

Study aims To evaluate GSK1795091 in combination with immunotherapies that have complementary mechanisms of action:

GSK3174998 a humanised wild-type IgG1 anti-OX40 agonistic monoclonal antibody6

GSK3359609 an IgG4 ICOS agonist antibody that is designed to enhance T cell function and enable antitumour responses7

pembrolizumab a humanised IgG4 PD-1 antagonist antibody8

Trial in progress: a Phase I, open-label study of GSK1795091 administered in combination with immunotherapies in participants with advanced solid tumours (NCT03447314)Abstract No: 3946 | Poster No: 511TiP

Hansen AR1, Strauss J2, Chaves J3, Piha-Paul S4, Park H5, Garralda E6, Matheny C7, Carver J7, Moore A7, Hug B7

1Princess Margaret Cancer Centre, Toronto, ON, Canada; 2Mary Crowley Cancer Research Center, Dallas, TX, USA; 3Northwest Medical Specialists, Tacoma, WA, USA; 4University of Texas MD Anderson Cancer Center, Houston, TX, USA; 5Washington University, St Louis, MO, USA; 6Hospital Universitari Vall d’Hebron, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain; 7GSK, Collegeville, PA, USA

Authors

Presenting author: Aaron.Hansen@uhn.ca

Affiliations

AbbreviationsCNS, central nervous system; ctDNA, circulating tumour DNA; DCR, disease control rate; DLT, dose limiting toxicity; DoR, duration of response; ECOG, Eastern Cooperative Oncology Group; ICOS, inducible T-cell co-stimulator; Ig, immunoglobulin; IT, intratumoural; IV, intravenous; N-CRM, Neuenschwander-continual reassessment method; ORR, overall response rate; OS, overall survival; PD, pharmacodynamic; PD-1, programmed cell death protein 1; PD-L1, programmed cell death ligand 1; PFS, progression-free survival; PK, pharmacokinetic; Q3W, every 3 weeks; RECIST, Response Evaluation Criteria in Solid Tumours; SCCHN, squamous cell carcinoma of the head and neck; TAA, tumour associated antigen; TLR, toll-like receptor; TTR, time to response

DisclosuresARH: Advisory or Consulting Role: Boehringer Ingelheim, Boston Biomedical, Bristol-Myers Squibb, Genentech/Roche, GSK, Merck; Honoraria: AstraZeneca, Bristol-Myers Squibb, GSK, MedImmune, Merck, Novartis, Pfizer; Research funding: Boehringer Ingelheim, Bristol-Myers Squibb, GSK, Karyopharm Therapeutics, Merck, Novartis; JS: Advisory or Consulting Role: Dialectic Therapeutics, Tempus; Stock and Other Ownership Interests: Abbott Laboratories, AbbVie, Bristol-Myers Squibb, Intuitive Surgical, Johnson and Johnson, Merck; JChaves: Research funding: Acerta Pharma, Array BioPharma, Calithera, EMD Serono, GSK, Halozyme, Immune design, Incyte, Merck, Nektar, Novartis, Regeneron, Roche/Genentech, Tesaro, Zymeworks; SP-P: Research funding: AbbVie, Aminex, BioMarin Pharmaceutical, Boehringer Ingelheim, Bristol-Myers Squibb, Cerulean Pharma, Chugai Pharma, Curis, Five Prime Therapeutics, Genmab, GSK, Helix BioPharma, Incyte, Jacobio, MedImmune, Medivation, Merck Sharp and Dohme Corp, NewLink Genetics Corporation/Blue Link Pharmaceuticals, Novartis, Pieris Pharmaceuticals, Pfizer, Principia Biopharma, Puma Biotechnology, Rapt Therapeutics, Seattle Genetics, Taiho Oncology, Tesaro, TransThera Bio, XuanZhu Biopharma; HP: Research funding: Amgen, Ambrx, Array BioPharma, AstraZeneca, Bayer, BeiGene, Bristol-Myers Squibb, Daiichi Sankyo, EMD Serono, Gilead Sciences, GSK, Incyte, Lilly, Macrogenics, MedImmune, Medivation, Merck, Millennium, Novartis, Pfizer, Puma Biotechnology, Regeneron, Taiho Pharmaceutical, Vertex; EG: Research funding: Beigene USA, Blueprint Medicines Corporation, Cellestia Biotech, F. Hoffmann La Roche Ltd, Genentech, Genmab, Glycotope, Incyte, Kura Oncology, Lilly, Loxo Oncology, Macrogenics, Menarini Ricerche Spa, Merck, Sharp & Dohme de Espana, Novartis, Pharma Mar, SA, Pierre Fabre Medicament, Principia Biopharma, Sierra Oncology, Symphogen A/S; Travel and Accommodation Funding: Bristol-Myers Squibb, Glycotope, Menarini, Merck Sharp and Dohme; Advisory or Consulting Role: AstraZeneca, Boehringer Ingelheim, Ellipses Pharma, F. Hoffman/La Roche, Janssen Global Services, NEOMED Therapeutics Inc, Roche/Genentech; Speakers Bureau: Bristol-Myers Squibb, Merck Sharp and Dohme. CM, JCarver, AM and BH are employees of and stock/shareholders in GSK.

Presented at The European Society for Medical Oncology (ESMO) Congress, Barcelona, Spain September 27 – October 1, 2019.

Introduction Trial design

Context The ‘cancer immunity cycle’ is a series of steps by which the immune system recognises and kills tumour cells, which is counterbalanced by tumour and host factors that inhibit antitumour immune responses.1, 2

TLR agonists can activate antigen presenting cells and enhance a range of antitumour immune responses via production of inflammatory cytokines.3

GSK1795091 GSK1795091 is a synthetic TLR4 agonist that showed immunomodulatory activity in preclinical cancer models including; inducing proinflammatory cytokines, enhancing antigen presentation, activating T cells, and reducing T regulatory cells.4

GSK1795091 successfully completed a first-in-human, safety, PK and PD study using IV administration in healthy volunteers.5

Hypothesis Combining GSK1795091 with immunotherapies acting at complementary steps in the immune cycle is hypothesised to elicit greater antitumour activity compared with monotherapy approaches.

This trial is a:In patients with advanced solid tumours who have progressed on, or are ineligible for, standard therapy

The study will be conducted in two parts:

Objective:To assess safety and tolerability, PK and PD of escalating doses of GSK1795091 in combination with fixed doses of GSK3174998 (OX40), GSK3359609 (ICOS), or pembrolizumab (PD-1), and to identify recommended dose(s) of GSK1795091 for further evaluation.

Up to 6 participants per dose level may be enrolled into a PK/PD cohort for each combination, up to a maximum of 45 patients. Patients must consent to a mandatory baseline and an on-treatment biopsy collection in order to assess the effects of treatment on immune response in the tumour microenvironment.

Dose escalation will be guided by a N-CRM9 using occurrence of DLT as the model input.

GSK1795091 will be administered IV weekly for 12 weeks, including a 2-week GSK1795091 monotherapy run-in period; combination partners will be administered Q3W from Week 3 onwards.

Approximately

24 patients with advanced solid tumour cancers will be enrolled into each of the three treatment arms:

4 Trafficking of T cellsto tumours

6 Recognition of tumourcells by T cells

5 Infiltration of T cellsinto tumours

3 Priming and activation

a. GSK3174998 (OX40 agonist)b. GSK3359609 (ICOS agonist)

7 Killing of tumour cells

1 Release of tumour-associated antigens

2 Tumourantigen presentation

a. GSK3174998 (OX40 agonist)

b. GSK3359609 (ICOS agonist)

c. Pembrolizumab (PD-1 antagonist)

GSK1795091 (TLR4 agonist)

GSK1795091 (TLR4 agonist)

Lymph nodes Blood vessels

GSK1795091 (TLR4 agonist)

Study population

• Aged ≥18 years• Archival tumour tissue available if not feasible to obtain fresh biopsy• Disease that has progressed after standard therapies• Presenting with at least 1 measurable lesion per RECIST version 1.110

• ECOG performance status 0–1• Life expectancy of at least 12 weeks• Adequate organ function• Part 1 only:

○ Histological documentation of advanced solid tumour• Part 2 only:

○ Histological or cytological documentation of SCCHN ○ Additional criteria for Part 2a and b (OX40 and ICOS): received or ineligible for platinum-based therapy and PD-1/PD-L1 therapy

Medical conditions• Other malignant disease than the disease under study, or disease-free for <2 years• Symptomatic or asymptomatic CNS metastases requiring steroids within 2 weeks prior to first

dose of study treatment• Active autoimmune disease that has required immunosuppressive treatment in the last 2 years• Concurrent condition requiring immunosuppressive treatment within 28 days prior to first dose • Known human immunodeficiency virus infection• Current unstable liver or biliary diseasePrior therapy• Prior systemic or IT therapy with TLR agonist, OX40 and ICOS agonist at any time• Anticancer therapy or investigational therapy within 30 days or 5 half-lives• Prior radiation therapy, unless at least 1 non-irradiated lesion is available• Received transfusion of blood products or administration of colony-stimulating factors within

2 weeks before first dose of study treatment• Additional criteria for Part 2c (pembrolizumab): received prior PD-1/PD-L1 therapy

Main exclusion criteriaMain inclusion criteria

OR

OR

GSK1795091(50–250 ng IV)

GSK3174998(24 mg IV)a

GSK1795091(50–250 ng IV) b GSK3359609

(80 mg IV)

GSK1795091(50–250 ng IV) c pembrolizumab

(200 mg IV)

Initial expansion cohorts

of up to 15 patients with SCCHN will be enrolled in each treatment arm at the recommended dose(s) identified in Part 1.

Objective:To further characterise safety and tolerability, PK and PD, and to evaluate preliminary antitumour activity.

GSK1795091 will be administered IV weekly for the first 12 weeks, then Q3W, coinciding with the combination partner.

Study duration will be a maximum of 2 years from start of study treatment, with follow-up for disease progression and overall survival every 12 weeks after treatment discontinuation.

SCCHN was chosen for further study due to a considerable unmet need in this population and based on previous observed responses with other immunotherapies.

GSK1795091(optimal fixed dose)

GSK1795091(optimal fixed dose)

GSK1795091(optimal fixed dose)

a

b

c

OR

OR

GSK3174998(24 mg IV)

GSK3359609(80 mg IV)

pembrolizumab(200 mg IV)

Dose escalation Advanced solid tumours (N≤72)

SCCHN (N≤45)Cohort expansion

1

2

Current status

15 patients have been enrolled into the first 3 dose cohorts6 patients have been enrolled into the PK/PD cohorts 4 patients have been enrolled into the first dose cohort of each of the arms

began in April 2019

As of August 2019:

Enrolment began in March 2018

GSK1795091 GSK3174998 (OX40)aGSK1795091 GSK3359609 (ICOS)b

GSK1795091cAND

MulticentreOpen-labelPhase I Non-randomised Multi-country study

Study treatment

The IV mode of administration for GSK1795091 is supported by preclinical tests comparing IT and IV delivery (unpublished data).

IV administration of GSK1795091 potentially enables the targeting of tumours not amenable to IT injection.

1Endpoints Biomarker strategy

Target engagement and mechanism of action1. Clinical flu-like symptoms2. Cytokine/chemokine increases3. Immune cell trafficking and activation4. Tumour immune responses5. T-cell receptor diversity/clonality changes

Correlative analyses

1. Immune cell phenotypes associated with antitumour responses

2. Tumour TLR expression, and other clinical features associated with antitumour responses

3. Tumour gene signatures4. Tumour mutational burden and ctDNA5. Microbiome and association with efficacy or

safety parameters

Primary• Safety and tolerability

Secondary• Antitumour activity

(ORR, DCR, TTR, DoR, PFS and OS)• PK • Immunogenicity

Exploratory• PD, including effect on plasma

cytokines, circulating immune cells and immune function

Acknowledgements Study NCT03447314 is sponsored by GSK. Editorial support was provided by Aaron Borg and Leigh O’Connor-Jones of Fishawack Indicia Ltd, UK, and was funded by GSK.

References 1. Chen DS, Mellman I. Immunity 2013;39(1):1–10.2. Chen DS, Mellman I. Nature 2017;541(7637):321–30.3. Pradere JP, et al. Oncogene 2014;33(27):3485–95.4. Gao HX, et al. J Clin Oncol 2018;36(15_suppl):12055–12055.5. A Phase I, 2-part (Part 1 Being a Single Dose Escalation and Part 2, a Parallel Group)

Study of Toll-like Receptor (TLR4) Agonist (GSK1795091) in Healthy Subjects. Available from: clinicaltrials.gov/ct2/show/NCT02798978. [last accessed 21 August 2019]

6. Infante JR, et al. J Clin Oncol 2016;34(15_suppl):TPS3107–TPS3107.7. Angevin E, et al. J Clin Oncol 2017;35(15_suppl):TPS3113–TPS3113.8. Garon EB, et al. N Engl J Med 2015;372(21):2018–28.9. Neuenschwander B, et al. Stat Med 2008;27(13):2420–39.10. Eisenhauer EA, et al. Eur J Cancer. 2009;45:228–247.

pembrolizumab (PD-1)

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