SOCLTFU up to 15 years

(Study 208750)

SOCLTFU up to 15 years

(Study 208750)

GSK3377794 Monotherapy(single IV infusion)of 1x109 to 8x109 transduced cells

Treatment

Screening

Follow-up

Enrollment for Arm 1will be completed beforecompleting enrollmentof patients to Arm 2

≥20 patients assigned toeither Arm 1 or Arm 2

EOT

EOTGSK3377794 (single IV infusion)of 1x109 to 8x109 transduced cells

Pembrolizumab (200 mg IV Q3W)starting Week 3 or Week 6 if toxicities

Patients positive for:HLA-A*02:01 ±HLA-A*02:05 ±HLA-A*02:06-and-NY-ESO-1 ± LAGE-1ain bone marrow

Visits daily forfirst 4 daysfollowingT-cell infusion

then visitson Weeks1, 2, 3, 4,6, 15, 24

then visits every 6 weeks untilWeek 72 and every 12 weeks thereafter until Week 108*

Arm 1(n=10)

Arm 2(n=10)

Visits every 6 monthsfor 5 years, then yearly

PART Lympho-depletion/treatment 3

Treatment eligibility (I/E)Baseline evaluations

LymphodepletionFludarabine/cyclophosphamide

G-CSF(Day -4 if clinically needed)

Study treatment

Leukapheresis/manufacture

Leukapheresis

Bridging therapy(if clinically needed)

Cell manufacturing

PART2

PART Eligibilityscreening

1

Screening ICF

Treatment assignment

Study eligibility (I/E)

ICF for Parts 2 and 3

HLA-A*02:01,HLA-A*02:05,and/orHLA-A*02:06blood testing

NY-ESO-1/LAGE-1aexpressionbone marrow testing

Rapoport AP1, Hoffman JE2, Kaufman JL3, Blouch K4, Butler E4, DeYoung MP4, Farsaci B4, Hasan AN4, Holmes AP4, Huff A4, Jain A4, Chisamore MJ5, Nishihori T6

1University of Maryland Greenebaum Comprehensive Cancer Center and School of Medicine, Baltimore, MD, USA; 2Sylvester Comprehensive Cancer Center, University of Miami Health System, Miami, FL, USA; 3Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA; 4GlaxoSmithKline, Collegeville, PA, USA; 5Merck & Co., Inc., Kenilworth, NJ, USA; 6Moffitt Cancer Center, Tampa, FL, USA

Open-Label Pilot Study of Genetically Engineered NY-ESO-1 Specific T Cells (GSK3377794) Alone or in Combination With Pembrolizumab in Relapsed and Refractory Multiple MyelomaPoster No. 455

Presented at the American Society for Clinical Oncology (ASCO) Congress, Virtual Scientific Program, May 29–31, 2020

Please find the online version of this poster by scanning the QR code or via http://tago.ca/ASCO_15

Copies of this poster obtained through Quick Response (QR) Code are for personal use only and may not be reproduced without

permission from ASCO® and the author of this poster.

Background

AbbreviationsCAR-T, chimeric antigen receptor T cells; CDR, complementarity-determining region; CNS, central nervous system; DoR, duration of response; ECOG, Eastern Cooperative Oncology Group; EOT, end of treatment; G-CSF, granulocyte colony stimulating factor; HLA, human leukocyte antigen; ICF, informed consent form; I/E, inclusion/exclusion; IgG4, immunoglobulin G4; IMWG, International Myeloma Working Group; IV, intravenous; LAGE-1a, L-antigen family member 1 isoform A; LTFU, long-term follow-up; MGUS, monoclonal gammopathy of undetermined significance; MM, multiple myeloma; MRD, minimal residual disease; NY-ESO-1, New York esophageal squamous cell carcinoma 1; ORR, overall response rate; OS, overall survival; PD-1, programmed cell death protein 1; PD-L1, programmed cell death ligand 1; PFS, progression-free survival; PR, partial response; PS, performance status; Q3W, every 3 weeks; RT-PCR, reverse transcription polymerase chain reaction; SOC, standard of care; TCR, T-cell receptor; TTR, time to response.

DisclosuresAPR: has no relationships to disclose. JEH: stock and other ownership interests: Loxo, Syndax, Sunesis Pharmaceuticals; honoraria: Celgene; consulting or advisory role: Celgene; speakers’ bureau: Celgene. JLK: consulting or advisory role: Janssen, Takeda, Celgene, Bristol-Myers Squibb, Karyopharm Therapeutics, Sanofi, Amgen, Tecnofarma; travel, accommodations, expenses: Janssen, Celgene, Bristol-Myers Squibb, Sanofi, Amgen, Takeda; honoraria: Tecnofarma; research funding: Merck, Celgene, Janssen, Sutro Biopharma Inc, Fortis, Amgen, AbbVie/Genentech, Bristol-Myers Squibb. KB: employee of GSK. EB, MPD: employees and stockholders in GSK. BF: employee of GSK; travel, accommodations, expenses: GSK. ANH: employee of GSK; stock and other ownership interests: GSK, Merck; patents, royalties, other intellectual property: Atara Biotherapeutics; travel, accommodations, expenses: GSK. APH: employee of Veramed UK; other relationship: GSK. AH: employee and stockholder in GSK and Pfizer. AJ: employee of GSK; stock and other ownership interests: CytomX Therapeutics. MJC: employee and stockholder in Merck. TN: research funding: Novartis, Karyopharm Therapeutics, Celgene.

AcknowldgementsThis study is funded by GlaxoSmithKline (GSK; 208470; NCT03168438). Medical writing assistance was provided by Tiffany Brake, PhD, and Gemma Corr, DPhil, at Fishawack Indicia Ltd, UK, and was funded by GSK.

Ethics approval statementThis study will be conducted under approval by the appropriate institutional review boards and independent ethics committees.

Encore statementThese data are presented on behalf of the original authors with their permission. A similar presentation was presented at the ASH Annual Meeting, Orlando, FL, USA, Dec 7–10, 2019.

References1. Ping Y, et al. Protein Cell 2018;9:254–66.2. Rapoport AP, et al. Nat Med 2015;21:914–21.3. Stadtmauer EA, et al. Blood Adv 2019;3:2022–34.4. D’Angelo SP, et al. J Clin Oncol 2018;3(15_suppl):3005.5. Robbins PF, et al. Clin Cancer Res 2015;21(5):1019–27.

6. Robbins PF, et al. J Clin Oncol 2011;29(7):917–24.7. Andrade VCC, et al. Cancer Immunity 2008;8:2.8. van Rhee F, et al. Blood 2005;105:3939–44.9. Fraietta JA, et al. Nat Med 2018;24:563–71.10. Lee HT, et al. Molecules 2019;24:E1190.

T-cell therapyAdoptive T-cell therapy aims to generate an antitumor T-cell immune response by infusing a cancer patient’s own T cells that have been extracted, engineered, and expanded to express a tumor-specific TCR.1

Emerging clinical data demonstrate that adoptive cellular therapy has potential to be practice-changing in the management of relapsed/refractory MM.1-3

NY-ESO-1–specific T cells (GSK3377794) are autologous polyclonal T cells transduced by a self-inactivating lentiviral vector to express an affinity-enhanced TCR capable of recognizing NY-ESO-1 or LAGE-1a antigenic peptides in complex with HLA-A*02 (Figure 1).2,3

Clinical experience with GSK3377794In prior studies, encouraging clinical activity has been observed with GSK3377794 treatment in patients with synovial sarcoma, melanoma, or myxoid/round cell liposarcoma, and in patients with MM receiving GSK3377794 after autologous stem cell transplant.2–6

NY-ESO-1 and LAGE-1a are immunogenic cancer/testis antigens frequently overexpressed in MM and are linked to poor clinical outcome.7–8

Multiple Phase I and II trials are evaluating GSK3377794 in solid tumors.PD-1 expression on CD8 T cells has been observed in patients with MM previously treated with GSK3377794 and can limit adoptive immune response. • PD-1 expression has also been described as a mechanism of resistance and

relapse in CD19 CAR-T cell trials.9

Combination therapyPembrolizumab, a selective humanized IgG4 anti-PD-1 monoclonal antibody that blocks the interaction of PD-1 with PD-L1 and PD-L210 may synergize with immunomodulatory drugs to enhance tumor suppression.We hypothesize that GSK3377794 alone, or in combination with the anti-PD-1 inhibitor pembrolizumab, may result in an antitumor effect in MM.

To evaluate safety and efficacy of GSK3377794 alone or in combination with the anti-PD-1 inhibitor, pembrolizumab, in patients with MM.Figure 1. GSK3377794 mechanism of action

TCRβ - chain

β CDRloops

β 2m

TCRα - chain

α CDRloops

EnhancedTCR

Peptide

HLA

HLA – A2

Alphachain

Betachain

CDRs

Constantregion

Variableregion

Patient’s T cell

Cancer cell

Study objective

Current status

August2017

Enrollmentbegan

Enrollmentand dosingare ongoing

Screening status as of April 6, 2020:

47(of 107) tested positive for HLA-A*02:01, HLA-A*02:05 ± HLA-A*02:06(only HLA positive patients were tested for antigen, with results for 30 patients available)

111patients consented for screening

16/30tested positive for NY-ESO-1 ± LAGE-1a,illustrating high expression of this antigen in MM

Patient flow

Study design

*A safety review team will monitor safety in both treatment arms; enrollment into Arm 2 will be temporarily paused for a complete safety review after the third subject in Arm 2 starts lymphodepletion

This study (NCT03168438) is:

Pilot Study Open-label Multicenter

■ Aged ≥18 years■ Histologically confirmed diagnosis of secretory MM■ Have a documented diagnosis of relapsed and

refractory MM:– Have received ≥3 prior therapies containing

at least one drug from each of the followingdrug classes as separate or combined linesof therapy (including autologous stem celltransplant):• Immunomodulatory imide• Proteasome inhibitor• Alkylator• CD38 monoclonal antibody• Glucocorticoid

– Were responsive to ≥1 prior regimen(per IMWG criteria)

– Were refractory to most recent therapy (≤25%response or progression on therapy or within60 days of completion)

■ HLA-A*02:01, HLA-A*02:05, and/or HLA-A*02:06positive by central laboratory assessment

■ NY-ESO-1/LAGE-1a positive by RT-PCR■ ECOG PS 0 or 1■ Adequate organ system function

Key inclusion criteria

■ Patients with only plasmacytomas, plasma cellleukemia, MGUS, smoldering MM, non-secretorymyeloma, or primary amyloidosis

■ Prior therapy with anti-PD-1, anti-PD-L1,or anti-PD-L2 inhibitor (Arm 2 only)

■ Insufficiently resolved toxicity from previousanticancer therapy

■ Concomitant second malignancies (unlessin remission for ≥2 years), known active CNSmetastases (unless radiologically stable) and/orcarcinomatous meningitis

■ Major surgery in last 4 weeks

■ Known history of myelodysplasia

■ Active immune-mediated disease or history ofsevere immune disease

Key exclusion criteria

Primary objectiveAssess safety and tolerability of GSK3377794 treatment (± pembrolizumab); endpoints include:■ Adverse events, including

serious adverse events■ Laboratory assessments

■ Cardiac assessment viaelectrocardiogram

Secondary objectiveAssess antitumor activity of GSK3377794 treatment (± pembrolizumab); endpoints include:■ ORR■ TTR■ DoR (for patients who

achieve ≥ PR)

■ PFS

Exploratory endpoints■ OS■ MRD rate at Week 15

■ Correlation of transduced cellpersistence, phenotype, andfunctionality with treatmentresponse and safety

Patients Study objectives & endpoints

For questions, please contact: arapoport@umm.edu