P325 A Phase 1 Dose Escalation Study of TSR-033, an Anti ......• TSR-033 monotherapy was well...
Transcript of P325 A Phase 1 Dose Escalation Study of TSR-033, an Anti ......• TSR-033 monotherapy was well...
A Phase 1 Dose Escalation Study of TSR-033, an Anti-LAG-3 Monoclonal Antibody, in Patients With Advanced Solid TumorsKelly Stratton,1 Aurélien Marabelle,2 Geoffrey I. Shapiro,3 Jong Chul Park,4 Solmaz Sahebjam,5 Srimoyee Ghosh,6 Jian Chen,6 Michelle Kneissl,6 Ying Wang,6 Amita Patnaik7
1College of Medicine, The University of Oklahoma, Oklahoma City, OK, USA; 2Gustave Roussy Integrated Cancer Research, Villejuif Cedex, France; 3Dana-Farber Cancer Institute, Boston, MA, USA; 4Massachusetts General Hospital, Boston, MA, USA; 5Moffitt Cancer Center & Research Institute, University of South Florida, Tampa, FL, USA; 6TESARO, Inc., Waltham, MA, USA; 7South Texas Accelerated Research Therapeutics, San Antonio, TX, USA
BACKGROUND
• Lymphocyte activation gene (LAG-3) is an immune checkpoint inhibitor receptor found on multiple immune cells, including effector T cells.
• LAG-3 interacts with major histocompatibility complex (MHC) class II on antigen-presenting cells and attenuates T-cell activatio.n.
• LAG-3 is often co-expressed with programmed death 1 (PD-1) on tumor-infiltrating lymphocytes and is associated with increased levels of exhaustion1-3; LAG-3 expression is upregulated in response to anti-PD-1 therapy (Figures 1 and 2).
• TSR-033 is an investigational, humanized, anti-LAG-3 monoclonal antibody (immunoglobulin G4/kappa) that blocks the interaction of LAG-3 with MHC class II.
• LAG-3 blockade with TSR-033 in combination with anti-PD-1 therapy (TSR-042) boosts immune function and elicits antitumor immunity in preclinical models (Figures 3 and 4).4
• Prior clinical data demonstrate that combined anti-PD-1 and anti-LAG-3 checkpoint blockade leads to increased antitumor activity compared with anti-PD-1 alone in patients who have progressed on anti-PD-1 therapy.5,6
Figure 1. LAG-3 Is a Key Immune Checkpoint That Is Frequently Co-expressed With PD-1 on Tumor-Infiltrating T Cells, Acts to Attenuate Activation, and Is Upregulated by Anti-PD-1 Treatment
LAG-3=lymphocyte activation gene 3; PD-1=programmed death 1.
Figure 2. LAG-3 Is Frequently Co-expressed With PD-1 on Tumor-Infiltrating Lymphocytes (A), CD8+ T Cells With Co-expression of PD-1 and LAG-3 Are Associated With a More “Exhausted” Phenotype as Assessed by Lower Frequency of Granzyme B+ Cells (B), and LAG-3 Is Upregulated Following PD-1 Blockade in a Humanized Mouse NSCLC Model (C)
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A. Co-expression of PD-1 and LAG-3 on CD8+ TILs in primary NSCLC tumors
B. PD-1+ LAG-3+ CD8+ T cells are more “exhausted,” ie, have lower granzyme B expression
C. Adaptive upregulation of LAG-3 on T cells following treatment with TSR-042 (anti-PD-1 antibody) in a humanized mouse NSCLC tumor model
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*P<0.05. LAG-3=lymphocyte activation gene 3; mDC=myeloid dendritic cell; NK=natural killer; NSCLC=non-small cell lung cancer; PD-1=programmed death 1; TIL=tumor-infiltrating lymphocyte; Treg=regulatory T cell.
Figure 3. Combinatorial Blockade of PD-1 and LAG-3 Improved Efficacy in a Humanized NSCLC (A549) Tumor Model
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LAG-3=lymphocyte activation gene 3; NSCLC=non-small cell lung cancer; PD-1=programmed death 1; TGI=tumor growth inhibition.
Figure 3. Combinatorial Blockade of PD-1 and LAG-3 Improved Efficacy in a Humanized NSCLC (A549) Tumor Model
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LAG-3=lymphocyte activation gene 3; NSCLC=non-small cell lung cancer; PD-1=programmed death 1; TGI=tumor growth inhibition.
Figure 4. Combination Therapy With TSR-042 and TSR-033 Was Associated With (A) Increased Proliferating CD8+ T Cells, Decreased TAMs, and Increased M1/M2 Ratios Within Mouse Tumors, Relative to TSR-042 (Anti-PD-1) Monotherapy and (B) Increase in Frequency of IFNg- and TNFa-Producing Splenic T Cells Upon Ex Vivo Stimulation
A. Increased immune activation in mouse tumors with combination therapy
B. Increased ex vivo IFNγ and TNFα production by T cells in spleens of mice treated with combination therapy
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*P<0.05. IFNg=interferon gamma; M1/M2=ratio of M1 to M2 macrophages; TAM=tumor-associated macrophage; TNFa=tumor necrosis factor alpha.
Figure 5. Study Design
Part 1: Dose Escalation
Part 2 – Expansion CohortsThe study will further explore the safety and clinical activity of TSR-033 + anti-PD-1 in various tumor types
Part 1A: Dose escalation to determine the RP2D of TSR-033 as a monotherapya
Part 1C: Dose escalation of TSR-033 in combination with anti-PD-1
Expected enrollment of 9, with ability to increase to up
to 36 patientsDose levels of TSR-033
determined based on DLT in Part 1A, in combination with
500 mg TSR-042 Q3W
Dose Q2W, mg N=23 Dose Q2W, mg N=7
Part 1B: To characterize the PK and PD profile of TSR-033 and to evaluate its immunogenicity and measures of clinical benefit
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DLT=dose-limiting toxicity; PD=pharmacodynamics; PK=pharmacokinetics; Q2W=every 2 weeks; Q3W=every 3 weeks; RP2D=recommended phase 2 dose.aOne DLT of ocular myasthenia gravis (grade 2) was reported after 21 days of dosing at the 80 mg dose level. TSR-033 was dose interrupted and then withdrawn due to the event. No treatment was given for the event. The event did not resolve at the end of study treatment.
METHODS
PatientsInclusion Criteria
• Patients aged ≥18 years with advanced (unresectable) or metastatic solid tumors who had disease progression or treatment intolerance after treatment with available therapies
• Adequate organ function and Eastern Cooperative Oncology Group (ECOG) performance status ≤1
Exclusion Criteria• Part 1: prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-LAG-3
agent that resulted in permanent discontinuation due to an adverse event (AE) EndpointsPrimary
• Safety and tolerability of TSR-033 by Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0), dose-limiting toxicity, and immune-related AEs
Secondary • Characterize the pharmacokinetic parameters of TSR-033 when given alone
and in combination with TSR-042Exploratory
• Characterize the pharmacodynamic profile of TSR-033
RESULTS
Patients• Slightly over one-half of the patients enrolled in Part 1A were female, and
the most common tumor sites were prostate and colon (Table 1).• Most patients had received ≥4 prior treatment lines.
Table 1. Patient Demographics
CharacteristicPart 1A (N=23)
Dose Escalation Population
Part 1A + 1B (N=30) PK, PD, and Safety
PopulationAge
Mean (SD), y 65.0 (11.51) 62.9 (13.22)Median (min, max) 69.0 (56, 75) 66.0 (56, 72)
Sex, n (%)Male 10 (43.5) 13 (43.3)Female 13 (56.5) 17 (56.7)
ECOG performance status score, n (%)0 9 (39.1) 11 (36.7)1 14 (60.9) 19 (63.3)
Number of prior treatment lines, n (%)Mean (SD) 4.3 (2.5) 4.3 (2.3)Median (min, max) 4.0 (1, 11) 4.0 (1, 11)
Tumor site, n (%)Prostate 5 (21.7) 5 (16.7)Colon 4 (17.4) 4 (13.3)Endometrial 3 (13.0) 4 (13.3)Lung 3 (13.0) 3 (10.0)Kidney 1 (4.3) 2 (6.7)Ovarian 1 (4.3) 1 (3.3)Bone 0 1 (3.3)Pancreas 0 1 (3.3)Rectum 0 1 (3.3)Bladder 0 1 (3.3)Unknown 1 (4.3) 1 (3.3)Other 5 (21.7) 6 (20.0)
ECOG=Eastern Cooperative Oncology Group; SD=standard deviation.
Safety• In the combined Part 1A and Part 1B population, most patients (n=28
[93.3%]) experienced treatment emergent adverse events (TEAEs).• The most frequently reported TEAEs related to study treatment were
nausea, dry mouth, and infusion-related reaction (Table 2).• No AEs of grade 3 or higher were considered related to the study drug.• Incidence of AE was independent of dose.
Table 2. Treatment-Related TEAEs Occurring in >5% of Patients (Part 1A + 1B)a
Treatment-Related TEAE, n (%) Part 1A and Part 1BN=30
Any treatment-related TEAE 13 (43.3)
Nausea 3 (10.0)
Dry mouth 2 (6.7)
Infusion-related reaction 2 (6.7)
TEAE=treatment-emergent adverse event.aOccurred in ≥2 patients.
Pharmacokinetics and Pharmacodynamics• TSR-033 exposure increased in a dose-proportional manner (Figure 6A).• Receptor occupancy on peripheral T cells increased as exposure increased,
confirming target engagement (Figure 6B)
Figure 6. Pharmacokinetic Profile of TSR-033 (A) and Receptor Occupancy on Peripheral T Cells (B)
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LAG-3=lymphocyte activation gene 3.
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CONCLUSIONS• TSR-033 monotherapy was well tolerated across multiple dose levels. • TSR-033 exposure increased in a dose-proportional manner; receptor
occupancy increased with exposure.• AEs were manageable and consistent with the safety profiles of other
immune checkpoint inhibitors. • Dose escalation of TSR-033 in combination with TSR-042 (anti-PD-1)
is ongoing.
Society for Immunotherapy of Cancer 33rd Annual Meeting | November 7-11, 2018 | Washington, DC, USA
P325
ACKNOWLEDGEMENTSWriting and editorial support, funded by TESARO, Inc. (Waltham, MA, USA) and coordinated by Ashujit Tagde, PhD, of TESARO, Inc., was provided by Jeremy Kennard, PhD, and Cara Hunsberger of Ashfield Healthcare Communications (Middletown, CT, USA).
REFERENCES1. Koyama S, et al. Nat Commun. 2016;7:10501.2. Taube JM, et al. Clin Cancer Res. 2015;21:3969-3976.3. Thommen DS, et al. Cancer Immunol Res. 2015;3:1344-1355.4. Ghosh S, et al. AACR-NCI-EORTC International Conference on Molecular Targets and Cancer
Therapeutics. 2017; Abstract 201.5. Lipson E, et al. J Immunother Cancer. 2016;4 (suppl 1):P232.6. Ascierto PA, et al. Ann Oncol. 2017;28 (suppl 5):LBA18.