John Kuruvilla, MD

PD1 Inhibition in Hodgkin Lymphoma

John Kuruvilla MD FRCPC

2 Oct 2015

Objectives

Discuss the Phase II trials of PD1 Antibodies in HL

Nivolumab

Pembrolizumab

Where are we?

The Purpose of the Immune Checkpoint

We need the immune system to fight pathogens and help eliminate abnormal cells We also need to have controls on this system

Maintain tolerance and prevent injury to self tissue

The immune checkpoint is the series of inhibitory signals for this system

While designed for self control, these signals can be exploited by cancer cells

Pardoll , 2012, Nat Rev Can, 5, 252-265

Cancer Cell T-cell

Immune Checkpoint Blockade

Pardoll , 2012, Nat Rev Can, 5, 252-265

Cancer Cell T-cell

Examples of Molecules used in Immune Checkpoint Blockade

Pardoll , 2012, Nat Rev Can, 5, 252-265

Pathology of cHL: rare malignant Reed-Sternberg cells within an extensive inflammatory/immune cell infiltrate.

Genetic analyses: frequent 9p24.1 amplification with upregulation of PD-1 ligands and JAK2.

Hypothesis: cHL may have a genetically driven dependence on PD-1.

Relevance of the Immune Checkpoint in Classical HL

Juszczynski et al PNAS 2007; 104: 13134

Green et al Blood 2010; 116: 3268; Chen et al. Clin Cancer Res 2013;

19:3462

56th Annual ASH Meeting December 2014

San Francisco, CA

Nivolumab in Patients with Relapsed or

Safety, Efficacy and Biomarker Results of a Phase I Study

Philippe Armand1, Stephen M. Ansell2, Alexander M. Lesokhin3, Ahmad Halwani4, Michael M. Millenson5, Stephen J. Schuster6, John Timmerman7, Ivan Borrello8, Martin Gutierrez9, Emma C. Scott10, Deepika Cattry3, Bjoern Chapuy1, Azra H. Ligon11, Scott J. Rodig11, Lili Zhu12, Joseph F. Grosso12, Su Young Kim12, and Margaret A. Shipp1 1Dana-Farber Cancer Institute, Boston, MA ; 2Mayo Clinic, Rochester, MN; 3Memorial Sloan Kettering Cancer Center, New York, NY; 4University of Utah Huntsman Cancer Institute, Salt Lake City, UT; 5Fox Chase Cancer Center, Philadelphia, PA; 6Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA; 7Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA; 8Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD; 9John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ; 10Oregon Health and Science University, Portland, Oregon; 11

Boston, MA; 12Bristol-Myers Squibb, Princeton, NJ

PD-1 engagement by its ligands results in transient down-regulation of T-cell function (T-cell exhaustion).

Nivolumab is a fully human IgG4 anti-PD-1 antibody which selectively blocks the PD-1 and PD-L1/PD-L2 interaction.

PD-1 blockade through monoclonal antibody therapy has single-agent activity in a range of solid tumors.

MHC

PD-L1

PD-1

PD-1

T-cell receptor

PD-L2

T cell

NF B Other

PI3K

Tumor cell

IFN

IFN R

Shp-2

Nivolumab

Background

Brahmer et al N Engl J Med 2012;366:2455 Topalian et al N Engl J Med 2012;366:2443-54

Relapsed or Refractory HM

(N=105)

No autoimmune disease No prior organ or stem cell allograft No prior checkpoint blockade

Endpoints

Primary Safety and Tolerability

Secondary Best Overall Response

Investigator assessed Objective Response

PET + CT Duration of Response PFS Biomarker studies

Rationale and Design

Dose Expansion (3mg/kg)

Dose Escalation

Nivolumab 1mg/kg

Wks 1,4 then q2w

NHL/MM (n=69)

(n=13)

Based on potential vulnerability to PD-1 blockade, cHL included as independent expansion cohort in Phase 1b study of nivolumab in hematologic malignancies.

Hodgkin Lymphoma (n=23)

Baseline Characteristics

Characteristic N (%)

Total 23 (100)

Age 35 (20 -54)

cHL histology

Nodular sclerosis 22 (96)

Mixed cellularity 1 (4)

Prior ASCT 18 (78)

Prior Brentuximab Vedotin 18 (78)

Prior systemic therapies

2 to 3 8 (35)

4 to 5 7 (30)

8 (35)

Any AE Related AE Grade 3

Related AE Grade 4

Related AE Discontinued for Related AE

Patients, n (%) 22 (96) 18 (78) 5 (22) 0 (0) 2 (9)

No drug-related grade 4 AEs or drug -related deaths

AEs leading to discontinuation:

MDS with grade 3 thrombocytopenia (6 prior treatments including ASCT)

Grade 3 pancreatitis

Other grade 3 related AEs:

Safety profile similar to that in solid tumors

Safety

Lymphopenia

Increased lipase

GI inflammation

Pneumonitis, colitis and stomatitis (post autologous stem cell transplant)

Efficacy

Total

(N = 23) n (%)

ASCT Failure Brentux Failure

(N = 15) n (%)

ASCT-Naïve Brentux Failure

(N = 3) n (%)

Brentux Naïve

(N=5) n (%)

Overall Response 20 (87) 13 (87) 3 (100) 4 (80)

Best Response CR 4 (17) 1 (7) 0 3 (60)

PR 16 (70) 12 (80) 3 (100) 1 (20)

SD 3 (13) 2 (13) 0 1 (20)

PD 0 0 0 0

24-week PFS 86% 85% n/c 80%

Best Response

PR (70%) CR (17%) SD (13%)

Response Duration P

atie

nts

Publication

17

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