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What is non-Hodgkin lymphoma, how is it treated, and what is the

unmet need?

Tim Illidge BSc PhD MRCP FRCR FRCPathInstitute of Cancer Sciences,

University of ManchesterManchester Cancer Research Centre,

Manchester, UK

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Professor Tim Illidge

• Professor of Targeted Therapy and Oncology at the Institute of Cancer Sciences, the Christie NHS Foundation Trust in Manchester, UK

• Fellow of the Royal College of Radiologists and the Royal College of Pathologists, and Member of the Royal College of Physicians

• Researches new antibody-based therapies for lymphoma

• Has led many early- and late-phase clinical trials

• Author of >100 publications

• Co-Chair of Nordic Nanovector's Scientific Advisory Board

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Non-Hodgkin lymphoma

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Non-Hodgkin lymphoma

• Approximately 1.5 million people worldwide are living with non-Hodgkin lymphoma (NHL)

• 81% increase in incidence of NHL between 1973–1990

• NHL is the third fastest growing cancer in the world (excluding the US) in terms of population

• An estimated 300,000 people die each year from NHL and it is the leading cause of death due to cancer in men aged 20–40 years

Based on US statistics4

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Frequency of NHL subtypes in adults

MALT: mucosa associated lymphoid tissue; NHL: non-Hodgkin lymphoma

Armitage JO, Weisenburger DD. J Clin Oncol 1998; 16: 2780–2795.

Follicular (22%)

Diffuse large B-cell (31%)

Small lymphocytic (6%)

Mantle cell (6%)

Peripheral T-cell (6%)

Marginal zone B cell, MALT (5%)

Other subtypes with a frequency <2% (9%)

Marginal zone B-cell, nodal (1%)Lymphoplasmacytic (1%)

Composite lymphomas (12%)

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B-cell NHL85%

NHL can be divided into several subtypes

*59% of indolent lymphomas, i.e. 24% of all B-cell NHL; ** 61% of aggressive lymphomas, i.e. 36% of all B-cell NHL

MALT: mucosa associated lymphoid tissue; NHL: non-Hodgkin lymphoma 6

• Follicular lymphoma (~59%*)

• Small lymphocytic lymphoma

• MALT lymphoma

• Lymphoblastic lymphoma

• Lymphoplasmacytic lymphoma

• Diffuse large B-cell lymphoma (~61%**)

• Mantle cell lymphoma

• Burkitt lymphoma

• Primary mediastinal large B-cell lymphoma

Aggressive lymphomas: More aggressive disease, may be cured by chemotherapy

Indolent lymphomas: Relatively long median survival, usually not curable in advanced stages

Indolent lymphomas~41%

Aggressive lymphomas~59%

NHL

T-cell NHL15%

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0 2 4 8 126 10

0

25

50

75

100

Pro

bab

ility

of

surv

ival

(%

)

Years

Indolent NHL(e.g. follicular lymphoma)

Aggressive NHL(e.g. diffuse large B-cell lymphoma)

Survival patterns for indolent and aggressive NHL in the 20th century

NHL: non-Hodgkin lymphoma

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Follicular lymphoma and diffuse large B-cell lymphoma are two NHL subtypes of interest

Follicular lymphoma

• Low-grade/indolent

• 20–30% of NHL cases

• 80–85% of patients are diagnosed in a late stage (stage III or IV) due to its slow growth

• Average age of diagnosis is 60 years

• May not always require treatment and for those who are asymptomatic with low disease burden - Watch-and-wait may be used.

NHL: non-Hodgkin lymphoma8

Diffuse large B-cell lymphoma

• High-grade / Aggressive

• Most common NHL; 31% of all cases

• Occurs most frequently in those aged >50 years ( average age 62 years)

• Immediate combination chemotherapy treatment is essential and potentially curable

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Treating non-Hodgkin lymphoma

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Healthcare professionals that treat patients with NHL

FDG PET/CT: fluorodeoxyglucose positron emission tomography/computer tomography; HCP: healthcare professional; NHL: non-Hodgkin lymphoma10

Radiation oncologist/ nuclear medicine specialist

There is an established pathway to the radiation oncologist in NHL.This HCP may already administer radiopharmaceuticals to oncology patients e.g. Xofigo® (used in the treatment of prostate cancer)

Hematologist oncologistPart of the standard treatment process. Increasingly involved with HCPs in nuclear medicine largely due to the development of FDG PET/CT and radiopharmaceuticals

SurgeonLimited role for surgeons because surgery is not part of the standard treatment pathway for NHL

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Therapies used for NHL

• Cytotoxic chemotherapy e.g. CHOP (cyclophosphamide, adriamycin, vincristine, prednisolone)

• Cell surface receptor-targeted therapies e.g. antibody therapies

• Includes drugs such as rituximab that target cell-surface proteins such as CD20

• Molecularly targeted therapies e.g. therapies targeting downstream signal transduction pathways—block cancer growth and spread by interfering with specific molecules involved in tumor growth and progression

• Targeted agents act on the tumor-specific genes, proteins or the tissue environment that contribute to growth and survival

• Targeted agents have several advantages over chemotherapy:

• Greater tumor specificity

• Potentially more favorable toxicity profile

NHL: non-Hodgkin lymphomaCancer.net, accessed October2015

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Rituximab: an engineered murine/human chimeric monoclonal antibody – granted US FDA approval for the treatment of cancer in 1997

FDA: Food and Drug AdministrationAdapted from: Ryback et al. 1992

Murine-variable regions bindspecifically to CD20 on B cells

Human k constant regions

Human IgG1 Fc domain works in synergywith human effector mechanisms

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Rituximab has revolutionized the treatment of B-cell malignancies through significantly improving patient outcomes

B-CLL: B-cell chronic lymphocytic leukemia; CHOP: cyclophosphamide, doxorubicin, vincristine, and prednisone; DLBCL: diffuse large B-cell lymphoma; Coiffier B et al. N Engl J Med 2002; 346: 235–242; Hallek M et al. Lancet 2010; 376: 1164–1174.

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Therapies used for NHL

• Cytotoxic chemotherapy e.g. CHOP (cyclophosphamide, adriamycin, vincristine, prednisolone)

• Cell surface receptors e.g. antibody therapies

• Includes drugs such as rituximab that target cell-surface proteins, e.g. CD20

• Molecularly-targeted therapies e.g. therapies targeting downstream signal transduction pathways—block cancer growth and spread by interfering with specific molecules involved in tumor growth and progression

• Targeted agents act on the tumor-specific genes, proteins or the tissue environment that contribute to growth and survival

• Targeted agents have several advantages over chemotherapy:

• Greater tumor specificity

• Potentially more favorable toxicity profile

• Not all tumors express the same targets

NHL: non-Hodgkin lymphomaCancer.net, accessed October2015

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Immunochemotherapy has become the mainstay of NHL treatment

• Immunochemotherapy, combining rituximab and chemotherapy, is used in both indolent and aggressive disease +/- radiotherapy

• Specific treatments vary depending on the patient, disease subtype, and stage of disease

• Several common immunochemotherapy regimens include:

ARA-C: cytarabine; R: rituximab15

R-CHOPcyclophosphamide,

hydroxydaunomycin (doxorubicin), Oncovin® (vincristine), prednisone

R-CVPcyclophosphamiode, vincrostine,

prenisone

R-ICEifosfamide, carboplatin,

etoposide

R-EPOCHetoposide, prednisone, Oncovin®,

cyclophosphamide, halotestin

R-ESHAPetoposide, adiramycin

(doxorubicin), Ara-C, platinum

R-DHAPdexamethasone, cytarabine,

cisplatin

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Diffuse large B-cell lymphoma treatment pathway

16ASCT: allogeneic stem cell transplant

Rituximab chemotherapy

Eligible for transplantation?

Salvage chemotherapy followed by high-dose therapy

and transplantation

Palliative chemotherapy

Novel agents/clinical trialsNovel agents/clinical trials

Yes No

Two-thirds of patients fail to get to transplant and 50% relapse after ASCT

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Follicular lymphoma treatment pathway proposed at ASH 2004

*Symptoms, cytopenias, rapid growth of disease, potential organ compromise (e.g. hydronephrosis); **Consider collection of peripheral blood progenitor cells for future transplantation. ASH; American Society of HematologyWinter JN et al. Hematology Am Soc Hematol Educ Program 2004: 203–220.

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Stage I–II disease

Involved field radiotherapy

Stage III–IV diseaseIndications to treat*

Watch and wait

Rituximab chemotherapy

Rituximab maintenanceIndications to treat

Radioimmunotherapy

Transplantation (age/fitness limitation!)

**

Yes No

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The unmet clinical need: Patients who ‘fail’ rituximab-chemotherapy treatment or are unfit for multi-agent treatment

• Rituximab has been successful in improving patient outcomes

• Rituximab-chemotherapy regimens have become the standard of care in first- and second-line

• Although there is a substantial number of patients with DLBCL can be cured by these treatments, many are refractory or relapse

• In follicular lymphoma, many patients eventually relapse and become refractory to rituximab

• Novel agents are required and targeting the cell surface receptors with improved antibodies and antibody conjugates allows the majority of lymphomas to be targeted

DLBCL, diffuse large B-cell lymphoma18

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B cells express several antigens that can be targeted

• CD20 is only one of the antigens expressed by B-cell lymphomas that could be targeted by antibody-based therapies

• CD37 is expressed by adult B cells and has been measured on the vast majority of B-cell lymphomas

• Targeting alternate antigens, such as CD37, could bypass the cellular mechanisms that lead to rituximab-refractory disease

• CD37 is therefore a useful therapeutic target for novel therapies in lymphoma patients that have relapsed after CD20-based therapy

Dahle J et al. Anticancer Res 2013; 33: 85–95; Figure adapted from Press OW. Semin Oncol 1999; 26 (5 Suppl 14): 58–65.

DR

sIg

CD20

CD37

CD22

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Radioimmunotherapy: Antibody-radionuclide conjugates

• Lymphoma cells are inherently sensitive to radiation

• Radiotherapy can be effective in chemotherapy-refractory and rituximab-refractory disease

• Continuous delivery of low-dose radiation and antibody effector mechanisms

• Radiation also destroys tumor cells distant from targeted tumor cell

Press WO. Semin Hematol 2000; 37(4 Suppl 7): 2–8; Krasner C, Joyce RM. Curr Pharm Biotechnol 2001; 2: 341–349; Zelenetz AD. Curr Opin Oncol 1999; 11: 375–380.

Betalutin®

177Lu

177Lu

177Lu

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Defining features of single treatment antibody-radionuclide conjugate in relapsed follicular lymphoma

• High response rates (ORR and CR)

• Durable long-term responses

• Simple and effective treatment; high quality-of-life for both older and younger patients

• Limited uptake and availability

CR: complete response; ORR: overall response rate

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The unmet need innon-Hodgkin lymphoma

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Where is the unmet need in NHL?

NHL: non-Hodgkin lymphoma23

Relapsed NHL No standard therapy past second-line

Rituximab resistance Patients who have developed resistance to the CD20-targeted antibody

Older patientsPatients aged >65 years might not be able to tolerate some chemotherapies

Comorbidities Some comorbidities can impact tolerability of treatment

Lack of response Patients with a poor response to first- or second-line treatment

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What features should we look for in a novel therapy to help us meet these unmet needs?

• Antibody-radionuclide conjugate therapy (radioimmunotherapy) that has a strong efficacy and safety profile in relapsed and refractory patient populations, including:

• Patients who have failed previous therapies

• Patients who are have relapsed or are refractory to rituximab

• Patients who are considered ‘frail’ that might not be eligible for current therapies, e.g. older patients, those with comorbidities

• A treatment that does not have strict compliance requirements

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Summary

• NHL has several subtypes; the most common are follicular lymphoma and diffuse large B-cell lymphoma

• Chemotherapy, rituximab, radiotherapy and targeted treatments are commonly used to treat NHL

• There is no standard treatment beyond second line, and there is an unmet need for new therapeutic options for patients who have failed previous therapies

• A novel antibody-radionuclide conjugate treatment could be a future option for second- or third-line therapy in patients with follicular lymphoma or diffuse large B-cell lymphoma, who are unable to tolerate transplantation or chemotherapy

NHL: non-Hodgkin lymphoma25