What is non-hodgkin lymphoma, how is it treated, and what is the unmet need?

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1 What is non-hodgkin lymphoma, how is it treated, and what is the unmet need? Tim Illidge BSc PhD MRCP FRCR FRCPath Institute of Cancer Sciences, University of Manchester Manchester Cancer Research Centre, Manchester, UK 1

2 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 2

3 Non-Hodgkin lymphoma 3

4 Non-Hodgkin lymphoma Approximately 1.5 million people worldwide are living with non-hodgkin lymphoma (NHL) 81% increase in incidence of NHL between 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 years Based on US statistics 4

5 Frequency of NHL subtypes in adults Composite lymphomas (12%) Follicular (22%) Small lymphocytic (6%) Mantle cell (6%) Peripheral T-cell (6%) Marginal zone B cell, MALT (5%) Diffuse large B-cell (31%) Other subtypes with a frequency <2% (9%) Marginal zone B-cell, nodal (1%) Lymphoplasmacytic (1%) MALT: mucosa associated lymphoid tissue; NHL: non-hodgkin lymphoma Armitage JO, Weisenburger DD. J Clin Oncol 1998; 16:

6 NHL can be divided into several subtypes NHL B-cell NHL 85% T-cell NHL 15% Indolent lymphomas: Relatively long median survival, usually not curable in advanced stages Indolent lymphomas ~41% Aggressive lymphomas ~59% Aggressive lymphomas: More aggressive disease, may be cured by chemotherapy 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 *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

7 Probability of survival (%) Survival patterns for indolent and aggressive NHL in the 20th century Indolent NHL (e.g. follicular lymphoma) 50 Aggressive NHL (e.g. diffuse large B-cell lymphoma) Years NHL: non-hodgkin lymphoma 7

8 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. 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 NHL: non-hodgkin lymphoma 8

9 Treating non-hodgkin lymphoma 9

10 Healthcare professionals that treat patients with NHL Hematologist oncologist Part of the standard treatment process. Increasingly involved with HCPs in nuclear medicine largely due to the development of FDG PET/CT and radiopharmaceuticals 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) Surgeon Limited role for surgeons because surgery is not part of the standard treatment pathway for NHL FDG PET/CT: fluorodeoxyglucose positron emission tomography/computer tomography; HCP: healthcare professional; NHL: non-hodgkin lymphoma 10

11 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 lymphoma Cancer.net, accessed October

12 Rituximab: an engineered murine/human chimeric monoclonal antibody granted US FDA approval for the treatment of cancer in 1997 Murine-variable regions bind specifically to CD20 on B cells Human k constant regions Human IgG 1 Fc domain works in synergy with human effector mechanisms FDA: Food and Drug Administration Adapted from: Ryback et al

13 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: ; Hallek M et al. Lancet 2010; 376:

14 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 lymphoma Cancer.net, accessed October

15 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: R-CHOP cyclophosphamide, hydroxydaunomycin (doxorubicin), Oncovin (vincristine), prednisone R-CVP cyclophosphamiode, vincrostine, prenisone R-ICE ifosfamide, carboplatin, etoposide R-DHAP dexamethasone, cytarabine, cisplatin R-ESHAP etoposide, adiramycin (doxorubicin), Ara-C, platinum R-EPOCH etoposide, prednisone, Oncovin, cyclophosphamide, halotestin ARA-C: cytarabine; R: rituximab 15

16 Diffuse large B-cell lymphoma treatment pathway Rituximab chemotherapy Eligible for transplantation? Yes No Salvage chemotherapy followed by high-dose therapy and transplantation Palliative chemotherapy Two-thirds of patients fail to get to transplant and 50% relapse after ASCT Novel agents/clinical trials Novel agents/clinical trials ASCT: allogeneic stem cell transplant 16

17 Follicular lymphoma treatment pathway proposed at ASH 2004 Stage I II disease Stage III IV disease Indications to treat* Yes No Involved field radiotherapy Watch and wait Rituximab chemotherapy Rituximab maintenance Indications to treat Radioimmunotherapy ** Transplantation (age/fitness limitation!) *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 Hematology Winter JN et al. Hematology Am Soc Hematol Educ Program 2004:

18 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 lymphoma 18

19 B cells express several antigens that can be targeted DR sig CD20 CD37 CD22 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 rituximabrefractory 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):

20 Radioimmunotherapy: Antibody-radionuclide conjugates Lymphoma cells are inherently sensitive to radiation 177 Lu Radiotherapy can be effective in chemotherapy-refractory and rituximabrefractory disease 177 Lu Continuous delivery of low-dose radiation and antibody effector mechanisms Radiation also destroys tumor cells distant from targeted tumor cell 177 Lu Betalutin Press WO. Semin Hematol 2000; 37(4 Suppl 7): 2 8; Krasner C, Joyce RM. Curr Pharm Biotechnol 2001; 2: ; Zelenetz AD. Curr Opin Oncol 1999; 11:

21 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 21

22 The unmet need in non-hodgkin lymphoma 22

23 Where is the unmet need in NHL? Relapsed NHL No standard therapy past second-line Rituximab resistance Patients who have developed resistance to the CD20-targeted antibody Older patients Patients 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 NHL: non-hodgkin lymphoma 23

24 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 24

25 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 lymphoma 25