Treating the NHL of Cancers: How to Score with Radioimmunotherapy

Treating the NHL of Cancers: How to score with Radioimmunotherapy

1 Table of Contents

• Overview of NHL • Structure and Mechanism of Action of 90Yttrium Ibritumomab Tieuxtan (90YIT) • Efficacy and Safety in Indolent NHL • Relapsed/Refractory Setting-label indication • First-Line setting-consolidation • Other applications: • Sunnybrook experimental clinical trial-RIT in High risk previously untreated Follicular lymphoma

ASCT, autologous stem cell transplant; NHL, non-Hodgkin’s lymphoma; 2 RIT, radioimmunotherapy; 90YIT, 90Y-ibritumomab tiuxetan Key Learning points

Discuss the current management of indolent lymphoma Review the effects of 90Yttrium Ibritumomab Tiuxetan in indolent lymphoma Describe the results of a Canadian Phase II trial of 90Yttrium Ibritumomab Tiuxetan in high risk follicular lymphoma

3 NHL Incidence

Leading Sites of New Cancer Cases in Canada: 2017 Estimates

MALE: 103,100 new cases FEMALE: 103,200 new cases Prostate Breast 20.7% (21,300 cases) 25.5% (26,300 cases) Colorectal Lung & bronchus 14.5% (14,900 cases) 13.8% (14,200 cases) Lung & bronchus Colorectal 14.0% (14,400 cases) 11.5% (11,900 cases) Bladder Body of uterus and uterus NOS 6.5% (6700 cases) 7.1% (7300 cases) NHL Thyroid 4.5% (4600 cases) 5.2% (5400 cases) Kidney & renal pelvis NHL 4.1% (4200 cases) 3.6% (3700 cases) Melanoma Melanoma 3.9% (4000 cases) 3.2% (3300 cases) Leukemia Ovary 3.5% (3600 cases) 2.7% (2800 cases) Oral Pancreas 3.1% (3200 cases) 2.6% (2700 cases) Pancreas Leukemia 2.7% (2800 cases) 2.5% (2600 cases) Stomach Kidney and renal pelvis 2.1% (2200 cases) 2.3% (2400 cases)

NHL, non-Hodgkin’s lymphoma; NOS, not otherwise specified Canadian Cancer Society’s Advisory Committee on Cancer Statistics. Canadian Cancer Statistics 2017. 4 Toronto, ON: Canadian Cancer Society; 2017. WHO-2016 Classification of lymphomas

Splenic Burkitt's Nodal marginal High 1% marginal zone grade B, zone 1% Lymphopl NOS 2% asmacytic 2% PMBCL 1% 3%

CLL/SLL 11% DLBCL Mantle cell 35% 7% MALT 9% Follicular 28%

5 WHO classification of indolent lymphomas

Indolent NHL Follicular CLL Marginal Follicular lymphoma (grades 1,2 and 3a) Zone Small lymphocytic lymphoma/chronic lymphocytic CD20 +++ + +++ leukaemia CD10 +++ - - Lymphoplasmacytic lymphoma/Waldenstrom’s CD5 - +++ - macroglobulinaemia CD23 - +++ - Extranodal marginal zone B-cell lymphoma of +++ +++ mucosa-associated lymphoid tissue (MALT BCL2 +++ (translocation (translocation lymphoma) common) uncommon) Nodal marginal zone B-cell lymphoma (monocytoid B-cell lymphoma) BCL6 +++ - - Splenic marginal zone lymphoma (splenic lymphoma with villous lymphocytes)

Swerdlow SH, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues (4th edition). Lyon, France: IARC Press, 2008.6 Indolent NHL: Disease background

Follicular lymphoma (FL) is the most common type of indolent NHL and represents ~70% of indolent NHL and20–25% of NHL overall

Indolent NHLs are slow-growing, also known as low-grade lymphomas, in contrast to the aggressive or high-grade lymphomas

The distinction between aggressive and indolent NHLs is made by histological analysis of tumour biopsies2

Indolent NHLs follow a relapsing and remitting course and have historically been considered incurable1

FL is considered incurable, with progressively shorter response durations with subsequent treatments1

Histologic transformation to aggressive DLBCL occurs in 10-70% of patients over time (risk of 2−3% per year)

1. Eichenauer DA, et al. Onco Targets Ther 2009; 2:189‒197. 7 2. Ansell SM and Armitage J. Mayo Clin Proc 2005; 80:1087‒1097. First line Therapy Follicular Lymphoma

8 Treatment Options-Indolent lymphomas

• Watchful waiting • Chemotherapy • Monoclonal antibody therapy • Radiation therapy • Radioimmunotherapy • Biologic therapies, including: • Interferon • Vaccines (under clinical investigation) • Immunotherapies (under clinical investigation) • Targeted therapies • Bone marrow or stem-cell transplants • Experimental treatments obtained through patient participation in clinical trials.

Lymphoma Canada. Treatment. Available at: https://www.lymphoma.ca/lymphoma/cll-sll/treatment. Accessed: November 14, 2017. 9 Rituximab – Enhanced outcome with CD20 monoclonal antibody

Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC)—Natural killer cells, T cells, and macrophages recognize and kill antibody-labeled target cells, leading to cell lysis

Complement-Dependent Cytotoxicity (CDC)—Binding of the antibody recruits complement proteins, which punch holes in the cell membrane, flooding the cell and leading to cell lysis

Apoptosis—Binding of the antibody signals the cell to self-destruct resulting in cell lysis.

10 R-chemotherapy combinations

In randomised trials, R-chemotherapy has been shown to improve survival compared with chemotherapy alone for all chemotherapy regimens evaluated

11 Bendamustine-Rituximab vs CHOP-Rituximab

• N=549, included MCL • newly diagnosed • Previously untreated

Figure 2 Progression-free survival B-R=bendamustine plus rituximab. R-CHOP=CHOP plus rituximab.

Rummel et al., Lancet, 2013, 381, 1203 12 FLIPI and Follicular lymphoma

0,1 risk • Age > 60 factors • Hb <120 2 risk • Stage 3,4 factors • >4 nodal sites 3 or more • Elevated risk factors LDH

14 Rituximab maintenance vs observation after first-line R-chemo (PRIMA): Study design

Maintenance Induction + 12 x rituximab 8 x rituximab (q2mo for 24 mo) Untreated CR follicular NHL High tumour + CRu 1,018 patients burden PR Induction hemotherapy Observation (8 x CVP or 6 x 1,217 patients CHOP or 6 x FCM) PD SD off study

Salles G, et al. Lancet 2011; 377:42–51.15 PRIMA: Progression-free survival

1.0

0.8 Rituximab maintenance 0.6

free rate free Observation - 0.4

HR = 0.55 Event 0.2 95% CI: 0.44–0.68 p < 0.0001 0 0 6 12 18 24 30 36 42 48 54 60 Time (months) Patients at risk Rituximab 505 472 445 423 404 307 207 84 17 0 – Observation 513 469 415 367 334 247 161 70 16 0 –

Salles G, et al. Lancet 2011; 377:42–51.16 PRIMA: Time to next anti-lymphoma treatment

1.0

0.8 Rituximab maintenance

0.6

Observation

free rate free - 0.4

HR = 0.60 Event 0.2 95% CI: 0.47–0.76 p < 0.0001 0 0 6 12 18 24 30 36 42 48 54 60 Time (months) Patients at risk Rituximab 505 483 455 441 414 312 209 91 17 0 – Observation 513 487 452 417 380 286 170 71 18 0 –

Salles G, et al. Lancet 2011; 377:42–51.17 PRIMA: Response rates to second-line therapy

⚫ Treatment with R-maintenance did not alter the effectiveness of second-line therapy

R-maintenance Observation Response (n = 144) (n = 227) ORR 76 79 CR/CRu 53 61 PR 22 19

Salles GA, et al. ASH 2013; Abstract 509 (oral).18 PRIMA: Conclusions

These data demonstrate a sustained and persistent PFS benefit of 2 years of Rituximab maintenance therapy after immunochemotherapy • ~60% of patients free of progression at 6 years No additional or unexpected long term toxicities were observed Second-line therapy efficacy results did not significantly differ between the 2 arms Overall survival appears very favourable for all randomized patients

19 Suggested First-Line Treatment Regimens for FL: NCCN Guidelines®

Grade 1-2 (in preference order) Grade 3* (alphabetical order) • Bendamustine + RTX • R-CHOP • Bendamustine + obinutuzumab • Dose-dense R-CHOP 14 • R-CHOP • Dose-adjusted EPOCH + RTX • CHOP + obinutuzumab If very frail or poor LVF: • R-CVP • R-CEPP • CVP + obinutuzumab • RCDOP First-line • RTX • DA-EPOCH • Lenalidomide + RTX • RCEOP If elderly or infirm: • RGCVP • RTX If >80 years with comorbidities: • Single-agent alkylator • R-mini-CHOP • Y90-RIT • RGCVP • Lenalidomide for patients 60–80 • RTX years of age First-line consolidation or • Obinutuzumab • Age-adjusted IPI high-risk extended dosing (optional) disease: high-dose therapy with • Y90-RIT ASC rescue

*Controversy exists regarding whether Grade 3 FL should be treated as for Grade 1-2 FL or as for DLBCL. Options shown here are those listed for DLBCL. ASC, autologous stem cell; CHOP, cyclophosphamide/doxorubicin/vincristine/prednisone; CVP, cyclophosphamide/vincristine/prednisolone; DA, dose-adjusted; EPOCH, etoposide/prednisolone/vincristine/cyclophosphamide/doxorubicin; FL, follicular lymphoma; IPI, International Prognostic Index; NCCN, National Comprehensive Cancer Network; RCDOP, rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone; RCEOP, rituximab/cyclophosphamide/etoposide/vincristine/prednisone; R-CEPP, rituximab/cyclophosphamide/etoposide/procarbazine/prednisolone; R-CHOP, rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone; R-CVP, rituximab/cyclophosphamide/vincristine/prednisolone; RGCVP, rituximab/gemcitabine/cyclophosphamide/vincristine/prednisolone; RIT, radioimmunotherapy; RTX, rituximab National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: B-cell Lymphomas. Version 6.2017. 20 Available at: https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf. Accessed: November 15, 2017. A Canadian Evidence-Based Guideline for the First-Line Treatment of Follicular Lymphoma: Joint Consensus of the Lymphoma Canada Scientific Advisory Board

What treatment options should be considered for first-line symptomatic advanced-stage FL? Recommendation 1 : Chemoimmunotherapy should be used in preference to rituximab monotherapy (except when chemotherapy is contraindicated), based on the observed lower response to rituximab monotherapy shown in clinical trials. Recommendation 2: BR currently recommended as the preferred chemoimmunotherapy given the superior efficacy and favorable tolerability of this regimen versus R-CHOP in 2 randomized trials. Recommendation 3: Maintenance rituximab is recommended after first-line treatment of FL.

Kuruvilla et al: Clinical Lymphoma, Myeloma & Leukemia, Vol. 15, No. 2, 59-74, 2015 21 Treatment of recurrent indolent lymphoma

22 Goals of Therapy in NHL: Relapsed/Refractory1

Chemotherapy induces remissions in many indolent B-cell lymphoma patients but does not usually prevent recurrent relapses/refractory disease1 • More than half of patients with follicular lymphoma are expected to relapse within 10 years of diagnosis2

Unlike frontline therapy, the goal of relapsed/refractory therapy is shifted toward disease and symptom control

1. Saguna, et al. Medica. 2011;6:100-108. 2. Pugh TJ, et al. Cancer. 2010;116:3843-3851.

23 Therapeutic options for Recurrent FL Repeat alkylator combination Still 2 Trial New mabs Obinutuzimab Ofatumomab Radiolabeled monoclonals Bexxar 90Yttrium Ibritumomab Tiuxetan (Zevalin) New targeted agents Imods (lenalidomide) BTK inhibitors (Ibrutinib) PI3K inhibitors (Idelalsib) BCL2 inhibitors (Venetoclax) High dose therapy and stem cell transplantation

24 Treatment of recurrence with combination chemotherapy Rituxan refractory FL patients-Sehn, L. et al. Lancet Oncology, 2016,17,8,1081 PFS- Randomized to: IRC Bendamustine or Bendamustine and Obinutuzimab PFS- Investigator AND Obinutuzimab maintenance 80% refractory to R plus chemo, 20% refractory to R OS alone Excluded if received B within 24 months

25 Treatment Options for Patients with Refractory Indolent NHL

SoC is not yet defined for patients with refractory indolent NHL.

Bendamustine Radioimmunoconjugate Ofatumumab Idelalisib monotherapy1 (131I-tositumomab)2 monotherapy3 monotherapy4

100 Median PFS 100 Median PFS 100 Median PFS 100 Median PFS 9.3 months 10.4 months 5.8 months 11.0 months

80 80 80 80

60 60 60 60

PFS (%) PFS PFS (%) PFS (%) 40 40 PFS (%) 40 40

20 20 20 20

0 0 0 0 1 2 1 2 1 2 1 2 Time (years) Time (years) Time (years) Time (years)

PFS, progression-free survival; SoC, standard of care 1. Kahl B et al. Cancer 2010; 116(1):106-14; 2. Horning SJ et al. J Clin Oncol 2005; 23(6):712-9; 26 3. Czuczman MS et al. Blood 2012; 119(16):3698-704; 4. Gopal AK et al. N Engl J Med 2014; 370(11):1008-18. Lenalidomide with or without Rituximab

27 Role of Autologous stem cell transplant- Pettengell et al

28 Pettengell et al., JCO, 2013

Auto transplant:

Can induce long remissions

Significant toxicity profile

May not be possible if:

Comorbid illnesses

Age

Extensive marrow infiltration

Not curative

Published in: Ruth Pettengell; Norbert Schmitz; Christian Gisselbrecht; Graeme Smith; William N. Patton; Bernd Metzner; Dolores Caballero; Herve Tilly; Jan A. Walewski; Isabelle Bence- Bruckler; Bik To; Christian H. Geisler; Rik Schots; Eva Kimby; Christian J. Taverna; Tomáš Kozák; Peter Dreger; Ruzena Uddin; Carmen Ruiz de Elvira; Anthony H. Goldstone; JCO 2013, 31, 1624-1630. DOI: 10.1200/JCO.2012.47.1862 Copyright © 2013 29 Suggested Second-Line Treatment Regimens for FL: NCCN Guidelines

Grade 1-2 (in preference order) Grade 3* (alphabetical order) • Chemotherapy (as for first-line) For candidates for high-dose therapy: • RTX • DHAP • Lenalidomide ± RTX • ESHAP • Bendamustine + obinutuzumab • GDP ± RTX or gemcitabine/ • Y90-RIT dexamethasone/carboplatin ± RTX • Idelalisib (refractory to both alkylator and RTX) • GemOx ± RTX • Copanlisib (refractory to ≥2 prior therapies) • ICE ± RTX • Fludarabine + RTX • MINE ± RTX • RFND For non-candidates for high-dose therapy: • Second-line therapy as for Second-line and • Bendamustine ± RTX DLBCL/grade 3 FL* subsequent therapy • Brentuximab vedotin for CD30+ disease • CEPP ± RTX – PO and IV • CEOP ± RTX • DA-EPOCH ± RTX • GDP ± RTX or gemcitabine/ dexamethasone/carboplatin ± RTX • GemOx ± RTX • Gemcitabine, vinorelbine ± RTX • Lenalidomide ± RTX • RTX • RTX • Obinutuzumab maintenance for RTX- Second-line consolidation refractory disease • High-dose therapy with ASC rescue • ASCT for highly selected patients *Controversy exists regarding whether Grade 3 FL should be treated as for Grade 1-2 FL or as for DLBCL. Options shown here are those listed for DLBCL. ASCT, autologous stem cell transplant; CEOP, cyclophosphamide/etoposide/vincristine/prednisone; CEPP, cyclophosphamide/etoposide/procarbazine/prednisolone; DA, dose-adjusted; DHAP, dexamethasone/high-dose cytarabine/cisplatin; EPOCH, etoposide/prednisolone/vincristine/cyclophosphamide/doxorubicin; ESHAP, etoposide/methylprednisolone/cytarabine/cisplatin; FL, follicular lymphoma; GDP, gemcitabine/dexamethasone/cisplatin; GemOx, gemcitabine/oxaliplatin; ICE, ifosfamide/carboplatin/etoposide; MINE, mesna/ifosfamide/novantrone/etoposide; NCCN, National Comprehensive Cancer Network; RFND, Y90- RITuximab/fludarabine/mitoxantrone/dexamethasone; Y90-RIT, radioimmunotherapy; RTX, Y90-RITuximab National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: B-cell Lymphomas. Version 6.2017. 30 Available at: https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf. Accessed: November 15, 2017. 90Y-ibritumomab tiuxetan

31 90YIT

• Yttrium-90 ibritumomab tiuxetan (90YIT) has 3 components: • Antibody1,2 ▪ Ibritumomab is a monoclonal antibody that targets the CD20 antigen found on >90% of B-cells • Chelator ▪ The chelate tiuxetan, which tightly binds Yttrium-90, is covalently linked to ibritumomab • Radioisotope1,2 ▪ Yttrium-90 is the high-energy beta emitter in 90YIT

90YIT, 90Y-ibritumomab tiuxetan 1. Witzig TE et al. J Clin Oncol 1999; 17(12):3793-803. 32 2. Krasner C et al. Curr Pharm Biotechnol 2001; 2(4):341-9. 90YIT In Low-Grade or Follicular Lymphoma

• 90YIT combines targeting and therapeutic activity of a monoclonal antibody with the cytotoxic activity of radiation1 • 90YIT binds to the CD20 antigen expressed on >90% of B-cells2

• The beta emission from Yttrium-90 induces cellular damage by the formation of free radicals in the targeted and neighbouring cells2

90YIT, 90Y-ibritumomab tiuxetan 1. Witzig TE, et al. J Clin Oncol. 1999;17(12):3793-803. 33 2. ZEVALIN® (Ibritumomab Tiuxetan) Product Monograph. Laval, QC: Servier Canada Inc.; 2016. Beta Emissions Occur in Spectrum of Path Lengths Related to Particle Energy

α-particle 50-80 μm range 5-8 MeV

β¯-particle 1-10 mm range 0.1-2.2 MeV

34 Milenic DE et al. Nat Rev Drug Discov 2004; 3(4):488-99. Isotope Properties

Property Y-90 I-131 Radiation type Beta Beta, gamma Half-life 2.7 days 8 Days Path length 5 mm 1 mm Particle energy 2.3 MeV 0.61 MeV Primary gamma energy None 0.35 MeV Thyroid protection Not required Required Shielding Acrylic Lead Isolation Not required Required

Kaminski MS et al. J Clin Oncol 1996; 14(7):1974-81. 35 Wiseman GA et al. Eur J Nucl Med 2000; 27(7):766-77. Risk of Radiation Exposure to Others Following 90YIT Treatment Is Minimal

• Most activity is retained • Urinary excretion = 7.3%  3.2% over 7 days • Assuming maximum 32.0 mCi dose and excretion of 7.3% over a week, total urinary excretion over a week is 2.3 mCi • This suggests urinary excretion is an unlikely cause of radiation exposure • For the majority of patients, ordinary amounts of blood (e.g., menstruation, bad cuts, hemorrhoids) will contain inconsequential levels of radioactivity

90YIT Precautions = Universal Radiation Precautions

90YIT, 90Y-ibritumomab tiuxetan 36 Wagner HN Jr. J Nucl Med 2002; 43(8):267-72. Risk of Radiation Exposure to Others

• Prospective study in 13 family members of patients treated with 90YIT • Family members with closest contact wore personal alarm dosimeter for 7 days • Family was instructed to avoid body wastes, but no other precautions were given • Median deep dose equivalent over 7 days = 3.5 mrem (range 1.4-7.9 mrem) ▪ mrem = the amount of energy that a radioactive source deposits in living tissue • Conclusion: exposure to others is negligible, in the range of background radiation

90YIT, 90Y-ibritumomab tiuxetan Wiseman GA et al. Eur J Nucl Med 2001; 28:1198; United States Nuclear Regulatory Commission. Measuring Radiation 37 Available at: https://www.nrc.gov/about-nrc/radiation/health-effects/measuring-radiation.html. Accessed: November 21, 2017. Safety Information for Patients

• With 90YIT, there is no direct effect of radiation outside of the body • A small part of the radioactivity will leave the body in the urine • The remainder will break down within the body • There is no need to stay in hospital or avoid contact with family, friends, and co-workers

• Safety precautions for 7 days: • Wash hands thoroughly after using the bathroom • Wear a condom during intercourse to avoid transfer of bodily fluids

• Safety precaution for 1 year: • Use reliable contraception to avoid pregnancy/fathering a child

90YIT, 90Y-ibritumomab tiuxetan 38 ZEVALIN® (Ibritumomab Tiuxetan) Product Monograph. Laval, QC: Servier Canada Inc.; 2017. Indication and Usage of 90YIT

39 Suggested Second-Line Treatment Regimens for FL: NCCN Guidelines

Grade 1-2 (in preference order) Grade 3* (alphabetical order) • Chemotherapy (as for first-line) For candidates for high-dose therapy: • RTX • DHAP • Lenalidomide ± RTX • ESHAP • Bendamustine + obinutuzumab • GDP ± RTX or gemcitabine/ • Y90-RIT dexamethasone/carboplatin ± RTX • Idelalisib (refractory to both alkylator and RTX) • GemOx ± RTX • Copanlisib (refractory to ≥2 prior therapies) • ICE ± RTX • Fludarabine + RTX • MINE ± RTX • RFND For non-candidates for high-dose therapy: • Second-line therapy as for Second-line and • Bendamustine ± RTX DLBCL/grade 3 FL* subsequent therapy • Brentuximab vedotin for CD30+ disease • CEPP ± RTX – PO and IV • CEOP ± RTX • DA-EPOCH ± RTX • GDP ± RTX or gemcitabine/ dexamethasone/carboplatin ± RTX • GemOx ± RTX • Gemcitabine, vinorelbine ± RTX • Lenalidomide ± RTX • RTX • RTX • Obinutuzumab maintenance for RTX- Second-line consolidation refractory disease • High-dose therapy with ASC rescue • ASCT for highly selected patients *Controversy exists regarding whether Grade 3 FL should be treated as for Grade 1-2 FL or as for DLBCL. Options shown here are those listed for DLBCL. ASCT, autologous stem cell transplant; CEOP, cyclophosphamide/etoposide/vincristine/prednisone; CEPP, cyclophosphamide/etoposide/procarbazine/prednisolone; DA, dose-adjusted; DHAP, dexamethasone/high-dose cytarabine/cisplatin; EPOCH, etoposide/prednisolone/vincristine/cyclophosphamide/doxorubicin; ESHAP, etoposide/methylprednisolone/cytarabine/cisplatin; FL, follicular lymphoma; GDP, gemcitabine/dexamethasone/cisplatin; GemOx, gemcitabine/oxaliplatin; ICE, ifosfamide/carboplatin/etoposide; MINE, mesna/ifosfamide/novantrone/etoposide; NCCN, National Comprehensive Cancer Network; RFND, Y90- RITuximab/fludarabine/mitoxantrone/dexamethasone; Y90-RIT, radioimmunotherapy; RTX, Y90-RITuximab National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: B-cell Lymphomas. Version 6.2017. 40 Available at: https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf. Accessed: November 15, 2017. Indications and Contraindications

Indication Contraindications • 90YIT, as part of the Zevalin • Known type I hypersensitivity or therapeutic regimen, is indicated for anaphylactic reactions to murine the treatment of patients with proteins or any component of the relapsed or refractory low-grade or Zevalin therapeutic regimen, follicular, CD20-positive, B-cell NHL, including yttrium chloride and RTX including patients with • Pregnant or nursing women RTX-refractory FL

90YIT, 90Y-ibritumomab tiuxetan; FL, follicular lymphoma; NHL, non Hodgkin's lymphoma; RTX, rituximab 41 ZEVALIN® (Ibritumomab Tiuxetan) Product Monograph. Laval, QC: Servier Canada Inc.; 2017. 90Yttrium IbritumomabTiuxetan GLOBAL APPROVALS

APPROVED DATE REGION/ INDICATION YYYY/MMM COUNTRY · relapsed or refractory, low-grade or follicular B-cell non-Hodgkin's lymphoma (NHL). 2002/FEB US · previously untreated follicular NHL who achieve a partial or complete response to first-line chemotherapy). · [ 90Y]-radiolabelled Zevalin is indicated as consolidation therapy after remission induction in EU previously untreated patients with follicular lymphoma. The benefit of Zevalin following rituximab in 2004/JAN combination with chemotherapy has not been established. · [ 90Y]-radiolabelled Zevalin is indicated for the treatment of adult patients with rituximab relapsed or （31countries） refractory CD20+ follicular B-cell non-Hodgkin's lymphoma (NHL). Zevalin is indicated as a consolidation therapy after remission induction in former times untreated patients with follicular lymphoma stage III or IV. The therapeutic Benefit after treatment with rituximab in combination with chemotherapy is still not sufficiently determined. 2004/APR Switzerland Zevalin is indicated for the treatment of relapsing or refractory indolent, follicular, or transformed B-cell non-Hodgkin's lymphoma, included on rituximab refractory follicular non-Hodgkin's lymphoma. Determining the effectiveness of treatment with Zevalin in the recurrent or Refractory patient group is based on the overall response rate.. · Treatment of patients with rituximab relapsed or refractory CD20+ follicular B-cell non-Hodgkin's lymphoma (NHL) 2005/FEB Korea · Consolidation therapy after remission induction in previously untreated patients with follicular lymphoma. The benefit of ZEVALIN following rituximab in combination with chemotherapy has not been established. • Treatment of adult patients with CD20 positive indolent B-cell non-Hodgkin's lymphoma (NHL) who have 2005/MAR New Zealand failed rituximab therapy · relapsed or refractory low-grade or follicular, CD20 positive, B-cell non-Hodgkin's lymphoma, including 2005/MAY Canada patients with rituximab-refractory follicular non-Hodgkin’s lymphoma • Zevalin is indicated as consolidation therapy after remission induction in previously untreated patients with follicular lymphoma 2006/JUL Thailand • Zevalin is indicated for the treatment of patients with relapsed or refractory, CD20+ indolent or transformed B-cell non-Hodgkin’s lymphoma (NHL) · [ 90Y]-radiolabelled Zevalin is indicated as consolidation therapy after remission induction in previously untreated patients with follicular lymphoma. The benefit of Zevalin following rituximab in 2006/OCT Hong-Kong combination with chemotherapy has not been established. · [ 90Y]-radiolabelled Zevalin is indicated for the treatment of adult patients with rituximab relapsed or refractory CD20+ follicular B-cell non-Hodgkin's lymphoma (NHL). 42 Studies in Relapsed follicular NHL

Chemo DX Relapse 90yRIT

43 90YIT Therapeutic Regimen

• Treatment schedule: • Day 1: 250 mg/m2 RTX • Day 7, 8 or 9: 250 mg/m2 RTX followed by the therapeutic dose of 90YIT as intravenous push over 10 minutes (0.2-0.4 mCi/kg) Total dose: <32 mCi • Rationale for pretreatment with RTX: • Improves biodistribution of the radionuclide • Reduces binding to CD20 on B-cells • Rationale for eliminating requirement for 111InIT dosimetry: • Dosimetry studies failed to demonstrate a significant correlation between biodistribution of radioactive antibody and hematological toxicity

90YIT, 90Y-ibritumomab tiuxetan; 111InIT, 111In-ibritumomab tiuxetan; RTX, rituximab 44 Lehnert M et al. Onco Targets Ther 2009; 2:199-208; Witzig TE, et al. J Clin Oncol. 1999:17(12):3793-3803. Studies of 90Y-IT monotherapy in Relapsed Refractory NHL

Mostly prospective Phase 2, also retrospective and Phase 3 N: 18-349 patients Includes relapsed and refractory indolent NHL Objective response: 73-80%, PFS- approximately 10 months, DOR-1 to 2.3 years Safety: primarily hematologic, grade 3-4 cytopenias in 60-75%

Tobinai K et al. Cancer Sci 2009; 100(1):158-64

Witzig TE et al. Cancer 2007; 109(9):1804-10

Gordon F et al. Blood 2004; 103(12):4429-33

Witzig TE et al. J Clin Oncol. 2003; 21(7):1263-70

Wiseman GA et al. Blood 2002; 99(12):4336-42

Witzig TE et al. J Clin Oncol 2002; 20(10):2453-63

Knox SJ et al. Clin Cancer Res 1996; 2(3):457-70. 45 Single-Arm Phase II Study of RIT in RTX- Refractory FL: Study Design

RTX RTX + 90YIT on day 1 on day 8

Patients with RTX-refractory FL

Objective Study of 90YIT in the treatment of RTX-refractory follicular NHL

Eligibility RTX-refractory FL with less than 25% BM involvement; no prior BM transplant

Sample Size n = 57

Primary: ORR, confirmed by LEXCOR Outcomes Secondary: TTP (time from date of first infusion on day 1 to the date of disease progression); DoR (date of first response observation to the date of disease progression); safety

90YIT, 90Y-ibritumomab tiuxetan; BM, bone marrow; DoR, duration of response; FL, follicular lymphoma; LEXCOR, Lymphoma Expert’s Confirmation of Response; NHL, non-Hodgkin’s lymphoma; ORR, overall response rate; RIT, radioimmunotherapy; RTX, rituximab; TTP, time to progression 46 Witzig TE et al. J Clin Oncol 2002; 20(15):3262-9. Single-Arm Study of RIT in RTX-Refractory FL: Baseline Characteristics

Characteristics n=57 Male, n (%) 28 (49) Median age, years (range) 54 (34-73) Stage III/IV, n (%) 51 (90) IPI risk group, n (%)* Low 25 (44) Low/intermediate 12 (21) Intermediate/high 7 (12) High 4 (7) Number of prior regimens, median (range) 4 (1-9) WHO performance status, n (%) 0,1 54 (95) 2 3 (5) • 37 patients (67%) showed resistance to last chemotherapy, while 45 patients (82%) showed resistance to any therapy (disease progression within 6 months)

*Note that the IPI value was only known for 48 of 57 patients IPI, International Prognostic Index; FL, follicular lymphoma; RIT, radioimmunotherapy; RTX, rituximab; WHO, World Health Organization 47 Witzig TE et al. J Clin Oncol 2002; 20(15):3262-9. Single-Arm Study of RIT in RTX-Refractory FL: Overall Response Rate

Results in Rituximab-Refractory Follicular NHL

Response Rates (n = 54) Response Rates Compared to Previous Regimens ORR 74% 100% CR 15% Median DoR 6.4 0.75 0.75 [range, months] [0.5 to ≥24.9] 75% Median TTP 6.8 [range, months] [1.1 to ≥25.9] 50%

0.31

Response Rate Response 25% p <0.001 p <0.32

0% RTX Ibritumomab Chemo tiuxetan

CR, complete response; DoR, duration of response; FL, follicular lymphoma; NHL, non-Hodgkin’s lymphoma; ORR, overall response rate; RIT, radioimmunotherapy; RTX, rituximab; TTP, time to progression 48 Witzig TE et al. J Clin Oncol 2002; 20(15):3262-9. Single-Arm Phase II Study of RIT in RTX- Refractory FL: Safety

Toxicity Duration of Hematologic Toxicity

Hematologic (grade IV) Days from • Neutropenia (35%) baseline to Variable Baseline Nadir nadir • Thrombocytopenia (9%) • Anemia (4%) ANC, cells/mm3 3,500 700 63 Non-hematologic* (most common – all grades) Platelets cells/mm3 214,000 33,000 55 • Asthenia (54%) Hemoglobin, g/dL 13.3 9.9 68 • Nausea (35%) • Chills (25%) • The incidence of grade IV ANC nadir correlated • Fever (21%) statistically with increasing bone marrow Secondary malignancy involvement with NHL (p = 0.004) • 1 death as a result of AML ~14 months post-treatment • *There were 83 non-hematologic AEs that occurred on a treatment day • 66 occurred on day 1 and 22 occurred on day 8 • All were grade I or II except for one grade III tumour pain • One patient died as a result of AML~14 months after treatment; note there were pretreatment chromosomal abnormalities in this patient

AE, adverse event; AML, acute myeloid leukemia; ANC, absolute neutrophil count; FL, follicular lymphoma; RIT, radioimmunotherapy; RTX, rituximab 49 Witzig TE et al. J Clin Oncol 2002; 20(15):3262-9. Single-Arm Study of RIT in RTX-Refractory FL: Conclusions

• 90YIT is effective in rituximab-refractory patients • The only significant toxicity is hematologic but transient • No patient discontinued treatment because of an AE

90YIT, 90Y-ibritumomab tiuxetan; AE, adverse event; FL, follicular lymphoma; RIT, radioimmunotherapy; RTX, rituximab 50 Witzig TE et al. J Clin Oncol 2002; 20(15):3262-9. Randomized Phase III Trial in Relapsed/ Refractory Indolent NHL

RTX + 111InIT RTX + 90YIT in day 1 in day 8

Relapsed/refractory indolent NHL

RTX qw x 4 RANDOMIZATION Day -14 -6 -5 -4 -3 -2 -1 0

Objective Comparison of RIT with a control immunotherapy, RTX, in patients with relapsed or refractory low-grade, follicular, or transformed CD20+ transformed NHL Relapsed or refractory low-grade or follicular B-cell NHL; no prior RTX therapy; Eligibility <25% BM involvement by NHL Stratification IWF Groups A, B-D, or transformed Sample Size n = 143 Primary: ORR response by LEXCOR Outcomes Secondary: TTP, DoR

90YIT, 90Y-ibritumomab tiuxetan; 111InIT, 111In-ibritumomab tiuxetan; BM, bone marrow; DoR, duration of response; IWF, International Working Formulation; LEXCOR, Lymphoma Expert’s Confirmation of Response; NHL, non-Hodgkin's lymphoma; ORR, overall response rate; RIT, radioimmunotherapy; RTX, rituximab; TTP, time to progression 51 Witzig TE et al. J Clin Oncol 2002; 20(10):2453-63. Randomized Phase III Trial in Relapsed/ Refractory Indolent NHL: Baseline Characteristics

RIT RTX Characteristics (n = 73) (n = 70) Male, n (%) 35 (48) 35 (50) Median age, years (range) 60 (29-80) 57 (36-78) Stage III/IV, n (%) 65 (89) 64 (91) FL, n (%) 55 (75) 58 (83) IPI risk group, n (%) Low 25 (34) 32 (46) Low/intermediate 38 (52) 23 (33) Intermediate/high 5 (6.8) 7 (10) High 3 (4.1) 2 (2.9) Unknown 2 (2.7) 6 (8.6) Number of prior regimens, 2 (1-6) 2 (1-5) median (range)

IPI, International Prognostic Index; FL, follicular lymphoma; NHL, non-Hodgkin's lymphoma; RIT, radioimmunotherapy; RTX, rituximab 52 Witzig TE et al. J Clin Oncol 2002; 20(10):2453-63. Randomized Phase III Trial in Relapsed/ Refractory Indolent NHL: Response

Response in all Patients

ORR 56% (p < 0.002) RTX PR 36% CR/CRu 20% (n = 70) Median DoR 12.1 months

ORR RIT ORR 80% (p <0.002) PR 46% CR/CRu 34% (n = 73) Median DoR 14.2 months

0 20 40 60 80 100% Response in FL Patients

RTX ORR 55% (p < 0.001) (n = 58) Median DoR 12.1 months

ORR RIT ORR 86% (p < 0.001) (n = 55) Median DoR 18.5 months

0 20 40 60 80 100%

CR, complete response; CRu, complete response unconfirmed; DoR, duration of response; FL, follicular lymphoma; NHL, non-Hodgkin's lymphoma; ORR, overall response rate; RIT, radioimmunotherapy; RTX, rituximab 53 Witzig TE et al. J Clin Oncol 2002; 20(10):2453-63. Randomized Phase III Trial in Relapsed/ Refractory Indolent NHL: A/E’s-non hematologic

Grades 1 and 2 Grades 3 and 4

44 4 Asthenia 41 43 Nausea 19 25 Chills 29 19 1 Pain 14 1 19 Fever 17 19 Abdominal Pain 11 1 19 Vomiting 7 19 Throat Irritation 16 16 RTX (n = 70) Headache 23 15 90 Increased Cough 7 YIT (n = 73) 15 Dizziness 7 15 Dyspnea 7 11 Pruritus 16 1 8 Angioedema 16

50 40 30 20 10 0 10 20 30 40 50 Patients (%)

90YIT, 90Y-ibritumomab tiuxetan; AE, adverse event; NHL, non-Hodgkin's lymphoma; RTX, rituximab 54 Witzig TE et al. J Clin Oncol 2002; 20(10):2453-63. Randomized Phase III Trial in Relapsed/ Refractory Indolent NHL: Hematological Toxicity

Patients Patients Median duration in with with days for patients with Median nadir grade III grade IV grade III-IV nadir (%) (%) Method A Method B ANC 900 cells/mm3 25 32 27 8 Platelets 41,000 cells/mm3 55 5 23 9 Hemoglobin 10.8 g/dL 1 1 15 1

• 18% of patients received platelet transfusions and 12% received RBC transfusions • 7% were hospitalized with infection or febrile neutropenia (all patients recovered)

ANC, absolute neutrophil count; NHL, non-Hodgkin's lymphoma; RBC, red blood cell 55 Witzig TE et al. J Clin Oncol 2002; 20(10):2453-63. Randomized Phase III Trial in Relapsed/ Refractory Indolent NHL: Conclusions

• 90YIT provides improved ORR and CR/CRu in relapsed/refractory indolent NHL

• RIT with 90YIT is well tolerated in this patient population • Reversible myelosuppression was the primary toxicity noted with 90YIT

• Treatment with 90YIT is safe and effective in the treatment of relapsed/refractory low-grade follicular or transformed NHL

90YIT, 90Y-ibritumomab tiuxetan; CR, complete response; CRu, complete response unconfirmed; NHL, non-Hodgkin's lymphoma; ORR, overall response rate 56 Witzig TE et al. J Clin Oncol 2002; 20(10):2453-63. Post Hoc Analysis of Long-Term Efficacy Data from 4 Registration Trials: Study Characteristics

• Phase I/II dose-finding trial in patients with indolent and aggressive NHL Included • Phase II trial of reduced-dose 90YIT in patients with mild thrombocytopenia Studies • Randomized phase III trial comparing 90YIT to RTX monotherapy • Phase III trial in patients with RTX-refractory NHL

Sample Size n = 211

RTX + 111InIT RTX + 90YIT Treatment on day 1 on day 7, 8 or 9 Regimen

Outcomes Primary: CR, CRu, PR, TTP and DoR

90YIT, 90Y-ibritumomab tiuxetan; 111InIT, 111In-ibritumomab tiuxetan; CR, complete response; CRu, complete response unconfirmed; DoR, duration of response; NHL, non-Hodgkin’s lymphoma; PR, partial response; RTX, rituximab; TTP, time to progression 57 Witzig TE et al. Cancer 2007; 109(9):1804-10. Post Hoc Analysis of Long-Term Efficacy Data from 4 Registration Trials: Patient Characteristics

Patients with long-term response Patients without long- All patients All histologies FL term response Characteristics (n = 211) (n = 78) (n = 59) (n = 133) Male, % 55 55 51 56 Median age, years (range) 58 (24-85) 58 (24-80) 59 (34-79) 58 (29-85) FL, % 73 76 100 71 BM involvement, % 45 41 41 47 Bulky disease, % 56 30 31 72 Stage III/IV disease, % 89 83 86 92 Previous therapies, median (range) 2 (1-9) 2 (1-7) 2 (1-7) 2 (1-9) No response to last therapy, % 52 37 36 60

BM, bone marrow; FL; follicular lymphoma 58 Witzig TE et al. Cancer 2007; 109(9):1804-10. Post Hoc Analysis of Long-Term Efficacy Data from 4 Registration Trials: OS

100

Patients with LTR 80 Median OS: not reached 5-year OS: 80.6%

60 ITT Population Median OS: 49.3 months 5-year OS: 53.0%

Alive (%) Alive 40

20 Patients with long-term responses (n = 78) Intent-to-treat population (n = 211) 0 0 8 16 24 32 40 48 56 64 72 80 88

Time (months)

ITT, intention to treat; LTR, long-term response; OS, overall survival 59 Witzig TE et al. Cancer 2007; 109(9):1804-10. Post Hoc Analysis of Long-Term Efficacy Data from 4 Registration Trials: Conclusions

• Treating refractory/relapsed NHL with RIT produces high ORR of ~80% • Predicting patients in whom RIT will produce LTR is difficult, but those who achieve LTR have excellent overall survival • As non-bulky disease was a predictor of LTR, patients with bulky disease might benefit from de-bulking prior to RIT therapy

LTR, long-term response; NHL, non-Hodgkin’s lymphoma; ORR, overall response rate; RIT, radioimmunotherapy 60 Witzig TE et al. Cancer 2007; 109(9):1804-10. Post Hoc Analysis of Safety Data from 5 Registration Trials: Study Characteristics

• Phase I/II dosimetry study in patients with low- or intermediate-grade MCL • Phase II trial of reduced-dose 90YIT in patients with mild thrombocytopenia Included • Randomized phase III trial comparing 90YIT to RTX monotherapy Studies • Non-randomized phase III trial in patients with RTX-refractory NHL • Open-label study

Sample Size n = 349

RTX ± 111InIT RTX + 90YIT on day 1 on day 8 Treatment Regimen

90YIT, 90Y-ibritumomab tiuxetan; 111InIT, 111In-ibritumomab tiuxetan; MCL, mantle cell lymphoma; NHL, non Hodgkin's lymphoma; RTX, rituximab 61 Witzig TE et al. J Clin Oncol. 2003; 21(7):1263-70. Post Hoc Analysis of Long-Term Safety Data from 5 Registration Trials: Median Blood Counts in Patients Treated with RIT (n = 349)

16 450 )

dL 400

Hemoglobin (g/ 350

12 ) 3

300

/mm 3

Platelets 250 (10 Hemoglobin 8

200

) 3

150 /mm ANC Platelets 3 4 100

50 ANC (10 ANC 0 0 0 2 4 6 8 10 12 14 Study Week

ANC, absolute neutrophil count; RIT, radioimmunotherapy 62 Witzig TE et al. J Clin Oncol. 2003; 21(7):1263-70. Post Hoc Analysis of Safety Data from 5 Registration Trials: Grade III and IV AEs

Toxicity n = 349 Non-hematologic 39 (11%) Infection 16 (5%) Asthenia 6 (2%) Abdominal pain 4 (1%) Hematologic Neutropenia 208 (60%) Thrombocytopenia 220 (63%) Anemia 60 (17%) Grade III-IV bleeding 7 (2%)

• 43 patients (20%) received RBC transfusions • 47 patients (22%) received platelet transfusions

AE, adverse event; RBC, red blood cell 63 Witzig TE et al. J Clin Oncol. 2003; 21(7):1263-70. Post Hoc Analysis of Long-Term Safety Data from 5 Registration Trials: Correlation of Grade IV Hematologic Toxicity and BM Involvement

BM involvement: 0% 0.1-5.0% 5.1-20.0% ≥20.0% 60 p = 0.001 53 50

40 36 37 p = 0.013 30 25 23 p = 0.040 20

patients349) (n = 13 13 10 9

% % of 7 3 2 0 0 Grade IV neutropenia Grade IV anemia Grade IV thrombocytopenia

BM, bone marrow 64 Witzig TE et al. J Clin Oncol. 2003; 21(7):1263-70. Post Hoc Analysis of Long-Term Safety Data from 5 Registration Trials: Secondary Malignancy

• 5 patients (1%) developed secondary malignancies 8-34 months after RIT • 2 cases of MDS • 2 cases of AML • 1 cases of MDS that later developed into AML • All 5 patients had previously received alkylating chemotherapy for ≥1 year • Annualized rate for time to development of MDS/AML: • 0.6% from date of diagnosis • 1.1% from date of first RTX infusion • 1 additional patient developed a benign meningioma

AML, acute myeloid leukemia; MDS, myelodysplastic syndrome; RIT, radioimmunotherapy; RTX, rituximab 65 Witzig TE et al. J Clin Oncol. 2003; 21(7):1263-70. Post Hoc Analysis of Long-Term Safety Data from 5 Registration Trials: Conclusions

• 90YIT was well tolerated • Primary toxicity was reversible myelosuppression, which reached nadir 7-9 weeks after RIT • BM involvement was significantly associated with risk for grade IV hematological toxicities

90YIT, 90Y-ibritumomab tiuxetan; BM, bone marrow; RIT, radioimmunotherapy 66 Witzig TE et al. J Clin Oncol. 2003; 21(7):1263-70. Consolidation treatment with 90Y ibritumomabtiuxetan-First line

Monotherapy 90yRIT DX

Consolidation Chemo 90yRIT DX

67 Y90 RIT-Studies of First-Line Therapy for FL

1 2 3 1. Ibatici A et al. Br J Haematol 2014;Ibatici 164(5):710 et al,-6; 2. 2014 Illidge TM et al. J Clin OncolIllidge 2014; et 32(3):212 al, 2014-8; 3. ScholzMORE CW et al. J Clin Oncol 2013;Scholz 31(3):308 et-13. al, 2013 Study design • Prospective phase II • Prospective phase II • Prospective phase II single-arm trial single-arm trial single-arm trial Patient • 50 patients with previously • 72 patients with previously • 59 patients aged ≥50 years with population untreated stage II bulky, untreated CD20+ grade 1-3a FL previously untreated CD20+ stage III or IV, CD20+, meeting ≥1 modified BNLI/GELF grade 1-3a, stage II-IV FL grade 1 or 2 FL criteria for initiation of treatment Treatment • RTX on day 1 • Induction therapy with weekly • RTX on day 1 • RTX + 90YIT on day 8 ± 1 RTX for 4 weeks for patients with • RTX + 90YIT on day 8 or 9 >20% BM involvement • RTX followed by RTX + 90YIT 7-8 days later • 8 weeks after first round of therapy, second round of RTX followed by RTX + 90YIT 7-8 days later Follow-up • Median follow-up: 38.8 months • Median follow-up: 3.1 years • Median follow-up: 30.6 months Efficacy • CR: 86% • CR/CRu: 58% (95% CI 46-70%) • CR: 41% • PR: 8% • PR: 36% • CRu: 15% • 3-year PFS: 63% • Median PFS: 3.4 years • PR: 31% • 3-year OS: 90% • 3-year PFS: 58% • Median PFS: 25.9 months • 3-year OS: 95% Safety • Grade III-IV neutropenia: 30% • Most SAEs were reversible • Grade III-IV neutropenia: 32% • Grade III-IV thrombocytopenia: hematologic toxicities • Grade III-IV thrombocytopenia: 48% 26% • Secondary cancers occurred • Grade III-IV lymphopenia: 20% • Secondary cancers diagnosed in 8% • Secondary cancers reported in 8% in 8% 90YIT, 90Y-ibritumomab tiuxetan; BM, bone marrow; BNLI, British National Lymphoma Investigation; CR, complete response; CRu, complete response unconfirmed; FL, follicular lymphoma; GELF, Groupe d'Etude des Lymphomes Folliculaires; OS, overall survival; PFS, progression-free survival; PR, partial response; RTX, rituximab; SAE, serious adverse event 68 1. Ibatici A et al. Br J Haematol 2014; 164(5):710-6; 2. Illidge TM et al. J Clin Oncol 2014; 32(3):212-8; 3. Scholz CW et al. J Clin Oncol 2013; 31(3):308-13. Consolidation studies in FL after First line therapy • mostly Phase 2 single arm trials • mostly less than 60 patients • f-u 20-84 months • Mostly after induction chemos including FM, R-CHOP • Efficacy: median PFS 4-7 years • Most a/e’s transient cytopenias and second malignancies from 5- 14% • Similar studies performed in mantle cell and other non-follicular indolent NHLs

Casadei B et al. Cancer Med 2016; 5(6):1093-7; 2.

Provencio M et al. Leuk Lymphoma 2014; 55(1):51-5;

Morschhauser F et al. J Clin Oncol 2013; 31(16):1977-83;

Zinzani PL et al. Ann Oncol 2012; 23(3):805-7;

Karmali R et al. Clin Lymphoma Myeloma Leuk 2011;11(6) 467-74

Hainsworth JD et al. Clin Lymphoma Myeloma 2009; 9(3):223-8; 69 Jacobs SA et al. Clin Cancer Res 2008; 14(21):7088-94. FIT – Phase III Trial of 90YIT as First-Line Consolidation Therapy: Study Design

Patients with previously 6-12 weeks after Start of study untreated FL last dose of induction Induction Consolidation 90 First-line therapy CR/CRu YIT (n = 207) 2 with chlorambucil, or PR RTX 250 mg/m IV on day −7 and day 0 + CVP, CHOP, CHOP- 90YIT 14.8 MBq/kg (0.4 mCi/kg) like, fludarabine [max 1184 MBq (32 mCi)] on day 0 combination, or RTX combination NR, PD Control

No further treatment (n = 202) RANDOMIZATION Not Eligible

Stage III or IV histologically confirmed CD20+ FL (grade 1 or 2) in CR/CRu or Eligibility PR after first-line therapy Sample Size n = 409 Primary: PFS Outcomes Secondary: PFS by type of 1st-line induction regimen, CR rate, OS, safety

90YIT, 90Y-ibritumomab tiuxetan; CHOP, cyclophosphamide/doxorubicin/vincristine/prednisone; CR, complete response; CRu, complete response unconfirmed; CVP, cyclophosphamide/vincristine/prednisolone; FL, follicular lymphoma; NR, no response; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; RTX, rituximab 70 Morschhauser F et al. J Clin Oncol 2013; 31(16):1977-83; Morschhauser F et al. J Clin Oncol 2008; 26(3^):5156-64. FIT: Baseline Characteristics

Control 90YIT Characteristics (n = 202) (n = 207) Male, n (%) 101 (50) 99 (48) Age at randomization (years) Median (range) 53 (27-74) 55 (29-78) Aged >60 years, n (%) 48 (24) 58 (28) Ann Arbor classification, n (%) Stage III 62 (31) 73 (35) Stage IV 134 (66) 132 (64) Response to first-line treatment, n (%) CR/CRu 108 (53) 107 (52) PR 88 (44) 100 (48)

Patient baseline characteristics and distribution of first-line induction treatments were well balanced between treatment arms.

90YIT, 90Y-ibritumomab tiuxetan; CR, complete response; CRu, complete response unconfirmed; PR, partial response 71 Morschhauser F et al. J Clin Oncol 2013; 31(16):1977-83; Morschhauser F et al. J Clin Oncol 2008; 26(3^):5156-64. FIT: Outcomes After a Median Follow-Up of 7.3 Years

CR/CRu

Control 53 62 After induction therapy After randomization 90Y-Ibritumomab 52 89

0 50 100 % of patients

90YIT, 90Y-ibritumomab tiuxetan; CR, complete response; CRu, complete response unconfirmed; CHOP, cyclophosphamide/doxorubicin/vincristine/prednisone; COP, cyclophosphamide/vincristine/prednisolone; CVP, cyclophosphamide/vincristine/prednisolone; RTX, rituximab 72 Adapted from: Morschhauser F et al. J Clin Oncol 2013; 31(16):1977-83. FIT: Overall PFS Over 8 Years

HR = 0.47 100 90 (95% CI: 0.37–0.67) YIT: n = 207 p <0.001 Median PFS: 4.1 years 8-year PFS: 41% 75 Control: n = 202 Median PFS: 1.1 year 8-year PFS: 22% 50

Cumulativepercentage N F Control 202 151 90YIT 207 119 0 0 2 4 6 8

At risk: Time (years) Control 202 81 62 48 16 90YIT 207 132 98 89 24

After 3.5 years median follow-up (initial results), median PFS was 36.5 months in the 90YIT arm vs. 13.3 months in the control arm; HR = 0.465; p <0.0001. 90YIT, 90Y-ibritumomab tiuxetan; CI, confidence interval; F, failure defined as number of patients who relapsed or died); HR, hazard ratio; PFS, progression-free survival 73 Morschhauser F et al. J Clin Oncol 2013; 31(16):1977-83. FIT: Time to Next Treatment

90YIT: n = 207 100 Median TTNT = 8.1 years

Control: n = 202 75 Median TTNT = 3.0 years

50 HR = 0.47 (95% CI: 0.36–0.61) p < 0.001

25 Cumulativepercentage N F N: number of patients at risk Control 202 128 F: failure (defined as number of 90YIT 207 93 patients who relapsed or died) 0 0 2 4 6 8

At risk: Time (years) Control 202 117 78 57 20 90YIT 207 165 120 106 30

90YIT, 90Y-ibritumomab tiuxetan; CI, confidence interval; F, failure (defined as number of patients who relapsed or died); HR, hazard ratio 74 Morschhauser F et al. J Clin Oncol 2013; 31(16):1977-83. FIT: Responses to Second-Line Therapy

Patients in control and 90YIT arms achieved comparable responses to second-line therapy

90% 79 81 Control (n = 128*) 80% 90Y-Ibritumomab90YIT (n = 93*) (n = 93*) 70% 61 59 60% 50% 40%

line therapy therapy line after PD 30% - 22 18 % with % with response to 20% 10% second 4 1 2 2 0% ORR CR/CRu PR SD PD

*Number of patients who received treatment after PD 90YIT, 90Y-ibritumomab tiuxetan; CR, complete response; CRu, complete response unconfirmed; ORR, overall response rate; PD, progressive disease; PR, partial response; SD, stable disease 75 Morschhauser F et al. J Clin Oncol 2013; 31(16):1977-83. FIT: Safety

• Most common grade III-IV toxicities with RIT were hematological: • Lymphopenia: 60.3% vs. 10.8% in control arm • Neutropenia: 66.7% vs. 2.5% in control arm • Thrombocytopenia: 60.8% vs. 0 in control arm • Anemia: 3.4% vs. 0 in control arm • 20.6% of RIT-treated patients received platelet transfusions and 1.9% required RBC transfusions • Grade III-IV infections occurred in 7.9% of patients treated with RIT vs. 2.4% of the control arm

RBC, red blood cell; RIT, radioimmunotherapy 76 Morschhauser F et al. J Clin Oncol 2013; 31(16):1977-83. FIT: Incidence of MDS/AML

90YIT Control group group p value Actuarial 8-year 4.2% 0.6% 0.042 incidence

0.50% 0.07% Annualized rate NS (95% CI 0.24-1.06%) (95% CI 0.01-0.53%)

90YIT, 90Y-ibritumomab tiuxetan; AML, acute myeloid leukemia; CI, confidence interval; MDS, myelodysplastic syndrome; NS, not significant 77 Morschhauser F et al. J Clin Oncol 2013; 31(16):1977-83. FIT: Conclusions

• 90YIT consolidation resulted in: • High conversion rates from PR to CR/CRu • Final overall CR rate: 87% • Improvement in PFS and TTNT (time to next treatment) at 8 years post-randomization with 90YIT consolidation compared with control • No unexpected toxicities emerging • Annualized rate of secondary MDS/AML was 0.50% in the 90YIT arm • For patients who relapse: • 90YIT consolidation does not appear to rule out any second-line treatment approach, including ASCT • After 90YIT, responses to second-line therapy appear comparable to those achieved in the control arm • At current follow-up, there is no significant difference in OS between treatment arms (p = 0.466)

90YIT, 90Y-ibritumomab tiuxetan; AML, acute myeloid leukemia; ASCT, autologous stem cell transplant; CR, complete response; CRu, complete response unconfirmed; MDS, myelodysplastic syndrome; OS, overall survival; PR, partial response BACK 78 Morschhauser F et al. J Clin Oncol 2013; 31(16):1977-83. Suggested First-Line Treatment Regimens for FL: NCCN Guidelines®

*Controversy exists regarding whether Grade 3 FL should be treated as for Grade 1-2 FL or as for DLBCL. Options shown here are those listed for DLBCL. ASC, autologous stem cell; CHOP, cyclophosphamide/doxorubicin/vincristine/prednisone; CVP, cyclophosphamide/vincristine/prednisolone; DA, dose-adjusted; EPOCH, etoposide/prednisolone/vincristine/cyclophosphamide/doxorubicin; FL, follicular lymphoma; IPI, International Prognostic Index; NCCN, National Comprehensive Cancer Network; RCDOP, rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone; RCEOP, rituximab/cyclophosphamide/etoposide/vincristine/prednisone; R-CEPP, rituximab/cyclophosphamide/etoposide/procarbazine/prednisolone; R-CHOP, rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone; R-CVP, rituximab/cyclophosphamide/vincristine/prednisolone; RGCVP, rituximab/gemcitabine/cyclophosphamide/vincristine/prednisolone; RIT, radioimmunotherapy; RTX, rituximab National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: B-cell Lymphomas. Version 6.2017. 79 Available at: https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf. Accessed: November 15, 2017. 90YIT has been studied in multiple NHL indications

Indolent First Line monotherapy consolidation Indolent Second Line monotherapy consolidation Stem cell transplantation with induction therapy as consolidation Mantle cell Lymphoma Aggressive Lymphomas

80 Canadian clinical trial-Consolidation post First line therapy in High Risk Follicular Lymphoma

Consolidation

Chemo 90yRIT DX

81 Canadian clinical trial-Consolidation post First line therapy in High and Int Risk FL

FLIPI separates patients into different prognostic categories

82 Sunnybrook Phase 2 trial: Management of newly diagnosed high and intermediate risk follicular lymphoma with 90Y ibritumomab tiuxetan in a phase II study

Objective: To enhance the ORR and PFS for high and intermediate risk FLIPI FL patients by incorporating 90Y RIT consolidation into first line therapy

Y90-RIT administered in nuclear medicine department

83 Sunnybrook Phase 2 trial: Management of newly diagnosed high and intermediate risk follicular lymphoma with 90Y ibritumomab tiuxetan in a phase II study

84 Results: Clinical efficacy

85 OS and PFS

86 A/E’s

Transient cytopenias Persistent B cell depletion and hypogamma-globulinemia in some patients MDS occurs at frequency expected in general population

87 Overall conclusions-Scoring on NHL:

Patients with indolent lymphoma have a relatively long natural history and will receive many different treatment options 90Yttrium ibritumomab tiuxetan (90YIT) has been shown to have anti-tumor activity and has been approved in Canada for patients with recurrent and refractory CD20 + low grade and follicular lymphoma Provides another safe treatment option for patients with indolent NHL May also extend remissions after chemotherapy for first line or recurrent follicular lymphoma Additional studies exploring 90YIT in other indications in CD20 B cell lymphoma suggest other opportunities for use of 90YIT 88 Acknowledgements: Lymphoma team and patients at Sunnybrook Department of Nuclear Medicine-Sunnybrook 89 Spectrum, Bayer, and Servier Pharmas 90 91 Studies in Relapsed/refractory follicular NHL- consolidation therapy

Chemo Chemo 90yRIT DX Relapse

92 Phase II Trial of RIT Consolidation Therapy in Relapsed FL: Trial Design

R-CHOP or R-CVP* x 3 cycles RIT

Patients with FL in PD Patients with at after chemotherapy least PR

CT scan RTX RTX + 90YIT 2 weeks after chemo on day 1 on day 8 or 9

Age ≥18 years with CD20+ grade 1-3a, stage II-IV FL, in first or second Eligibility relapse with PD after chemotherapy and requiring treatment

Sample Size n = 52

Primary: ORR after 3 cycles of RTX-chemotherapy and 2 months after RIT Outcomes Secondary: OS, PFS, TTNT and safety

*R-CVP was given to patients with ejection fraction <50%, previous anthracycline tolerance reached or know cardiac disease CT, computed tomography; FL, follicular lymphoma; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; R-CHOP, rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone; R-CVP, rituximab/cyclophosphamide/vincristine/prednisolone; RIT, radioimmunotherapy; RTX, rituximab; TTNT, time to next treatment 93 Illidge TM et al. Br J Haematol 2016; 173(2):274-82. Phase II Trial of RIT Consolidation Therapy in Relapsed FL: Baseline Characteristics of ITT Population

Characteristics n = 52 Male, n (%) 29 (55.8) Median age, years (range) 62 (31-87) Median time from diagnosis to consent to 43 (13-227) study, months (range) FLIPI, n (%) Low 12 (23.1) Intermediate 16 (30.8) High 24 (46.2) Prior treatment with RTX, n (%) 37 (71.2) In second recurrence at study entry, n (%) 22 (42.3)

FL, follicular lymphoma; FLIPI, Follicular Lymphoma International Prognostic Index; ITT, intention to treat; RIT, radioimmunotherapy; RTX, rituximab 94 Illidge TM et al. Br J Haematol 2016; 173(2):274-82. Phase II Trial of RIT Consolidation Therapy in Relapsed FL: Response to Therapy

After RTX-chemotherapy After RIT

ORR 94.2 98.0

CRu 1.9 6.0

CR 5.8 24.0

0 20 40 60 80 100

% of patients

CR, complete response; CRu, complete response unconfirmed; FL, follicular lymphoma; ORR, overall response rate; RIT, radioimmunotherapy; RTX, rituximab 95 Illidge TM et al. Br J Haematol 2016; 173(2):274-82. Phase II Trial of RIT Consolidation Therapy in Relapsed FL: PFS Over Median Follow-Up of 5 Years

1.00

0.75

0.50

0.25 Proportion EventFree Median follow-up: 5 years Median PFS: 23.1 months (95% CI 17.9, 34.5) Estimated 5-year PFS: 21.9% 0.00 0 6 12 18 24 30 36 42 48 54 60 Time to progression (months)

Number at risk 52 51 48 32 24 20 17 14 11 10 5

CI, confidence interval; FL, follicular lymphoma; OS, overall survival; PFS, progression-free survival; RIT, radioimmunotherapy 96 Illidge TM et al. Br J Haematol 2016; 173(2):274-82. Phase II Trial of RIT Consolidation Therapy in Relapsed FL: OS Over Median Follow-Up of 5 Years

1.00

0.75

0.50

0.25 Proportion EventFree Median follow-up: 5 years Median OS: 75.2 months (95% CI 65.1, not reached) Estimated 5-year OS: 77.5% 0.00 0 6 12 18 24 30 36 42 48 54 60 Time to death (months)

Number at risk 52 52 52 50 47 46 45 42 38 31 20

CI, confidence interval; FL, follicular lymphoma; OS, overall survival; RIT, radioimmunotherapy 97 Illidge TM et al. Br J Haematol 2016; 173(2):274-82. Phase II Trial of RIT Consolidation Therapy in Relapsed FL: Toxicity

• 30 SAEs reported in 18 individuals • 7 events deemed related to RIT • 1 reported case of MDS 10 months after RIT • No other reported second malignancies • 11.5% of patients (6/52) required blood product support • 13.5% of patients (7/52) developed grade 3 or 4 infection/pyrexia and 1.9% (1/62) experienced grade 3 or 4 febrile neutropenia

FL, follicular lymphoma; MDS, myelodysplastic syndrome; RIT, radioimmunotherapy; SAE, serious adverse event 98 Illidge TM et al. Br J Haematol 2016; 173(2):274-82. Phase II Trial of RIT Consolidation Therapy in Relapsed FL: Conclusions

• Abbreviated RTX-chemotherapy followed by RIT consolidation therapy: • Led to high response rates in relapsed FL population with mostly high-intermediate risk FLIPI • Was well tolerated, with few SAEs and manageable hematologic toxicity • Shows potential for more convenient treatment approach in older and comorbid previously treated patients and is worthy of further study

FL, follicular lymphoma; FLIPI, Follicular Lymphoma International Prognostic Index; RIT, radioimmunotherapy; RTX, rituximab; SAE, serious adverse event BACK 99 Illidge TM et al. Br J Haematol 2016; 173(2):274-82. 90Y-RIT and Autologous stem cell transplantation

Can be used safely with FCR conditioning regimens allo transplantation Can be used safely post auto transplantation High dose therapy Chemo Chemo 90yRIT DX Relapse

100 Phase II Trial of 90YIT as First-Line Therapy for FL: PFS in ITT Population

3-year PFS p value <20% BM 60% 100 0.19 >20% BM 49%

(%) Low risk 65% 80 Intermediate risk 76% 0.051

High risk 43% urvival

S 60 Free Free

- Objective response-94% 40 Median PFS: 3.35 years Median age-61 3-year PFS: 58% 18% > 20% BM involvement 20

All patients (32 of 72) Progression 0 0 1 2 3 4 Time (years)

At risk 72 58 44 24 1

ITT population (n = 72; 33 male and 39 female) received at least one dose of 90YIT. 90YIT, 90Y-ibritumomab tiuxetan BM, bone marrow; FL, follicular lymphoma; ITT, intention to treat; PFS, progression-free survival 101 Illidge TM et al. J Clin Oncol 2014; 32(3):212-8. Phase II Trial of 90YIT as First-Line Therapy for FL: Hematological Toxicity

Grade III-IV Toxicities Occurring in ≥5%

Grade III or IV toxicity, Duration in day, Toxicity n (%) median (range) Thrombocytopenia (1st course) 15 (20.8) 20 (8-39) Thrombocytopenia (2nd course) 31 (56.4) 40 (6-336) Neutropenia (1st course) 15 (20.8) 18 (2-47) Neutropenia (2nd course) 20 (36.4) 31 (4-154) Anemia (2nd course)* 3 (5.5) 10 (2-174)

• 5.5% of patients required blood product support after 1st 90YIT course • 14.5% required platelets and 14.0% received red cell transfusions after 2nd 90YIT course

Note: n = 72 for first course and n = 55 for second course *Anemia (1st course) value is zero 90YIT, 90Y-ibritumomab tiuxetan; FL, follicular lymphoma Illidge TM et al. J Clin Oncol 2014; 32(3):212-8. 102 Phase II Trial of 90YIT as First-Line Therapy for FL: Grade III/IV Non-hematological Toxicity

Toxicity Grade III toxicity, n (%) GradeLethargy III-IV Non-hematological Toxicities 1 (1.4) Infections 2 (2.8) Dermatologic 1 (1.4) Other 2 (2.8)

Note: There were no grade IV non-hematologic toxicities reported.

90YIT, 90Y-ibritumomab tiuxetan; AML, acute myeloid leukemia; FL, follicular lymphoma; MDS, myelodysplastic syndrome 103 Illidge TM et al. J Clin Oncol 2014; 32(3):212-8. Phase II Trial of 90YIT as First-Line Therapy for FL: MDS and Other Secondary Malignancies

MDS • 3 cases of MDS: • 1 pre-existed before study entry • 2 felt to be potentially treatment-related (1 after multiple salvage CTX and 1-20 months after completing study protocol)

Other Secondary Malignancies • 2 breast cancer • 1 AML • 1 basal-cell skin cancer • 1 endometrial cancer • 1 sigmoid carcinoma

90YIT, 90Y-ibritumomab tiuxetan; AML, acute myeloid leukemia; CTX, cyclophosphamide; FL, follicular lymphoma; MDS, myelodysplastic syndrome 104 Illidge TM et al. J Clin Oncol 2014; 32(3):212-8. Phase II Trial of 90YIT as First-Line Therapy for FL: Authors’ Conclusions

• Patients with >20% initial BM involvement can safely be treated with 90YIT 6 weeks after pre-treatment with 4 weekly infusions of RTX • High ORR and CR/CRu rates observed in high-risk population, leading to durable responses and median PFS of 40.2 months • Fractionated 90YIT regimen is feasible and has a favourable safety profile

90YIT, 90Y-ibritumomab tiuxetan; BM, bone marrow; CR, complete response; CRu, complete response unconfirmed; FL, follicular lymphoma; ORR, overall response rate; PFS, progression-free survival; RTX, rituximab 105 Illidge TM et al. J Clin Oncol 2014; 32(3):212-8.