NHL: How will emerging therapies change the treatment paradigm? Pier Luigi Zinzani Institute of Hematology «L. e A. Seràgnoli» University of Bologna, Italy

NHL, non-Hodgkin lymphoma 1 Speaker credentials

• Member of the Italian Society of Haematology, the Italian Society of Experimental Haematology, the American Society of Hematology and the American Society of Clinical Oncology

• Presented his research at more than 250 national and international meetings

• Written more than 445 peer-reviewed articles, mostly dedicated to Hodgkin lymphoma (HL), non-Hodgkin lymphomas (NHLs) and hairy cell leukaemia (HCL)

• Associate Editor of Annals of Oncology since January 2014

• Current research interests include clinical trial methodology, prognostic factors in NHL, HL, HCL, chronic lymphocytic leukaemia, and new drug development

• Co-chair of Nordic Nanovector’s Scientific Advisory Board

2 Non-Hodgkin lymphoma (NHL) is a highly prevalent cancer that is associated with significant mortality

• Approximately 1.5 million people worldwide are living with NHL ‒ Incidence increased by 81% between 1973–1990 ‒ Third fastest growing cancer in the world (excluding the US) in terms of population • Approximately 300,000 people die from NHL each year ‒ NHL is the leading cause of cancer death in men aged 20-40 years

Based on US statistics 3 NHL can be divided into several subtypes

NHL – the majority are B-cell lymphomas NHL

T cell 15% B-cell NHL T-cell NHL

B cell Indolent lymphomas Aggressive lymphomas 85% Relatively long median survival, More aggressive disease, may be usually incurable in advanced stages cured by chemotherapy

• Follicular lymphoma (~16.8-22%) • Diffuse large B-cell lymphoma (~36.9-43.1%) • Small lymphocytic lymphoma • Mantle cell lymphoma • MALT lymphoma • Burkitt lymphoma • Lymphoblastic lymphoma • Primary mediastinal large B-cell lymphoma • Lymphoplasmacytic lymphoma

MALT, mucosa associated lymphoid tissue; NHL, non-Hodgkin lymphoma 4 Mortality is higher over the first 5 years with aggressive than with indolent NHL

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

100

Indolent NHL (e.g. follicular lymphoma) 75

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

25 Probability of survival (%) survival of Probability

0 0 2 4 6 8 10 12

Years

NHL, non-Hodgkin lymphoma 5 FL and DLBCL are two NHL subtypes of interest

Follicular lymphoma (FL) Diffuse large B-cell lymphoma (DLBCL) • Low-grade/indolent • High-grade/aggressive • 20–30% of NHL cases • Most common NHL; 31% of all cases • 80–85% of patients are diagnosed in a late • Occurs most frequently in those aged >50 stage (stage III or IV) due to its slow growth years (average age 62 years) • Average age at diagnosis is 60 years • Immediate combination chemotherapy • May not always require treatment and for treatment is essential those who are asymptomatic with low disease burden - Watch-and-wait may • Treatment is given with curative intent be used • Treatment aims to prolong progression-free survival until relapse

NHL, non-Hodgkin lymphoma 6 Treating non-Hodgkin lymphoma FL treatment pathway

Watch and Wait Until debilitating symptoms CR Follow up

Stage I/II: or RT to Debulk Move to 2nd Line if indicated chemotherapy/rituximab maintenance

PR 1st Line 1st Radioimmunotherapy (Stage III/IV)

Not a candidate for transplant >2 yr. remission CR Follow up Repeat 1st line PR Move to third line Candidate for Allo xplant Move to 3rd line chemo Line Re-biopsy or Candidate for Auto Transplant to ready for allo transplant Rituximab- or CR Auto Not a candidate for Allo xplant

2nd -based Conditioning Transplant Move to 3rd line chemo <2 yr. remission chemotherapy PR to prolong remission

If no response Reduced Intensity “mini-Allo” Transplant if Conditioning response achieved

Line Rituximab- or Novel Agents/ or Obinutuzumab-based CR Follow up Clinical Trial

chemotherapy 3rd 3rd PR Palliative Chemo

CR, complete response, FL, follicular lymphoma; PR, partial response; RT, radiotherapy 8 DLBCL treatment pathway

CR Follow up

Stage I/II: Rituximab chemotherapy/rituximab maintenance RT to Debulk

1st Line 1st PR Move to 2nd Line if indicated

Not a candidate for transplant CR Follow up Repeat 1st line PR Move to third line Candidate for Allo xplant Move to 3rd line chemo Line Transplant? or to ready for allo transplant Candidate for Auto Transplant CR Rituximab- or Transplant if Not a candidate for Allo xplant

2nd Obinutuzumab-based Conditioning response Move to 3rd line chemo chemotherapy achieved PR to prolong remission

If no response Reduced Intensity “mini-Allo” Transplant if Conditioning response achieved

Line Rituximab- or Novel Agents/ or Obinutuzumab-based CR Follow up Clinical Trial

chemotherapy 3rd 3rd PR Palliative Chemo

CR, complete response, FL, follicular lymphoma; PR, partial response; RT, radiotherapy 9 Patients who ‘fail’ rituximab-chemotherapy treatment require alternative therapies

• Rituximab is a ‒ Binds to the CD20 antigen expressed on B-cell lymphomas • Rituximab-chemotherapy regimens are standard of care in first- and second-line treatment • Many patients with FL and DLBCL relapse or are refractory to treatment with rituximab

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

DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma 10 Relapsed/Refractory FL

FL, follicular lymphoma Novel treatment options for relapsed/refractory FL

Polatuzumab vedotin Anti-CD79b antibody-drug Duvelisib (IPI-145) conjugate Potent, selective inhibitor of PI3Kδ,γ

Phase I Phase II Phase III Approved

Ibrutinib + rituximab Lenalidomide + Idelalisib Inhibitor of the BTK pathway rituximab Potent, selective inhibitor of PI3Kδ Tumor necrosis factor-α FDA: July 2014: single agent for synthesis inhibitor the treatment of relapsed or Venetoclax refractory small lymphocytic Oral drug targeting BCL2 lymphoma, and FL

BTK, Bruton’s tyrosine kinase; FL, follicular lymphoma; PI3K, phosphatidylinositol-3-kinase 12 Idelalisib: Experience in patients with relapsed indolent NHL

13 Idelalisib: Efficacy and safety of antitumor activity demonstrated in patients who had received extensive prior treatment

Class: PI3 kinase inhibitor; Target indication: Refractory FL; Status: Approved

Efficacy1,2 Safety (all NHL patients)1

• 90% of all NHL patients had a reduction in lymph Toxicity Grade 3-4 1 node size Neutropenia 34 (27%) Thrombocytopenia 8 (6%) Transaminitis 16 (13%)* Diarrhea 16 (13%)* Vomiting 3 (2%) Nausea 2 (2%) Fatigue 2 (2%) Pneumonia 9 (7%)* Dyspnea 4 (3%) In FL patients: Rash 2 (2%) • Overall response rate: 54%2 Edema 3 (2%) Headache 1 (1%) • Complete response: 14%1 • • Median duration of response: 11.8 months1 A third of patients required a dose reduction to manage toxicities • Median progression-free survival 11 months FL, follicular lymphoma; NHL, non-Hodgkin lymphoma; PI3K, phosphatidylinositol-3-kinase 1. Gopal AK, et al. N Engl J Med 2014;370:1008-18; 2. Gopal AK, et al. Abstract 2744, presented at the 57th American Society of Hematology annual meeting, December 2015, Orlando, FL, USA 14 Ibrutinib: Active, with modest ORR as single-agent in R/R FL

Class: Bruton’s tyrosine kinase inhibitor; Target indication: FL; Status: In development (in combination with rituximab)

Efficacy Safety (all NHL patients)1

Fowler, ASH annual Bartlett, ASH Single-agent 1 meeting 2012 annual meeting • Grade 3-4 AEs in 30% of patients: Anemia (2), Phase 1 study 20142 Phase 2 study neutropenia (3), and infection (2) in more than N (evaluable FL 11 38 one patient patients) Combination therapy Overall response 54.5% 30% • Grade 3-4 toxicities in 48 patients across all cycles: rate - Complete: 3 - Complete: 1 - Partial: 3 - Partial: 11 Neutropenia (34%), lymphopenia (77%), Median duration of 12.3 months thrombocytopenia (19%), and rash (25%) response most frequent Median time to 2.4 months • Febrile neutropenia in 2 patients response • Rash in 11/41 (27%) patients at ibrutinib 560 mg and Median PFS 13.4 months 9.9 months 1/7 (14%) at 280 mg; most in cycle1

AE, adverse event; ASH, American Society of Hematology; FL, follicular lymphoma; ORR, overall response rate; PFS, progression free survival; R/R, relapsed-refractory 1. Fowler NH, et al. Abstract no. 623, presented at the 54th American Society of Hematology annual meeting, December 2012, Atlanta, GA, USA; 2. Bartlett NL, et al. Abstract no. 800, presented at the 56th American Society of Hematology annual meeting, December 2014, San Francisco, CA, USA; 3. Maddocks K et al. Blood. 2015; 125(2):242-8 15 Duvelisib: Experience in patients with relapsed/refractory iNHL, including FL

A Phase 1 evaluation of duvelisib (IPI-145), a PI3K-δ,γ inhibitor, in patients with relapsed/refractory iNHL

16 Duvelisib: Clinical activity was observed across all iNHL subtypes, including FL

Class: PI3K-δ and PI3K-γ inhibitor; Target indication: R/R iNHL; Status: In development, Phase II (iNHL)

Efficacy Safety (all NHL patients)1 Amongst patients receiving 25 mg BID (the dose chosen The most common adverse events were related to for subsequent phase 2 and 3 studies): liver function 25 mg BID (n=19) • ORR was 72%, including complete response in 33% Adverse Event (N,%) Any Grade Grade 3 Grade 4 • In FL patients, ORR was 69%, including complete ALT or AST increased 9 (47) 6 (32) 1 (5) response in 38% Cough 8 (42) 0 0 Rash (combined) 7 (37) 1 (5) 0 • 76% of patients had ≥50% reduction in lymph node Nausea 7 (37) 1 (5) 0 enlargement Diarrhea 6 (32) 3 (16) 0 Pyrexia 6 (32) 0 0 • Median PFS not reached; 69% were progression free Fatigue 6 (32) 0 0 at 24 months Neutropenia 4 (21) 2 (11) 2 (11) Pneumonia (combined) 4 (21) 2 (11) 1 (5) Decreased appetite 3 (16) 0 0 Dyspnea 2 (11) 0 0

ALT, alanine aminotransferase; AST, aspartate aminotransferase; BID, twice daily; FL, follicular lymphoma; iNHL, indolent non-Hodgkin lymphoma; ORR, overall response rate; PI3K, phosphatidylinositol- 3-kinase; PFS, progression free survival; R/R, relapsed-refractory Flinn I, et al. Abstract no. 802, presented at the 56th American Society of Hematology annual meeting, December 2014, San Francisco, CA, USA 17 Polatuzumab and (plus rituximab): Evidence in patients with relapsed/refractory NHL

Preliminary Results of a Phase II Randomized Study (ROMULUS) of or Pinatuzumab Vedotin Plus Rituximab in Patients with Relapsed/Refractory Non-Hodgkin Lymphoma

18 Polatuzumab and pinatuzumab vedotin (plus rituximab): Clinical activity and toxicity in patients with R/R FL

Class: Anti-CD79b antibody-drug conjugate; Target indication: R/R NHL; Status: In development, Phase I/II (R/R FL )

Efficacy Safety (all NHL patients)1

R+pinatuzumab R+polatuzumab R+pinatuzumab R+polatuzumab (N=21) (N=20)

Objective response, n (%) 13 (62%) 14 (70%) Complete Response 2 (10%) 8 (40%) Partial Response 11 (52%) 6 (30%)

Median duration of 5.8 (2.6-10.1) NR (5.7-NR) response, mo. (95% CI)

Median progression free 8.9 11.4 survival, mo.

CI, confidence interval; FL, follicular lymphoma; NHL, non-Hodgkin lymphoma; NR, not reached; R/R, relapsed-refractory; RTX, rituximab Morschhauser F et al. Abstract 8519, presented at the 56th American Society of Clinical Oncology annual meeting, May 2014, Chicago, IL, USA 19 Lenalidomide + rituximab: Experience in patients with R/R indolent NHL

Class: Tumor necrosis factor-α synthesis inhibitor; Target indication: R/R indolent NHL; Status: Phase III

Efficacy Safety (all NHL patients)1 • ORR: 76.1% Reported side effects: • CR: 39.1% • Fatigue • Duration of response: • Cytopenias 52% event-free survival at 2 years • Thrombosis

Leonard JP, et al. J Clin Oncol 2015; 33(31):3635-40.

CR, complete response; NHL, non-Hodgkin lymphoma; ORR, overall response rate; R/R, relapsed-refractory 20 Venetoclax: Evidence in patients with R/R FL

Class: Bcl-2 inhibitor; Target indication: R/R FL; Status: Phase I

Venetoclax has been tested in combination with rituximab and with rituximab plus bendamustine

Efficacy Safety (all NHL patients)1 39 patients with FL Reported side effects: • ORR: 38% • Cytopenias • CR: 14% • Fatigue • Diarrhoea • Hyponatremia • Tumor lysis syndrome

Gerecitano et al, ASH 2015.

CR, complete response; NHL, non-Hodgkin lymphoma; ORR, overall response rate; R/R, relapsed-refractory 21 Relapsed DLBCL ineligible for stem cell transplantation (SCT)

DLBCL, diffuse large B-cell lymphoma Novel treatment options for relapsed DLBCL ineligible for SCT

Denintuzumab Phase II: DLBCL; FL Antibody drug conjugate Checkpoint targeting CD19 inhibitor

Phase I Phase II Phase III Approved

Selinexor Lenalidomide Novel, small molecule *Not in commercial selective inhibitor of XPO1 development for DLBCL* CAR-T cell therapy T cells extracted from the patient are re-engineered and re-infused following chemotherapy

CAR-T, chimeric antigen receptor T-cell therapy; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; SCT, stem cell transplant 23 Selinexor: Moderate ORR in heavily pretreated patients with NHL

Class: SINE XPO1 antagonist; Target indication: NHL; Status: Phase II (DLBCL)

Efficacy Safety (all NHL patients)1 Most common drug-related AEs were nausea, fatigue and anorexia

Dose Cancer Type N* ORR (%) CR (%) PR (%) SD (%) PD (%) (mg/m2) Drug-related AEsAE incidence incidence (% (% of pofts) pts) 0 10 20 30 40 50 60

Nausea Fatigue ≤ 20 4 1 (25%) -- 1 (25%) 1 (25%) 2 (50%) Anorexia Vomiting Aggressive B- Diarrhea Dysgeusia Grade 1 NHL (DLBCL, FL 20–50 19 7 (37%) 4 (21%) 3 (16%) 5 (26%) 7 (37%) Weight loss grd3b, Dizziness Grade 2 Constipation Grade 3 Transformed) Muscle weakness ≥ 60 10 4 (40%) -- 4 (40%) 4 (40%) 2 (20%) Confusion Grade 4 Dyspepsia Syncope AEs for ³ 5% of pts Proteinuria Sensory neuropathy Data for other populations not shown Dehydration N=67

Blurred vision TOTAL (all patients) 52 19 (37%) 5 (10%) 14 (27%) 19 (37%) 14 (27%) Hyponatremia Thrombocytopenia Anemia Neutropenia 1 patient is pending response; 15 patients were not evaluable for response Leukopenia (Responses as of 1-December-2014)

AE, adverse event; CR, complete response; DCR, disease control rate (CR+PR+SD); DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; NHL, non-Hodgkin lymphoma; ORR, overall response rate (CR+PR); PD, progressive disease (+ patient remains on study); PR, partial response; SD, stable disease; SINE, selective inhibitor of nuclear export 24 : Moderate ORR in R/R B-cell NHL

A Phase 1 Study of Denintuzumab Mafodotin (SGN-CD19A) in relapsed/refractory B-Lineage Non-Hodgkin Lymphoma

25 Denintuzumab mafodotin: Moderate ORR in R/R B-cell NHL

Class: Anti-CD19 drug-conjugate; Target indication: R/R NHL; Status: Phase II (DLBCL)

Efficacy Safety (all NHL patients)1 Ocular adverse events are relatively common Patients

ORR, % (95% CI) 38 (26.1, 51.8)

Complete response, % (95% CI) 23 (13.4, 36.0)

Estimated median duration of Relapsed: 47.1 (16.1, -) response, weeks (95% CI) Refractory: 41.1 (13.7, -)

Progression-free survival, mo. Relapsed: 25.1 (16.1, -) (95% CI) Refractory: 6.1 (5.1, 12.3) a Includes patients with at least 1 post-baseline evaluable response assessment and/or documented clinical progression

CI, confidence interval; NHL, non-Hodgkin lymphoma; ORR, overall response rate; R/R, relapsed-refractory Moskowitz CH, et al. Abstract No.182, presented at the 57th American Society of Hematology annual meeting December 2015, Orlando, FL, USA 26 Lenalidomide: Some effect in relapsed/refractory DLBCL patients

Class: Tumor necrosis factor-α synthesis inhibitor; Target indication: Not in development for DLBCL; Status: Investigational

Efficacy Safety (all NHL patients)1

The rate of response to lenalidomide is lower in DLBCL than other forms of NHL1

Neutropenia, thrombocytopenia and fatigue Lenalidomide is active in were the most elderly patients with common treatment- relapsed/refractory DLBCL emergent adverse when combined with events rituximab2

*Median follow up of 16 months CI, confidence interval; DLBCL, diffuse large B-cell lymphoma; MCL, mantle cell lymphoma; NHL, non-Hodgkin lymphoma; ORR, overall response rate 1. Wiernik PH, et al. J Clin Oncol. 2008;26(30):4952-7. 2. Zinzani PL, et al. Clin Lymphoma Myeloma Leuk 2011;11(6):462-6 27 CAR-T (chimeric antigen receptor T-cell therapy)

Class: CAR-T cell therapy; Target indication: R/R DLBCL; Status: Phase II

Efficacy Safety (all NHL patients)1 • Current challenges in development: • Current safety challenges include: ‒ Overcoming tumor evasion ‒ Cytokine release syndrome ‒ Improving durability of persistence ‒ B cell aplasia ‒ Tumor lysis syndrome Results published to date ORR CR mPFS DOR • Chemotherapy required prior to CAR-T therapy DLBCL 47% ND 3 months ‒ Adverse events associated with chemotherapy are not CTL0191 FL 73% ND 11.9 months avoided JCAR0182 NHL 50%* 8%** 1 pt. 9 months, 2 pts. 6 months, KTE-C193 DLBCL† 71% 57% 1 pt. below 6 months

CR, complete response; DLBCL, diffuse large B-cell lymphoma; DOR, duration of response; FL, follicular lymphoma; mPFS, median progression free survival; ND, not disclosed; NHL, non-Hodgkin lymphoma; ORR, overall response rate *Increased to 72% when adding 25mg/sqm of Fludarabine plus Cyclophosfamide; **Increased to 50% when adding 25mg/sqm of Fludarabine plus Cyclophosfamide; †and transformed FL 1. Schuster SJ, et al. Abstract 183, presented at the 57th American Society of Hematology annual meeting December 2015, Orlando, FL, USA; 2. Turtle CJ, et al. Abstract 184, presented at the 57th American Society of Hematology annual meeting December 2015, Orlando, FL, USA; 3. Locke FL, et al. Abstract 3991, presented at the 57th American Society of Hematology annual meeting December 2015, Orlando, FL, USA 28 Nivolumab: Evidence in R/R DLBCL

Class: Checkpoint inhibitor; Target indication: R/R DLBCL; Status: Phase II

Efficacy Safety (all NHL patients)1 • ORR: 36% Reported side effects included: • CR: 9% • Fatigue • PFS: • Skin reactions 24% at 6 months • Diarrhea • Abdominal pain • Anemia • Fever • Painful joints

CR, complete response; DLBCL, diffuse large B-cell lymphoma; PFS, progression free survival; ND, not disclosed; ORR, overall response rate; R/R, relapsed-refractory 29 Response rates for novel agents being developed in FL and DLBCL

% response rate in different histologies Pathway Drug DLBCL FL Idelalisib - 54% PI3K/AKT/mTOR Duvelisib - 69% Copanlisib 13% 40% B Cell Receptor (BCR) Ibrutinib 26% 46% Apoptosis Venetoclax 40% 38% Immunomodulation Lenalidomide + rituximab (combination) 19% 76.1% Anti-CD19 Denintuzumab 38% - Checkpoint inhibitor Nivolumab 36% - Inhibitor of XP01 Selinexor 37% - Immunomodulation CAR-T 47%/71% 50%/73%

CAR-T, chimeric antigen receptor T-cell therapy; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma 30 Where is the unmet need in NHL?

NHL, non-Hodgkin lymphoma 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 32 Radioimmunotherapy: Antibody-radionuclide conjugates (ARCs)

• Lymphoma cells are inherently sensitive to radiation Lymphoma cells • 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

Antibody Radioactive tag

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

• ARC 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 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

ARC, antibody radionuclide conjugate 34 Summary

• NHL has several subtypes; the most common are FL and DLBCL

• 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 ARC treatment could be a future option for second- or third-line therapy in patients with FL or DLBCL, who are unable to tolerate transplantation or chemotherapy

ARC, antibody radionuclide conjugate, DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; NHL, non-Hodgkin lymphoma 35