Innovación terapéutica en LNH Antonio Salar Hospital del Mar, Barcelona TIMER Disclosure Information: Antonio Salar, MD

I have the following financial relationships to disclose:

Membership on advisory committees or consultant or speakers bureau for: Amgen, Celgene, Gilead, Mundipharma, Roche

I will include discussion of investigational or off-label use of a product in my presentation TIMER Incidencia de linfomas no hodgkinianos

Incidencia de 9/100.000 hab/año

Salar A et al. Eur J Hematol 1997; 59: 231-7. TIMER Quimioterapia: historia

. Descripciones históricas: 2,000 años AC . Edad media: minerales y metales . Siglo XIX: . Compuestos químicos (1er libro de QT) . 2ª guerra mundial: . Mostaza nitrogenada TIMER Quimioterapia: presente Agentes más usados en LNH: Combinaciones más usadas en LNH: . ALQUILANTES: ciclofosfamida, ifosfamida, . CP clorambucilo, dacarbacina, procarbacina, . CVP/COP temozolamida, bendamustina… . CHOP . CHOEP . ANTIMETABOLITOS: metotrexate, . MegaCHOP premetrexed, citarabina, gemcitabina, 6- . MiniCHOP mercaptopurina, fludarabina, pentostatina, . EPOCH cladribina . FC/FCM . ANTITOPOISOMERASAS: adriamicina, . ESHAP etopósido, tenipósido . DHAP . ANTIMICROTUBULOS: vincristina, . GEMOX vinblastina, taxanos . IFE . DERIVADOS PLATINO: cisplatino, . CODOX-IVAC carboplatino, oxaliplatino . HyperCVAD . SMILE . OTROS: prednisona, bleomicina, L- . Y otras muchas….. asparraginasa…

TIMER Quimioterapia: presente Agentes más usados en LNH: Combinaciones más usadas en LNH: . ALQUILANTES: ciclofosfamida, ifosfamida, . CP clorambucilo, dacarbacina, procarbacina, . CVP/COP temozolamida, bendamustina… . CHOP . CHOEP . ANTIMETABOLITOS: metotrexate, . MegaCHOP premetrexed, citarabina, gemcitabina, 6- . MiniCHOP mercaptopurina, fludarabina, pentostatina, . EPOCH cladribina . FC/FCM . ANTITOPOISOMERASAS: adriamicina, . ESHAP etopósido, tenipósido . DHAP . ANTIMICROTUBULOS: vincristina, . GEMOX vinblastina, taxanos . IFE . DERIVADOS PLATINO: cisplatino, . CODOX-IVAC carboplatino, oxaliplatino . HyperCVAD . SMILE . OTROS: prednisona, bleomicina, L- . Y otras muchas….. asparraginasa…

LNH indolentes, agresivos, muy agresivos LNH B, T, NK TIMER Innovación en linfomas T: nuevos fármacos

Supervivencia libre progresión: LNH-T recaídos refractarios . Palatrexate (antifolato) . Lenalidomida (agente IMID) Pralatrexate N=109

. Vorinostat (inhibidor deacetilasa histonas) . Belinostat (inhibidor deacetilasa histonas) . Panobinostat (inhibidor deacetilasa histonas) . Romidepsina (inhibidor deacetilasa histonas) Romidepsina N=130 . Alisertib (inhibidor aurora kinasa) . Duvelisib (inhibidor de PI3K γδ) . Crizotinib (inhibidor de ALK) . Alemtuzumab (AcMo anti-CD52) Belinostat N=129 . Denileukin diftitox (AcMo anti-CD25) . Mogamulizumab (AcMo anti-CCR4) . Brentuximab vedotin (AcMo anti-CD30)

O’Connor OA et al. J Clin Oncol 2011;29:1182-1189. Coiffier B et al. J Clin Oncol 2012;30 :631-636. O’Connor OA et al. ASCO 2013. TIMER Brentuximab vedotin (AcMo anti-CD30)

N=58 IRF Maximum tumor reduction Overall response rate (95% CI) 86% (75, 94) Complete remission 53% Partial remission 33% Stable disease 3% Progressive disease 5% Outcomes Median duration of OR (95% CI) 12.6 months Median duration of CR (95% CI) 13.2 months Median PFS (95% CI) 13.3 months Median OS Not reached Pro B et al. J Clin Oncol 2012;30:2190-6. TIMER Mogamulizumab (AcMo anti-CCR4) Phase II Study of Mogamulizumab for PTCL/CTCL: Design

Mogamulizumab Relapsed Registration CCR4 assessment 1.0 mg/kg/day (iv) PTCL/CTCL with IHC CCR4+ weekly x 8

Dosing and assessment schedule Premedication before each infusion (Antihistamine, Antipyretic & Hydrocortisone 100mg) Mogamulizumab 1.0 mg/kg

Day 1 8 15 22 29 36 43 50 1 m o n t h 1 month 2 months

Efficacy assessment

1Defucosylation from the Ogura M, Tobinai K, et al.: J Clin Oncol 2014;32:1157-63 oligosaccharides on the Fc domain

Niwa R et al. Cancer Res 2004; 64: 2127. Ogura Met al. J Clin Oncol 2014; 32:1157-63. TIMER Innovación en linfomas B

T cell NHL interaction: TIMER Historia de los AcMo anti-CD20

TRU-015 Ofatumumab

(SMIP™) (human IgG1)

PRO131921 GA101 (humanised Ocrelizumab glycoengineered IgG1) (humanised IgG1) 131I tositumomab (m2a) Veltuzumab

into patients into History mAb of History Rituximab (clgG1) (humanised IgG1) Ibritumomab tiuxetan

(Y90 m1a) Rituximab AME -133v46 FDA approved B1 1F5 (m2a)

1980 1985 1990 1995 2000 2005 2010

Murine Chimeric Humanised Human SMIP™ Mutated Fc

Ab Ab Ab Ab mice domain Ab technology Ab

mAb development

Generation I II III

Lim SH et al. Haematologica 2010; 95:135-143. TIMER Rituximab intravenoso

. Rituximab is a quimeric murine/human monoclonal antibody that binds to cluster of differentiation 20 (CD20), a hydrophobic transmenbrane protein, which is present on the cell surface of pre-B and mature B-lymphocytes . Rituximab was approved by the FDA in 1997 and EMA in 1998 . Now the standard of care in CD20+ NHL . Indications for rituximab use continue to expand

R-quimio en 1ª línea del LDCGB: GELA TIMER LNH-98.5

Improvement in PFS and OS in patients treated with R-CHOP

Coiffier B et al. N Engl J Med 2002; 346: 235-42. TIMER R-quimio en LDCGB: ensayos y práctica clínica

Rituximab benefit N Chemo Response (%) EFS or PFS OS 399 76 vs 63 GELA1 CHOP-21 x 8 0.00002 0.0073 Elderly (60–80) p = 0.005 1222 CHOP-14 x 6 78 vs 68 RICOVER-602 < 0.001 0.003* Elderly (61–80) CHOP-14 x 8 76 vs 72 199 HOVON/NORDIC3 CHOP-14 x 8 ND < 0.01 0.05 Elderly (65–80) Intergroup USA4† 632 CHOP-21 77 vs 76 0.003 0.05 (Habermann) Elderly (> 60) 824 CHOP-21 86 vs 68 MInT5 Young (18–60) < 0.0001 0.0001 or others Low risk p < 0.0001 292 British Columbia6 CHOP-like ND 0.002 < 0.0001 All ages 376 Czech Republic7 CHOP-like ND 0.0001 0.0007 Young

* p-values for R-CHOP-14 x 6 † Secondary analysis without maintenance 1. Feugier P, et al. JCO 2005; 23:4117–4126; 2. Pfreundschuh M, et al. Blood 2006; Abstract 205; 3. Sonneveld P, et al. J Blood 2006; 108:Abstract 210; 4. Habermann TM, et al. JCO 2006; 24:3121–3127; 5. Pfreundschuh M, et al. Lancet Oncol 2006; 7:379–391; 6. Sehn LH, et al. JCO 2005; 23:5027–5033; 7. Trnĕný M, et al. Blood 2005; 106:Abstract 2444. TIMER R-quimio en 1ª línea l. folicular TIMER R-quimio en 1ª línea l. folicular

Seguimiento Supervivencia libre de fallo (meses) Supervivencia global mediano (meses)

QT R-QT p QT R-QT p

R. Marcus SLP 15 34 <0,0001 77% a 4 83% a 4 0,029 53

W. Hiddemann TFT 30 NA <0,001 90% a 2 95% a 2 0,016 18*

G. Salles SLA 35 NA 0,0004 79% a 5 84% a 5 0,155 60

M. Herold SLP 29 NA <0,0001 74% a 4 87% a 4 0,0096 47

Marcus R et al. Blood 2005;105:1417-23 Marcus R et al. J Clin Oncol 2008;26:4579-86 Hiddemann W et al. Blood 2005;106.3725-32 Herold M et al. J Clin Oncol 2007;25:1986-92 Salles G et al. Blood 2008;112:4824-31 Rituximab mantenimiento tras R-quimio en 1ª TIMER línea de l. folicular: estudio PRIMA

Progression free survival at 6 years

*Seguimiento mediano desde aleatorización: 73 meses Salles G et al. Lancet 2011; 377: 42-51. Salles G et al. Blood 2013; 122: Abstract 509. R-quimio en LCM: European Mantell Cell TIMER Lymphoma Network

Menores de 65 años Mayores de 60 años

Supervivencia libre de fallo Supervivencia global

Hermine O et al. Blood 2012;120:Abstract 151. Kluin-Nelemans HC et al.N Engl J Med 2012,367:520-31. TIMER R-quimio en l. MALT

International Extranodal Lymphoma Study Group - IELSG 19 Randomised Study SupervivenciaEvent-Fre elibreSu derv iacontecimientoval Supervivencia libre de acontecimiento

Log-rank HR 95% C.I. 5-year EFS (95%CI): R vs. Chl, P=0.957 0.99 (0.82-1.20) Chlorambucil , 52% (42%-60%) R-Chl vs. Chl, P=0.0005 0.52 (0.35-0.75) R-Chlorambucil, 70% (61%-77%) R-Chl vs. R, P= 0.0015 0.51 (0.33-0.78) Rituximab, 51% (40%-61%)

Zucca E et al. J Clin Oncol 2013;31:565-72. Zucca E et al. J Clin Oncol. 2013;31(5):565-72. Zucca E et al. ICML2013: Abstract 07. Salar A et al. Lancet Hematology 2014; 1:e104-111 Rituximab Subcutaneous: how does it differ TIMER from rituximab IV formulation?

. The rituximab SC formulation is concentrated 12-fold (120 mg/mL) to reduce the injection volume

. Co-formulation with recombinant human hyaluronidase (rHuPH20: 2000 U/mL) allows for administration of injection volumes typically considered too large for subcutaneous injection Fixed dose and BSA-adjusted dosing of TIMER monoclonal antibodies perform similarly

. Population PK modelling of a panel of monoclonal antibodies shows that fixed dose and BSA-adjusted rituximab dosing approaches perform similarly1

Median rituximab concentration Simulated area under the curve Simulated Cmax

500 1.2 2.0

400 BSA-adjusted BSA-adjusted BSA-adjusted

1.5 300 Fixed dose 0.8 Fixed dose Fixed dose

1.0

µg/mL Density 200 Density 0.4 100 0.5 0 0.0 0.0 0 10 20 30 40 50 0 1 2 3 0.5 1.0 1.5 2.0

Time (days) AUC (ratio of median) Cmax (ratio of median)

Vd. Rituximab ≈ 1,7-12,8 l  All drug in intravascular space Blood volume 5-6 l  Scarce influence of weight

1 Wang DD, et al. J Clin Pharm 2009; 49:1012-24. TIMER SparkThera: Two-stage phase Ib study in FL

A Two-Stage Phase Ib Study to Investigate the pharmacokinetics, Safety and Tolerability of subcutaneous Rituximab in Follicular Lymphoma as Part of Maintenance Treatment

Salar A et al. J Clin Oncol 2014;32:1782-91. TIMER SparkThera: Two-stage phase Ib study in FL

SparkThera: Serum concentration of rituximab

Absolute bioavailability of the subcutaneous formulation was estimated at 65%

SparkThera Ctrough modelling

In > 80% of simulations, FL patients receiving rituximab SC 1,400 mg were predicted

to achieve non-inferior Ctrough levels compared with rituximab IV 375 mg/m2

Salar A et al. J Clin Oncol 2014;32:1782-91. TIMER SparkThera: Two-stage phase Ib study in FL

Non-inferior Ctrough or AUC for rituximab SC compared with rituximab IV

Salar A et al. J Clin Oncol 2014;32:1782-91. TIMER SABRINA: Two-stage phase III study in FL

Stage 1, n = 127 (IV, n = 64; SC, n = 63): stratified by FLIPI, chemotherapy and region

. Non-inferior Ctrough for rituximab SC compared with rituximab IV:

PK endpoint Rituximab SC:IV ratio Endpoint

Ctrough at Cycle 7 1.62 (90% CI: 1.36, 1.94) Primary

AUC at Cycle 7 1.38 (90%CI: 1.24, 1.53) Secondary

Davies A et al. Lancet Oncology 2014;15:343-52. TIMER SABRINA: Two-stage phase III study in FL

. SC Rituximab + chemotherapy is comparable to IV administration in patients with FL in first-line setting:

Patients, n (%) CT + Rituximab IV CT + Rituximab SC

Any-grade AE 57 (88) 57 (92)

Any-grade 30 (46) 45 (73) treatment-related AE

ARRs (>90% grade ½) 21 (32) 31 (50)

Grade ≥ 3 AE 30 (46) 29 (47)

Grade ¾ neutropenia 14 (22) 16 (26)

ORR 54 (84.4) 57 (90.5)

CR/CRu 19 (29.7) 29 (46.0)

ARR = administration-related reactions Davies A et al. Lancet Oncology 2014;15:343-52. 2 0 th EHA Congress, 1 1 – 1 4 June 2 0 1 5 , Vienna, Austria P6 8 7 COMPARI SON OF SUBCUTANEOUS AND I NTRAVENOUS RI TUXI MAB I N THE MAI NTENANCE SETTI NG: UPDATED SAFETY RESULTS OF THE PHASE I I I SABRI NA STUDY I N PATI ENTS W I TH FOLLI CULAR LYMPHOMA TIMER Andrew Davies,1 Biljana Mihaljević, 2 Santiago Mercadal, 3 Georgi Mihaylov,4 SirpSABRINA:a Leppä,5 Denis eTwo Cottin-gstage,6 Francis cphaseo Javier M uIIIno zstudy, 6 Klaas V einens tFLra,7 Natalia Berthillon,6 * Martin Barrett,8 David MacDonald 9 1 Faculty of Medicine, University of Southam pton, Southam pton, United Kingdom ; 2 I nstitute of Hem atology, Clinical Center of Serbia School of Medicine, Belgrade, Serbia; 3 Hem atology Departm ent, Catalan I nstitute of Oncology, Barcelona, Spain; 4 Departm ent of Hem atology, Hospital for Treatm ent of Hem atological Diseases, Sofia, Bulgaria; 5 Departm ent of Oncology, Helsinki University Central Hospital Cancer Center, Helsinki, Finland; 6 Product Developm ent, 7 Statistical Program m ing, F. Hoffm ann- La Roche Ltd, Basel, Sw itzerland; 8 Clinical Science, Roche Products Ltd, W elw yn Garden City, United Kingdom ; 9 De.partSCm ent Rituximabof Medicine, QEI I isHea lwellth Scie ntoleratedces Centre, Ha linifax ,the Cana dmaintenancea of patients with FL in first-line setting: BACKGROUND RESULTS Table 2. Summary of AEs during maintenance therapy by treatment arm. Table 3. Summary of AEs during maintenance therapy by treatment arm and gender. SC + CT IV + CT Male Female ● Rituximab (MabThera®, Rituxan®, F Hoffmann-La Roche) in combination with Patients (n=172) (n=178) SC + CT IV + CT SC + CT IV + CT chemotherapy, improves time-to-treatment failure and overall survival in the first-line Adverse events (all grades), n (%)* (n=72) (n=89) (n=100) (n=89) ● In total, 407 patients received ≥1 dose of rituximab (safety population). Adverse events (all grades), n (%)* treatment of follicular lymphoma (FL)1,2 and further improves progression-free survival in Infections and infestations 71 (41) 75 (42) 3,4 5 ● Six rituximab SC patients discontinued treatment after cycle 1 (rituximab IV in both arms) Infections and infestations 27 (38) 33 (37) 44 (44) 42 (47) first and subsequent remission of FL when used as maintenance therapy following Upper respiratory tract infection 14 (8) 11 (6) and were included in the rituximab IV safety population (rituximab SC n=197 [81 male, 116 Upper respiratory tract infection 6 (8) 5 (6) 8 (8) 6 (7) first-line induction. Urinary tract infection 7 (4) 13 (7) ● A recently developed subcutaneous (SC) formulation of rituximab offers improved patient female]; rituximab IV n=210 [109 male, 101 female]). Urinary tract infection 1 (1) 3 (3) 6 (6) 10 (11) Nasopharyngitis 8 (5) 9 (5) convenience and healthcare resource savings compared with the current intravenous (IV) Nasopharyngitis 4 (6) 4 (4) 4 (4) 5 (6) ● In total, 86% of patients started maintenance rituximab (SC n=172, 87%; IV n= 178, 85%). Pneumonia 8 (5) 3 (2) formulation which can take several hours to administer.6 Bronchitis 1 (1) 3 (3) 5 (5) 4 (4) ● Patient baseline demographic and disease characteristics were comparable with the overall Sinusitis 7 (4) 9 (5) ● The two-stage Phase III SABRINA study (BO22334; NCT01200758) investigated induction Pneumonia 3 (4) 2 (2) 5 (5) 1 (1) patient population7 and were well matched in the maintenance rituximab IV and SC groups rituximab (SC or IV) in combination with chemotherapy followed by maintenance rituximab Rhinitis 4 (2) 9 (5) Sinusitis 4 (6) 4 (4) 3 (3) 5 (6) with the exception of gender, where more female patients (58%) were randomised to (SC or IV) in patients with previously untreated FL. General disorders and administration site Influenza 0 (0) 1 (1) 4 (4) 5 (6) receive rituximab SC (Table 1). 49 (28) 34 (19) ● End-of-induction safety and efficacy outcomes from a pooled analysis of data from stages 1 conditions Rhinitis 2 (3) 4 (4) 2 (2) 5 (6) – Overall, 66% of patients in both arms received CHOP plus rituximab and 34% received and 2 of the SABRINA study (n=410, median follow-up 14 months) showed comparable Pyrexia 5 (3) 9 (5) Gastrointestinal disorders 14 (19) 17 (19) 27 (27) 16 (18) CVP plus rituximab as induction therapy. response rates and safety profiles for the rituximab SC and IV arms, without any new Asthenia 14 (8) 6 (3) Constipation 1 (1) 3 (3) 5 (5) 4 (4) 7,8 clinically relevant safety signals reported for rituximab SC. ● A total of 33 patients (19%) in the rituximab SC arm and 29 patients (16%) in the rituximab Injection site erythema 13 (8) 0 (0) Nausea 3 (4) 0 (0) 6 (6) 3 (3) ● However, longer follow up is needed to define the safety of rituximab SC versus IV in the IV arm withdrew from treatment during the maintenance phase. Gastrointestinal disorders 41 (24) 33 (19) Diarrhoea 3 (4) 3 (3) 6 (6) 4 (4) maintenance setting. – Reasons for withdrawal included AEs (n=9), disease progression (n=22) or ‘other’ Nausea 9 (5) 3 (2) Abdominal pain 2 (3) 1 (1) 6 (6) 4 (4) ● Here we present an updated safety analysis of rituximab SC and IV for the maintenance (patient withdrawal, physician decision, n=2) in the rituximab SC group and AEs (n=3), Diarrhoea 9 (5) 7 (4) General disorders and administration site phase of SABRINA (median follow-up time 26 months). 20 (28) 20 (22) 29 (29) 14 (16) death (n=2), disease progression (n=18) or ‘other’ (patient withdrawal, physician Abdominal pain 8 (5) 5 (3) conditions decision, lost to follow up, n=6) in the rituximab IV group. Musculoskeletal and connective tissue disorders 40 (23) 38 (21) Fatigue 2 (3) 4 (4) 5 (5) 4 (4) METHODS Arthralgia 12 (7) 11 (6) Pyrexia 4 (6) 6 (7) 1 (1) 3 (3) . AsthNoenia new safety signals emerged during Table 1. Baseline demographics and disease characteristics Back pain 6 (3) 11 (6) 6 (8) 4 (4) 8 (8) 2 (2) Patients Injection site erythema 4 (6) 0 (0) 9 (9) 0 (0) (maintenance population).* Pain in extremity 5 (3) 9 (5) maintenance rituximab SC or IV ● Eligible patients were aged ≥18 years with treatment-naïve histologically confirmed CD20+ Nervous system disorders 9 (13) 8 (9) 15 (15) 12 (13) Respiratory, thoracic and mediastinal disorders 31 (18) 31 (17) grade 1–3a FL, an Eastern Cooperative Oncology Group performance status of 0–2, and Rituximab Skin and subcutaneous tissue disorders 12 (17) 13 (15) 16 (16) 14 (16) Cough 18 (10) 18 (10) . Similar incidence of any grade AEs, grade bidimensionally measureable disease (computed tomography or magnetic resonance Rash 4 (6) 3 (3) 2 (2) 2 (2) SC (n=172) IV (n=178) Total (N=350) Blood and lymphatic system disorders 29 (17) 30 (17) imaging). Prur≥3itus AEs, and SAEs 0 (0) 4 (4) 2 (2) 6 (7) Median age, years (range) 54.5 (28–85) 57.0 (28–86) 56.0 (28–86) Neutropenia 19 (11) 17 (10) ● Patients were required to have an indication for treatment defined as bulky disease (mass Respiratory, thoracic and mediastinal disorders 15 (21) 15 (17) 16 (16) 16 (18) ≥7 cm in its greatest dimension), B symptoms, elevated serum lactate dehydrogenase or Female sex, n (%) 100 (58) 89 (50) 189 (54) Skin and subcutaneous tissue disorders 28 (16) 27 (15) . Exception: increased incidence of mild Cough 10 (14) 9 (10) 8 (8) 9 (10) β2-microglobulin, involvement of ≥3 nodal sites (each with a diameter >3 cm), symptomatic Median body surface area, m2 Pruritus 2 (1) 10 (6) 1.8 (1.4–2.5) 1.8 (1.3–2.5) 1.8 (1.3–2.5) Dyspnoea 1 (1) 1 (1) 2 (2) 5 (6) spleen enlargement, compressive syndrome, or pleural/peritoneal effusion. (range) injection site erythema in the SC arm G rade ≥3 adverse events, n (%)† Blood and lymphatic system disorders 10 (14) 10 (11) 19 (19) 20 (22) ● Key exclusion criteria were: presence or history of central nervous system disease, White, n (%) 139 (87) 136 (84) 275 (85) transformation to a high-grade lymphoma secondary to FL, or a history of malignancies Blood and lymphatic system disorders 18 (10) 18 (10) Neutropenia 9 (13) 6 (7) 10 (10) 11 (12) Median time to first diagnosis, 1.54 (0.1–99.8) 1.72 (0.1–279.9) 1.61 (0.1–279.9) Neutropenia 15 (9) 13 (7) Musculoskeletal and connective tissue disorders 10 (14) 17 (19) 30 (30) 21 (24) other than FL. months (range) Study design Infections and infestations 13 (8) 6 (3) Arthralgia 4 (6) 5 (6) 8 (8) 6 (7) FLIPI risk group, n (%) ● SABRINA is an international, randomised, controlled, open-label study. Gastrointestinal disorders 3 (2) 6 (3) Back pain 0 (0) 6 (7) 6 (6) 5 (6) Low (0–1) 34 (20) 39 (22) 73 (21) ● Patients (n=410) were randomised (1:1) to receive standard chemotherapy (either CHOP Neoplasms benign, malignant and unspecified Pain in extremity Davies A, et al.1 (1 )EHA 42015: (4) Abstract4 (4) 5 687. (6) Intermediate (2) 69 (40) 57 (32) 126 (36) 1 (<1) 5 (3) [cyclophosphamide, doxorubicin, vincristine and prednisolone] or CVP [cyclophosphamide, (including cysts/polyps) G rade ≥3 adverse events, n (%)† vincristine and prednisolone] as chosen by the treating physician) plus either 1400 mg H igh (≥3) 69 (40) 82 (46) 151 (43) ‡ Infections and infestations 3 (4) 1 (1) 10 (10) 5 (6) 2 Serious adverse events, n (%) rituximab SC (n=205) or 375 mg/m rituximab IV (n=205; Figure 1). Follicular lymphoma grade,† n (%) Blood and lymphatic system disorders 7 (10) 6 (7) 11 (11) 12 (13) Infections and infestations 13 (8) 4 (2) ● Patients were stratified by Follicular Lymphoma International Prognostic Index score, Grade 1 54 (32) 39 (22) 93 (27) Neutropenia 7 (10) 6 (7) 8 (8) 7 (8) chemotherapy regimen and region. Pneumonia 3 (2) 2 (1) Grade 2 78 (46) 89 (50) 167 (48) ‡ ● All patients received rituximab IV 375 mg/m2 in the first induction cycle (cycle 1) regardless Blood and lymphatic system disorders 2 (1) 4 (2) Serious adverse events, n (%) G rade 3a 39 (23) 50 (28) 89 (25) of their randomisation treatment group. Gastrointestinal disorders 2 (1) 7 (4) Infections and infestations 2 (3) 1 (1) 11 (11) 3 (3) ● During cycles 2–8, patients received either rituximab SC 1400 mg or rituximab First-line chemotherapy, n (%) Neoplasms benign, malignant and unspecified Blood and lymphatic system disorders 1 (1) 1 (1) 1 (1) 3 (3) 1 (<1) 4 (2) IV 375 mg/m2 every 3 weeks. CHOP 116 (67) 114 (64) 230 (66) (including cysts/polyps) Gastrointestinal disorders 1 (1) 2 (2) 1 (1) 5 (6) ● Patients received 6–8 cycles of CHOP or 8 cycles of CVP. CVP 56 (33) 64 (36) 120 (34) Musculoskeletal and connective tissue disorders 3 (2) 2 (1) CT, chemotherapy; IV, intravenous; SC, subcutaneous *System organ classes with overall occurrence ≥15%; preferred terms with overall occurrence ≥5% either group. ● After induction immunochemotherapy, patients with a complete response (CR), unconfirmed CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; CVP, cyclophosphamide, vincristine, and prednisone; FLIPI, Follicular CT, chemotherapy; IV, intravenous; SC, subcutaneous †System organ classes with overall occurrence ≥5%; preferred terms with overall occurrence ≥5% either group. CR (CRu) or partial response (PR) continued to receive rituximab monotherapy by the same Lymphoma International Prognostic Index; IV, intravenous; SC, subcutaneous. *Parameters refer to patient values at baseline (i.e. at the start of *System organ classes with overall occurrence ≥15% either group; preferred terms with overall occurrence ≥5% either group. ‡System organ classes with overall occurrence ≥5%; preferred terms with overall occurrence ≥5% either group. induction); †Grade 1=0–5 centroblasts per high-power field (hpf); grade 2=6–15 centroblasts/hpf; grade 3=15 centroblasts/hpf; grade 3a=15 †System organ classes with overall occurrence ≥3%; preferred terms with overall occurrence ≥3% either group. Analysis included all patients who started the maintenance phase (maintenance safety population). dose and route as maintenance treatment every 8 weeks for up to 2 years. centroblasts/hpf, but centrocytes are still present. ‡System organ classes with overall occurrence ≥2%; preferred terms with overall occurrence ≥2% either group. Safety assessments Analysis included all patients who started the maintenance phase (maintenance safety population). ● Adverse events (AEs) were graded according to the National Cancer Institute Common Safety ● Other common grade ≥3 AEs (≥3%) belonged to the SOCs gastrointestinal disorders CONCLUSI ONS Terminology Criteria for Adverse Events, version 4.0. ● During maintenance treatment, the most common AEs were of the system organ class (SC 2%; IV 3%) and neoplasms (SC <1%; IV 3%). ● Maintenance rituximab SC and rituximab IV were well tolerated in treatment-naïve patients with follicular – An administration-related reaction (ARR) was defined as any event that occurred during lymphoma. or within 24 hours of treatment that was considered to be related to rituximab by the (SOC) infections and infestations, occurring in 41% of patients in the SC rituximab arm and ● The most common SAEs reported during maintenance therapy (≥2% of patients) were study investigator. 42% of patients in the rituximab IV arm (Table 2). infections and infestations, gastrointestinal disorders, musculoskeletal and connective tissue ● No new safety signals emerged during maintenance treatment with rituximab SC or IV. ● Non-serious AEs were reported for 28 days following the last dose of rituximab. – The majority of these AEs were grade 1/2 upper respiratory tract infections, urinary tract disorders, blood and lymphatic system disorders and neoplasms (Table 2). ● The incidence of any grade AEs, grade ≥3 AEs, and SAEs were generally similar for the SC and IV ● Serious AEs (SAEs) were recorded for 1 year post-treatment or until the start of new anti- infections, nasopharyngitis, pneumonia, sinusitis and rhinitis. – Febrile neutropenia was reported by <1% patients receiving rituximab SC and formulations of rituximab. One exception to this was an increase in general disorders and administration site conditions in the SC arm due to an increased incidence of mild injection site erythema. lymphoma treatment. SAEs considered possibly related to study treatment were recorded ● Other common AEs (≥15% patients) belonged to the SOCs general disorders and 1% patients receiving rituximab IV. indefinitely. ● The increase in mild injection site erythema with rituximab SC was not unexpected and reflects the administration site conditions (SC 28%; IV 19%), gastrointestinal disorders (SC 24%; IV ● With the exception of pneumonia SAEs, which were reported in 3 patients in the rituximab expected change in profile of administration-related reactions when switching to the SC route. 19%), musculoskeletal and connective tissue disorders (SC 23%; IV 21%), respiratory, SC arm and in 2 patients in the rituximab IV arm, all other individual SAEs were reported in Figure 1. SABRINA study design. ● There was a trend towards a higher incidence of grade ≥3 AEs among female than among male patients, thoracic and mediastinal disorders (SC 18%; IV 17%), blood and lymphatic system no more than 1 patient in either treatment arm. mainly as a result of a higher incidence of infection/infestation-related AEs; however, the incidence of disorders (17% each) and skin and subcutaneous tissue disorders (SC 16%; IV 15%). ● Overall, female patients experienced a higher incidence of AEs belonging to the SOCs individual grade ≥3 AEs belonging to this SOC was low (≤2%) in both female SC and IV rituximab groups. Induction Maintenance ● The difference (9%) in the overall incidence of AEs belonging to the SOC general disorders infections and infestations, gastrointestinal disorders, blood and lymphatic system disorders ● The availability of a SC formulation of rituximab for administration over approximately CR, CRu Rituximab IV (375 mg/m2) and administration site conditions was driven mainly by a higher incidence of grade 1 and musculoskeletal and connective tissue disorders (Table 3). 6 minutes has positive implications for patient convenience and healthcare resource savings, without R Rituximab IV (375 mg/m2) + CHOP or PR every 8 weeks for 2 years compromising safety. A or CVP* for 8 cycles injection site erythema in the SC arm (8% vs 0%). or until PD ● In both arms, grade ≥3 AEs were more common in females (rituximab SC 27%; rituximab IV N (n=205) (n=178) Previously untreated D ● For all other SOCs, the difference in the overall incidence of AEs between the rituximab SC 29%) than in males (rituximab SC 18%; rituximab IV 19%) during maintenance therapy; this CD20+ FL O Stratified by CHOP/CVP, FLIPI, region and IV arms was relatively small (≤5% difference), as was the incidence of individual AEs by was predominantly driven by grade ≥3 AEs belonging to the SOC infections and infestations REFERENCES grade 1, 2, or 3a M preferred term (PT) for these SOCs (≤5% difference). (females: SC 10%, IV 6%; males: SC 4%, IV 1%). (N=410) I Rituximab IV (375 mg/m2) + CHOP CR, CRu Rituximab SC (1400 mg) † or PR 1. Hiddemann W, et al. Blood 2005;106:3725–32. 5. Van Oers MH, et al. J Clin Oncol 2010;28:2853–8. S or CVP for cycle 1 rituximab SC every 8 weeks for – The overall safety profile was as expected and manageable. 2. Marcus R, et al. J Clin Oncol 2008;26:4579–86. 6. De Cock E. Blood 2013;122 (Abstract 1724). † ● Higher incidences of SAEs belonging to the SOCs infections and infestations E (1400 mg) + CHOP or CVP for 2 years or until PD 3. Hochster H, et al. J Clin Oncol 2009;27:1607–14. 7. Davies A, et al. Lancet Oncol 2014:15;343–52. D cycles 2–8 (n=205) (n=172) ● The most common grade ≥3 AEs belonged to the SOC blood and lymphatic system (11% rituximab SC) and gastrointestinal disorders (6% rituximab IV) were reported among 4. Salles G, et al. Lancet 2011;377:42–51. 8. Davies A, et al. Haematologica 2014;99:Abstract S652. disorders, occurring in 10% of patients in both treatment arms. The majority of these AEs female patients; however, no specific AEs were responsible for this increase in incidence. CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; CR, complete response; CRu, unconfirmed complete response; CVP, were grade ≥3 neutropenia (SC 9%; IV 7%). cyclophosphamide, vincristine, and prednisone; FL, follicular lymphoma; FLIPI, Follicular Lymphoma International Prognostic Index; IV, ● In total, 5% of rituximab SC patients and 3% of rituximab IV patients discontinued ACKNOW LEDGEMENTS intravenous; PD, progressive disease; PR, partial response; SC, subcutaneous; *CHOP administered as cyclophosphamide (750 mg/m2 IV on 2 2 ● Grade ≥3 infections and infestation AEs occurred in 8% of patients in the rituximab SC arm maintenance therapy due to AEs. day 1), doxorubicin (50 mg/m IV on day 1), vincristine (1.4 mg/m IV on day 1 [2 mg maximum]), and prednisone (100 mg oral or IV on days The authors would like to thank the patients and their families, the study investigators, study coordinators, and nurses † 2 2 1–5) of every cycle; CVP administered as cyclophosphamide (750 mg/m IV on day 1), vincristine (1.4 mg/m IV on day 1 [2 mg maximum]), and in 3% in the rituximab IV arm; however, no individual grade ≥3 AE belonging to this who assisted with the MabThera SC clinical programme. Support for third-party writing assistance for this poster was and prednisone (40 mg oral or IV on days 1–5) of every cycle. ● At data cut-off (03 February 2015), 27 patients (rituximab SC n=11, 6%; rituximab IV n=16, provided by F. Hoffmann-La Roche Ltd. *Natalia Berthillon was an employee of F. Hoffmann-La Roche Ltd at the time SOC occurred with an incidence of >1% in either arm. 8%) had died. this work was carried out, and is now an employee of Pharmacyclics GmbH. TIMER MabEase: Ritux SC+CHOP phase III in DLBCL

Lugtenburg P et al. EHA 2015;Abstract. Time-and-motion: Patient chair time and TIMER active HCP time per IV vs SC administration

. Patients receiving rituximab SC spent 66- 94% less time in the infusion chair than those receiving rituximab for intravenous use

. In all countries, rituximab SC administration was associated with reduced “active” HCP time compared with rituximab for intravenous use

De Cock E et al. EHA 2013; Abstract P507. Obinutuzumab (GA101): Type II, TIMER glycoengineered anti-CD20 mAb

Type II anti-CD20 antibody1,2 . First Type II, glycoengineered, humanised IgG1 anti-CD20 monoclonal antibody1–3

. Fv-mediated effects:

. direct-cell effects

. Fc-mediated effects:

. ADCC

. CDC

Glycoengineered . phagocytosis Fc region1

1. Mössner E, et al. Blood 2010; 115:4393–402. 2. Niederfellner G, et al. Blood 2011; 118:358–67. 3. Alduaij W, et al. Blood 2011; 117:4519–29. Obinutuzumab binds CD20 in a completely TIMER different orientation that type I

. Obinutuzumab binds to subtly different motif . Obinutuzumab is rotated 90º around Fab middle axis and tilted 70º toward carboxy-terminal side of ANP motif (interaction with Asn 176) . The elbow angle between VH and CH1 of obinutuzumab is around 30º wider than that of type I mAbs (aa substitution at position 11: substituting a Leu by a Val) . Obinutuzumab binds half CD20 molecules compared with rituximab . Translocation of mAbs-CD20 complexes into lipid rafts allows Fc portions clustering into lipid rafts: favourable condition to recruit C1q proteins leading to exert potent CDC

Cragg MS. Blood 2011;118:219–20. Niederfellner G et al. Blood 2011; 118:358–67. Obinutuzumab induces increased antibody- TIMER dependent cellular cytotoxicity . The lack of fucose on IgG improves binding to FcgRIIIa (whatever the allotype V or F)

. Increase ADCC and neutrophil-ADCP than rituximab and Fc-mutant mAbs

Okazaki A et al. J Mol Biol 2004;336:1239-49. Mössner E et al. Blood 2010; 115: 4393-402. Golay J et al. Blood 2013;122:3482-91. TIMER Type I and Type II anti-CD20 mAbs

Type I Type II Rituximab, Tositumomab, Mechanism Ofatumumab Obinutuzumab Localize CD20 into lipid rafts ++ –

CDC ++ –

Homotypic adhesion – ++

Caspase-dependent cell death ++ –

Bind CD20 molecules ++ + (half)

CD20 modulation ++ –

ADCC

ADCP

Gagez AL et al. Curr Opin Oncol 2014;26:484-91. TIMER GAUGUIN (BO20999): Phase II in rec/ref NHL

. Efficacy in relapsed/refractory indolent NHL: Efficacy outcome 1,600/800 400/400

55% 17% EoTR (primary endpoint) (rituximab refractory: 50%) (rituximab refractory: 8%)

BOR (FL patients) 60%* 36%† . Efficacy in relapsed/refractory aggressive NHL:

Efficacy outcome All patients 1,600/800 400/400

EoTR (primary endpoint) 28% 32% 24%

Median PFS (FU 7.7 months; DLBCL patients) 2.7 1.9

. GA101 showed an acceptable safety profile in relapsed/refractory NHL

Salles G, et al. J Clin Oncol 2013; 31: 2920-6. Morschhauser F, et al. J Clin Oncol 2013; 31: 2912-9. GADOLIN (GAO4753g) Phase III in Rituximab- TIMER refractory iNHL

Induction Maintenance CR, PR, GA101 SD GA101 + bendamustine Rituximab-refractory iNHL q2mo x 2 years x 6 cycles (N = 360) •Age ≥ 18 years Randomise •Previously treated with ≤ 4 chemotherapy-containing regimens •Refractory to any previous rituximab-containing regimen Bendamustine x 6 cycles

1.0

0.8

0.6

0.4 Median follow-up:

Probability of PFS of Probability 21 months 0.2 G-B B + 0.0 Censored 0 6 12 18 24 30 36 42 48 54 No. at risk Time (months) G-B 194 157 106 75 47 27 7 2 1 B 202 149 86 42 26 13 4 1

IRF, independent radiology facility; HR, hazard ratio; CI, confidence interval; NR, not reached. Sehn LH et al. J Clin Oncol 2015; 33(suppl): abstr LBA8502. GAUDI (BO21000): Efficacy and safety in first- TIMER line treatment of FL after maintenance

Responses at the end of the induction Study desing for untreated FL patients and maintenance by induction arm

2 100 2 2 2 5 5 2 90 2 25 Missing 80 32 Disease progression 70 56 60 Stable disease

) 60 %

( Partial response

s t

n 50 Complete response

e

i

t a

P 40 70 30 61

20 37 35 10

0 End of induction End of maintenance End of induction End of maintenance G-B (n=41) G-CHOP (n=40)

. In the overall safety population at 32 months (median FU time), 92% of patients in the G-B arm and 84% of patients in the G-CHOP arm were progression free . Median PFS from the start of induction was not reached; 10 patients had PD (G-B: n=4; G-CHOP: n=6) . During 2 years’ maintenance, most patients had AEs: . G-B, 100% (grade ≥3: 44%); G-CHOP, 78% (grade ≥3: 31%) . AEs led to dose delays in 17% (G-B) and 6% (G-CHOP) of patients

Dyer MJS et al. ASH 2014; abstract 1743.

Targeting FcgRIIB on B Cells to Enhance Antibody- TIMER Dependent Lymphoma Immunotherapy

. FcgRIIB is a single inhibitory antibody receptor expressed on immune cells and certain cancers . FcgRIIB is implicated in intrinsic and acquired antibody drug resistance and treatment failure in lymphoma

Roghanian A et al. Cancer Cell 2015,27:473-88. Targeting FcgRIIB on B Cells to Enhance Antibody- TIMER Dependent Lymphoma Immunotherapy

. FcgRIIB is a single inhibitory antibody receptor expressed on immune cells and certain cancers . FcgRIIB is implicated in intrinsic and acquired antibody drug resistance and treatment failure in lymphoma

. Antibodies blocking FcgRIIB prevent internalization of anti- CD20 antibodies type I, thereby maximizing immune effector cell-mediated antitumor activity

Roghanian A et al. Cancer Cell 2015,27:473-88. 6G11, an FcgRIIB-specific antibody,enhances TIMER activity of rituximab and obinutuzumab

. Cytotoxic effects of 6G11 . 6G11 impairs rituximab internalization

. Increased efficacy of the . Increased efficacy of the combination rituximab/6G11 combination GA101/6G11

*in primary CLL cells Roghanian A et al. Cancer Cell 2015,27:473-88. TIMER Lenalidomide: an oral immune modulator

Gribben JG et al. J Clin Oncol 2015;33: Ahead of print. TIMER Lenalidomide: in folicular lymphoma

Author Regimen FL N ORR % CR % PFS/TTP OS Relapsed/refractory FL Witzig al at Len G3 22 42 11 8.9 m NA

Tuscano et al Len+R G1-2 22 77 41 NA NA

Leonard et al Len+R G1-3a 46 76 39 2 y NA Len 45 53 20 1.1 y * Chong et al Len+R G1-2 (#) 26 65 35 16.5 m NA

Newly diagnosed FL Fowler et al Len+R NA 50 98 87 78.5% at 3 y 94.4% at 3 y (52%GELF) (93% PET-) Martin et al Len+R G1-3a 65 93 72^ 89% at 2 y NA NA Yamshon et al Len+R NA 15 100 61 14.5 m NA NA Kimby et al Len+R G3a 77 87 42 NA NA R NoT 77 66 28 NA NA

# refractory Witzig TE et al. Ann Oncol 2011;22:1622-27; Tuscano JM et al. Br J Haematol 2014;165:375-81; Leonard J et al. J Clin Oncol 2015; in *p=0.0023 press; Chong EA et al. Clin Cancer Res 2015;21:1835-42; Fowler NH et al. Lancet Oncol 2014;15:1311-8; Martin P et al. ASCO 2014; ^By PET Abstract 8521; Yamshon et al. ASH 2013; Abstract 249; Kimby E et al. ASH 2014; Abstract 799. TIMER RELEVANCE: chemo-free trial in FL

CR/CRu/PR R2 R2 maintenance (lenalidomide 1 yr + rituximab 2 years) First-line FL R N = 1,000 CR/CRu/PR R-chemo’ Rituximab maintenance (2 years)

6 months 24 months

• Stratification: FLIPI (0–1 v 2 v 3–5), age (> 60 vs ≤ 60), diameter of largest node (> 6 vs ≤ 6 cm) • R-chemo’ arm: Investigator’s choice of R-CHOP, R-CVP or BR TIMER Bortezomib: proteasome inhibitor in MCL

Progression-free Survival Overall Survival

Robak T et al. N Engl J Med 2015;372:944-53. TIMER Ibrutinib: First-in Class Inhibitor of BTK

. Small molecule covalent inhibitor of BTK (binds cysteine-481) . Potent: MIC50 = 0.5 nmol/L . Inhibits BTK signaling . Including ERK, NFκB, PI3K . Dec. cell proliferation, tumor-cell migration . Inhibition is independent of BTK catalytic activity . An oral, irreversible BTK inhibitor, a critical mediator of BCR signaling . Standard MCL Dose: 560 mg daily . Generally very well tolerated . Toxicities: . Diarrhea, Rash, Fatigue, Mild Cytopenias, Increased Risk for Infection, Bleeding Complications, Peripheral lymphocytosis

Ibrutinib: BCR inhibitor in mantle cell TIMER lymphoma

Overall response rate Progression free survival

Wang ML et al. N Engl J Med 2013;369:507-16. TIMER Inhibitors of PI3K

PI3Kδ has a unique role in migratory, proliferative, survival, and differentiation pathways of B-cells

. Idelalisib is a first-in-class PI3Kδ inhibitor, and has shown promising activity in indolent lymphoma . IPI-145 is a PI3Kγδ inhibitor that has demonstrated promising activity in both B- and T-cell lymphoma . Idelalisib and IPI-145 display high structural similarity and contain nitrogen based heterocyclic backbones known to induce hepatotoxicity . TGR-1202 has a different backbone designed to potentially minimize toxicity while preserving delta specificity. In vivo studies have shown no hepatotoxicity

Fruman DA et al. Nat Rev Drug Disc 2014; 13, 140-56. TIMER Idelalisib: PI3Kδ inhibitor in follicular lymphoma

Phase 2 Idelalisib in Monotherapy in Double Refractory iNHL (Study 101-09)

Adverse events Any grade Grade ≥3 (%) (%) Diarrhea 43 13

Nausea 30 2 . Tumor reduction: 90% Fatigue 30 2 . ORR: 57% Cough 29 0 . Decreased neutrophils 56 27 Median treatment duration:

Increased ALT 47 13 . 12.5 months (0.03-14.8+)

Increased AST 35 8 . Discontinuation due to AE: 20% Increased alkaline 22 0 . G3/4 AEs: 54% of pts phosphatase Increased bilirubin 10 0 Gopal AK et al. New Engl J Med 2014:370:1008-18. TIMER BCL2 inhibitors 4/16/2015

RESULTS FROM THE PHASE 1/2A STUDY OF NAVITOCLAX (ABT-263) IN PATIENTS WITH RELAPSED OR REFRACTORY LYMPHOID MALIGNANCIES Best Change in Tumor Size From Baseline

• 10 of 46 assessable patients had PR • Median PFS 455 days

TIMER BCL2 inhibitors: Venetoclax (ABT-199) Wilson et al, Lancet 2010 39

PHASE 1 STUDY OF ABT-199: BEST PERCENT Phase 1 Study of ABT-199 for relapsed/refractoryCHANGE FROM BASELINE IN NODAL SIZE BNHLY CT SCA N • N = 29 evaluable (at minimum, 6 week assessment) • Median Time to 50% Reduction = 43 days (range 36 to 113)

• ABT-199 200-900 mg orally • ORR (in 32 pts): • 53% (CR 6%) • 27% in FL

40 • Most common toxicity: • nausea (41%), diarrhea (31%), vomiting (22%), fatigue (22%), and upper 20 respiratory tract infection (22%) • AEs G3/4: anemia (15%), neutropenia (13%), and thrombocytopenia (13%) • Tumor lysis syndrome • Dosage for phase 2: ≥ 600 mg daily • Will BCL2 expression level predict ABT-199 activity?

Davids MS et al. Blood 2013;122:1789 TIMER The blockade of immunologic checkpoint

Impronta G et al. OTT 2015;8:2535-44. TIMER PD-1 blockade of immunologic checkpoint

Phase 2 Anti-PD-1 (Pidilizumab) and Rituximab for Relapsed FL

• Pidilizumab 3 mg/kg IV q28d x 4 cycles (+8 if ≥ SD) + Rituximab x 4 • ORR (in 29 evaluable pts): 66% (52%) • NO factor identified a poor response • Time to response median: 88 days

• PFS median: 18.8 months (influenced Progression free survival by FLIPI) • NO AEs G3/4 • Toxicity: anemia, fatigue (G1); respiratory infection (G2)

Months Westin JR et al. Lancet Oncol 2014;15:69-77. TIMER Agents for blockade of immunologic checkpoint

Anti-CTLA4 Fully human IgG1 ipilimumab Yervoy; Bristol-Myers Squibb Anti-CTLA4 Fully human IgG2 tremelimumab Pfizer; MedInmmune

Anti-PD1 Humanized IgG4k pembrolizumab Keytruda; Merck & Co.

Anti-PD1 Fully human IgG4 nivolumab Opdivo; Bristol-Myers Squibb/Ono Pharmaceuticals Anti-PD1 Humanized IgG1k pidilizumab CureTech

Anti-PD1 ND MEDI0680 (AMP-514) MedImmune/AstraZeneca

Anti-PD-L1 Fully human IgG4 BMS-936559 (MDx- Bristol-Myers Squibb 1105) Anti-PD-L1 Engineered human IgG1 MPDL3280A Genentech/Roche (no ADCC) Anti-PD-L1 Humanized IgG1k MEDI4736 MedImmune/AstraZeneca (no ADCC) Anti-PD-L1 Fully human IgG1 MSB0010718C EMD-Serono

Anti-PD-L2 PD-L2 IgG1 Fc AMP-224 GlaxoSmithKline fusion TIMER Dual antibody therapy to harness the innate anti-tumor immune response to enhance antibody targeting of tumors

Activating co- Decreasing stimulatory inhibitory signaling signaling

CD137 PD-1 axis

CD27 KIRs CD40 CD47 GIRT ICOS

Chester C et al. Curr Op Immunol 2015;33:1-8. TIMER Y muchos más agentes en desarrollo……

Therapy Target Monoclonal antibodies Ublituximab CD20 MEDI-551 CD19 MOR208 CD19 Antibody-drug conjugates Inotuzumab ozogamicin CD22 Pinatuzumab vedotin CD22 Polatuzumab vedotin CD79a IMGN529 CD37 Tumor microenvironment CC-122 T and B cells Blinatumumab T cells and CD19 CAR-modified T cells T cells and CD19 Small-molecule kinase inhibitors Entospletinib SYK ACP-196 BTK ONO-4059 BTK MK-2206 AKT Alisertib Aurora-A kinase Selinexor XPO1 Cerdulatinib SYK and JAK Pacritinib JAK/STAT TIMER Acknowledgments

Lymphoma Unit Onco-Hematology Day Unit Blanca Sánchez-González Elena Torres Eva Gimeno Clinical Trials Coordinator Mariana Ferraro Francesc García Silvia Fontana Pathology Department Carlos Besses Lluis Colomo Sergi Serrano TIMER