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ASCO REVIEW 2011 T Martin, MD ASCO, Lugano, IMF-Paris Highlights May - June, 2011

ASCO REVIEW 2011 T Martin, MD ASCO, Lugano, IMF-Paris Highlights May - June, 2011. ASCO in Review 2011. Non-Hodgkin’s Lymphoma ( Abs 8031, 8032, 3065) SGN35 trials BTK Inhibitor trial, CA-101 (PI3-kinase inh) trial Chronic Lymphocytic Leukemia ( Abs 6508, 3065 )

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ASCO REVIEW 2011 T Martin, MD ASCO, Lugano, IMF-Paris Highlights May - June, 2011

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  1. ASCO REVIEW 2011T Martin, MDASCO, Lugano, IMF-Paris Highlights May - June, 2011

  2. ASCO in Review 2011 • Non-Hodgkin’s Lymphoma (Abs8031, 8032, 3065) • SGN35 trials • BTK Inhibitor trial, CA-101 (PI3-kinase inh) trial • Chronic Lymphocytic Leukemia (Abs6508, 3065) • BTK Inhibitor trial, CA-101 trial • Acute and Chronic Myeloid Leukemias (Abs6509, 6510, 6511, 6518) • Front line CML-CP therapy trial updates • Second line TKI therapy • Myeloproliferative Neoplasms (Abs6500, 6501,6514, 6515 ) • Ruxolitinib Phase III trials • Ongoing Phase II JAK2 inhibitor trials • Multiple myeloma (Abs8007, 8020 ) • Phase III trials • Phase II trials

  3. ABSTRACT 8031: Results of a Pivotal Phase 2 Study of Brentuximab Vedotin (SGN-35) in Patients with Relapsed or Refractory Hodgkin LymphomaR Chen, AK Gopal, SE Smith, SM Ansell, JD Rosenblatt, R Klasa, JM Connors, A Engert, EK Larsen, DA Kennedy, EL Sievers, A YounesABSTRACT 8032:Durable Remissions with SGN-35 (Brentuximab Vedotin): Updated Results of a Phase II Study in Patients with Relapsed or Refractory Systemic Anaplastic Large Cell LymphomaB Pro , R Advani , P Brice , NL Bartlett, JD Rosenblatt, T Illidge, J Matous, R Ramchandren, M Fanale, J M Connors, Y Yang, EL Sievers, DA Kennedy, A. R. Shustov

  4. Brentuximab Vedotin Mechanism of Action Brentuximab vedotin (SGN-35) ADC monomethyl auristatin E (MMAE), potent antitubulin agent protease-cleavable linker anti-CD30 monoclonal antibody ADC binds to CD30 ADC-CD30 complex traffics to lysosome MMAE is released G2/M cellcycle arrest MMAE disruptsmicrotubule network Apoptosis

  5. Pivotal, Multicenter, Open-Label Study of Brentuximab Vedotin in Relapsed/Refractory HL Treatment (N=102) Follow-up Eligibility • Relapsed or refractory CD30+ HL • Age ≥12 years • Measurable disease ≥1.5 cm • ECOG 01 • Prior ASCT • Brentuximab vedotin 1.8 mg/kg IV every 21 days • Administered outpatient over 30 min • Max 16 cycles for SD or better • Restage at Cycles 2, 4, 7, 10, 13, 16 Every 12 weeks Objectives: ORR (CR+PR), Survival (DOR, PFS, OS)

  6. Demographics and Baseline Characteristics

  7. Brentuximab Vedotin: Response Results

  8. Maximum Tumor Reduction per IRF 100 94% (96 of 102) of patients achieved tumor reduction Tumor Size (% Change from Baseline) Individual Patients (n=98)* • * 4 patients were not included in the analysis • 3 patients had no measurable lesions per IRF • 1 patient had no postbaseline scans

  9. 2º Endpoints: PFS and OS % Patients Free of PD or Death Time (Weeks) Median (range) cycles of treatment = 9 (116) Median DOR: 29 Wk (IRF); 47 Wk investigator

  10. Treatment-Emergent Adverse Events of any Relationship Occurring in ≥20% of Patients Patients with AEs leading to discontinuation = 20% OTHER <20%: G3+4: Low Plats 8%, Anemia 6%, neuropathy reversible (68%), onset at 27 wks, time to resolution 6.9 wks.

  11. 1´ Endpoint: ORR 2 Endpoint: CR, DOR, PFS, OS Pro et al, Ab 8032; ASCO 2011

  12. N = 58Male 57%Age 52 (14-76)Alk negative 72%Median Prior therapies 2 (1-6)Refractory to last treatment 50%Primary refractory 62% SGN-35 in ALCL Patient Characteristics

  13. ■ RESULTS: ORR 86% CR 53% DOR NR (0.3-45.3 wks) ■ SAFETY: PN 36% (> gr 3 10%) Nausea 24% Neutropenia 17% SGN-35 in ALCL

  14. Conclusions SGN35 in 102 HD patients with post ASCT relapse ORR = 75%; CR = 34%, median duration of response of 29 weeks 94% of patients achieved tumor reduction Estimated 12-month overall survival = 88% Manageable adverse events, PN largely reversible SGN35 in R/R ALCL ORR = 86% CR = 53% Adverse events manageable (PN, neutropenia, nausea, fatigue) Further studies are ongoing

  15. Non-Hodgkin’s Lymphoma/ B-cell TargetsB-Cell Signaling Kinases CAL-101 PCI-32765 • B-cell antigen receptor (BCR) signaling is required for tumor expansion and proliferation • Bruton’s Tyrosine Kinase (Btk) and PI3-Kinase are essential elements of the BCR signaling pathway • Inhibitors of Btk and PI3-kinase block BCR signaling and induce apoptosis Nat Rev Imm 2:945

  16. Abstract 6508: Activity and Tolerability of the Btk Inhibitor PCI-32765 in Patients with CLL/SLL: Interim Results From a Phase IB/II Study J Byrd, K Blum, J Burger, S Coutre, J Sharman, R Furman, I Flinn, B Grant, D Richards, W Zhao, N Heerema, A Johnson, R Izumi, A Hamdy and S. O’Brien

  17. Study Design • Single Agent BTK Inh: oral dosing • Cohort 1 • Treatment Naïve (TN): >65 yo • BTKI 420mg qd for 28-day cycle until disease progression • Cohort 2 (two doses) • Relapse Refractory (R/R): 2 prior treatments including 1 with Fludarabine • 420mg qd for 28-day cycle until disease progression • 840mg qd for 28-day cycle until disease progression • Objectives • ORR, DOR, PFS • Safety, PK/PD

  18. Subject Characteristics

  19. Subject Characteristics (cont.)

  20. RESULTS: Responses

  21. Best Response by Risk Features Relapsed/refractory pts: 420 mg/d

  22. Common AEs (All Grades) Treatment-Naive420 mg/d (n=23) Relapsed/Refractory420 mg/d (n=27) 70% Diarrhea 48% 33% Nausea 39% 22% Vomiting 17% 19% 22% Dyspepsia 33% 4% Confusion Musclespasms 17% 26% 11% 26% Rash 37% 13% URI 17% 33% Fatigue 11/13/2014 9:15:49 PM 24

  23. Conclusions • PCI-32765 is highly active in both treatment-naïve and relapsed/refractory CLL/SLL patients • Responses appear to be durable and independent of high risk genomic features • A high proportion (81%) of relapsed/refractory pts are free- of –progression beyond 6 months (420mg/d cohort) • Toxicity of PCI-32765 is modest. The majority of the AES are grade1 or 2

  24. Abstract 3064: A Phase I Study of CAL-101, an isoform-selective inhibitor of phosphatidylinositol 3-kinase P110d, in Combination with anti-CD20 monoclonal antibody therapy and/or Bendamustine in Patients with Previously Treated B-cell MalignanciesW Flinn, M Schreeder, S Coutre, J Leonard, N Wagner-Johnston, S De Vos, R Boccia, L Holes, S Peterman, L Miller, and A Yu Background CAL-101 is a selective inhibitor of p110d which may be more active in hematopoietic malignancies In a phase I trial, CAL-101 has shown promising activity in indolent lymphoma (15/24, 62%), mantle cell lymphoma (10/16, 62%) and CLL (ASH 2010 Abs 1777; ASCO 2011 Abs 3032)

  25. Study Design • Two CAL-101 dose levels • CAL-101 100mg bid + Bendamustine 90mg/m2 d1,2 • CAL-101 100mg bid + Rituximab 375mg/m2 d1 • CAL-101 150mg bid + Bendamustine 90mg/m2 d1,2 • CAL-101 150mg bid + Rituximab 375mg/m2 d1 • Relapsed/refractory indolent NHL (iNHL) or CLL • Accrual:

  26. Patient Characteristics Median age 64 years (range 41 – 87) Males 65% Refractory disease 43% Median number of prior therapy: 3 (range 1 – 9)

  27. RESULTS: • Efficacy • Toxicity (Grade 3-4) • Neutropenia in Benda+CAL: 10/24 • Thrombocytopenia in Benda+CAL: 10/24 • Increased AST/ALT: • 6/28 in iNHL • 1/21 in CLL

  28. Conclusions • CAL-101 shows acceptable toxicity • Very Promising clinical activity in both Rituximab and bendamustine cohorts • Further studies on-going

  29. ASCO 2011 • Non-Hodgkin’s Lymphoma (Abs 8031, 8032, 6508, 3065) • SGN35 trials • BTK Inhibitor trial, CA-101 (PI3-kinase inh) trial • Chronic Lymphocytic Leukemia (Abs 6508, 3065) • BTK Inhibitor trial, CA-101 trial • Acute and Chronic Myeloid Leukemias (Abs6511, 6518, ) • Front line TKI therapy • Second line TKI therapy • Myeloproliferative Neoplasms (Abs 6500, 6501,6514, 6515 ) • Ruxolitinib Phase III trials • Ongoing Phase II JAK2 inhibitor trials • Multiple myeloma (Abs 8007, 8020 ) • Phase III trials • Phase II trials

  30. “These two studies cap a remarkable decade of progress in CML therapy and, for some, may raise the question of whether we have reached the limit of what we can hope to achieve. We know that imatinib induces a long-lasting remission but not a cure. Presumably, dasatinib and nilotinib will perform similarly, but with deeper, longerlasting remissions.” Kantarjian et. al. ASCO a6510 Larson et. al. ASCO a6511

  31. Study Design R A N D O M I Z E Bosutinib 500 mg/day n = 250 5-year follow-up Phase 3 open-label trial in newly diagnosed chronic phase CML N = 502 139 sites 31 countries Imatinib 400 mg/day n = 252 5-year follow-up Randomization is stratified based on Sokal risk score and geographical regions. 1-year analysis • Key eligibility criteria: cytogenetic diagnosis of Philadelphia chromosome-positive chronic phase chronic myeloid leukemia (CP CML) 6 mo prior, with no prior therapy other than hydroxyurea or anagrelide • Primary endpoint: complete cytogenetic response (CCyR) at 12 months • Key secondary and exploratory endpoints: • Major molecular response (MMR) at 12 months, duration of CCyR and MMR, time to and incidence of transformation to accelerated or blast phase CML, event-free survival, and overall survival • Safety and tolerability Gambacorti-Passerini et. al. ASCO a6509

  32. Complete Cytogenetic Response Rates:Intent-to-treat Population a a aIndicates statistical significance with a P value 0.05. P values for all timepoints with the exception of Month 12 were exploratory and provided for descriptive purposes only. • The cumulative CCyR rate by 18 months was 79% for each treatment arm • Median time to first CCyR was faster for bosutinib (12.7 weeks) compared with imatinib (24.6 weeks) Gambacorti-Passerini et. al. ASCO a6509

  33. Major Molecular Response Rates:Intent-to-treat Population a a a a a aIndicates statistical significance with a P value 0.05. P values for all timepoints with the exception of Month 12 were exploratory and provided for descriptive purposes only. • Cumulative MMR rates by 18 months were 55% for bosutinib and 45% for imatinib, and cumulative CMR rates by 18 months were 18% and 10%, respectively • Median time to first MMR was faster with bosutinib (36.9 weeks) compared with imatinib (72.3 weeks) Gambacorti-Passerini et. al. ASCO a6509

  34. Transformation to AP/BP and Overall Deaths a AP, accelerated phase; BP blast phase. aTreatment failure includes both disease progression and lack of efficacy (including transformation to AP/BP). • Transformation to AP/BP CML occurred in 4 (2%) patients in the bosutinib arm and 13 (5%) in the imatinib arm while on study treatment; no new transformation events have occurred on bosutinib since the 12-month primary analysis, compared with 3 new events on imatinib • Overall deaths occurred in 6 patients receiving bosutinib versus 13 receiving imatinib during the study, the majority of which occurred after treatment discontinuation • Deaths due to CML progression occurred in 5 patients receiving bosutinib and 9 receiving imatinib Gambacorti-Passerini et. al. ASCO a6509

  35. Treatment-emergent Adverse Events Reported for 10% of Patients Blue highlighting indicates adverse events more common with bosutinib than imatinib. Green highlighting indicates adverse events more common with imatinib than bosutinib. Gambacorti-Passerini et. al. ASCO a6509

  36. Abstract 6518: Ponatinib in patients with CML/AML: Preliminary findings from a Phase I study in hematologic malignanciesM Talpaz, N Shah, M Deininger, M Mauro, I Flinn, S Lustgarten, W Lindmark, J Gozgit, T Cclackson, C Turner, F Haluska, and J Cortez

  37. Ponatinib(AP245534): Study Design • Oral multi-tyrosine kinase inhibitor; including inhibition of bcr-abl and Flt3/ITD. • Goals: identify RP2D and estimate activity • Standard 3+3 Design • Oral daily dosing (cohorts 2, 4, 8, 15, 30 and 60 mg) • Demographics n=56 • Age 66 (26-85) • Disease • CML 42 (31 CP, 6AP, 5 BP) • PH (+) ALL 2 • AML 12 (Flt3/ITD 10/12) • # Prior Therapies 3 (median)

  38. Results: Ponatinib Responses • CML (R/R) • CHR 85% • CCyR 33% • MCyR 48% • CML – T315I • CHR 100% • CCyR 57% • MCyR 14% • CML AP/BC or ALL • MHR 36% • CCyR 9% • AML • ORR 25% • CRi 16% Responses in Flt3 (+) • PR 8% Only Talpaz et al. Abstr 6518; ASCO 2011

  39. Results: Safety • Related AE’s >10%: • Nausea/vomiting 20%/15% • Fatigue 15% • Headache 13% • Arthalgia /muscle spasma 10%/10% • Hot flashes 10% • Rash 10% • Elevated Lipase/Pancreatitis 10% (4/12 at 60mg) • G3/4 neutropenia 43% • G3/4 thrombocytopenia 40%

  40. Results: Responses • Conclusions • RP2D= 45mg • Well tolerated at RP2D • CML: very promising • Active in T315 I mutation • Active in AP/BC • AML: potentially promising • Active in treatment naïve Flt3(+) • Combination with chemotherapy in Flt3 warranted Talpaz et al. Abstr 6518; ASCO 2011

  41. ASCO 2011 • Non-Hodgkin’s Lymphoma (Abs 8031, 8032, 6508, 3065) • SGN35 trials • BTK Inhibitor trial, CA-101 (PI3-kinase inh) trial • Chronic Lymphocytic Leukemia (Abs 6508, 3065) • BTK Inhibitor trial, CA-101 trial • Acute and Chronic Myeloid Leukemias (Abs 6509, 6510, 6511, 6518 ) • Front line TKI therapy • Second line TKI therapy • Myeloproliferative Neoplasms (Abs 6500, 6501, 6514, 6515 ) • Ruxolitinib Phase III trials • Ongoing Phase II JAK2 inhibitor trials • Multiple myeloma (Abs 8007, 8020 ) • Phase III trials • Phase II trials

  42. Phase III Registration Trials COMFORT I Primary Endpoint Number of subjects achieving ≥ 35% reduction in spleen volume from baseline to week 24* COMFORT II Primary Endpoint Number of subjects achieving ≥ 35% reduction in spleen volume from baseline to week 48* Verstovsek et. al. ASCO 2011 a6500 COMFORT I INC424 (oral) 15 mg BID or 20 mg BID Patients with MF (N = 309) Randomized 1:1 Placebo (oral) BID USA, Canada, Australia Harrison et. al. ASCO 2011 a6501 COMFORT II INC424 (oral) 15 mg BID or 20 mg BID Patients with MF (N = 219) Randomized 2:1 Best available therapy EUROPE: Austria, Belgium, France, Germany, Italy, Netherlands, Spain, Sweden, UK Both trials ongoing but completed enrollment * As measured by MRI (or CT scan in applicable subjects).

  43. Hematology Laboratory Values(Worst Grade on Study)* *Patients are included at their worst on study grade regardless of whether this represents a change from their baseline. • Grade 3 and grade 4 anemia and thrombocytopenia were more common in those with higher baseline grade • Discontinuation of treatment because of anemia and thrombocytopenia was rare (1 patient in each treatment group for each event) 49 Verstovsek et. al. ASCO 2011 a6500

  44. COMFORT-II Efficacy Results Primary Endpoint Key Secondary Endpoint Ruxolitinib 95% CI: 21.3, 36.6 P < .0001 Ruxolitinib 95% CI: 24.4, 40.2 P < .0001 28.5% 31.9% % With ≥ 35% Spleen Volume Reduction % With ≥ 35% Spleen Volume Reduction BAT 95% CI: 0.0, 5.0 BAT 95% CI: 0.0, 5.0 0 0 Ruxolitinib BAT Ruxolitinib BAT Week 48 Week 24 Harrison et. al. ASCO 2011 a6501

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