Phase II PCYC-1121 Trial: Ibrutinib Monotherapy Active in R/R Marginal Zone Lymphoma New Findings in Hematology: Independent Conference Coverage of ASH 2016*; December 3-6, 2016; San Diego, California *CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs. R/R, relapsed/refractory. This activity is supported by educational grants from Amgen, Celgene Corporation, Incyte, Merck, and Seattle Genetics.

Ibrutinib in R/R MZL (PCYC-1121): Background Marginal zone lymphoma: indolent B-cell lymphoma; ~ 10% of NHL cases Treatment No standard of care, with no specifically approved treatment Options include chemoimmunotherapy and anti-CD20 antibodies Linked to infection-induced B-cell growth and survival[1] Ibrutinib: first-in-class oral inhibitor of BTK Approved to treat CLL/SLL, mantle cell lymphoma, and Waldenström’s macroglobulinemia BTK: major component of B-cell receptor signaling[1] Multicenter, open-label phase II trial studied efficacy and safety of ibrutinib in pts with R/R MZL[2] CLL, chronic lymphocytic leukemia; MZL, marginal zone lymphoma; NHL, non-Hodgkin’s lymphoma; R/R, relapsed/refractory; SLL, small lymphocytic leukemia. Slide credit: clinicaloptions.com 1. Niemann et al. Semin Cancer Biol. 2013;23:410-421. 2. Noy A, et al. ASH 2016. Abstract 1213.

Ibrutinib in R/R MZL (PCYC-1121): Study Design Pts with R/R MZL with ≥ 1 prior therapy including ≥ 1 anti-CD20-directed regimen, ECOG PS 0-2 (N = 63) Until disease progression or unacceptable toxicity Ibrutinib 560 mg PO once daily Primary endpoint: ORR by IRC using 2007 IWG criteria Secondary endpoints: DoR, PFS, OS, and safety DoR, duration of response; ECOG, Eastern Cooperative Oncology Group; IRC, independent review committee; IWG, International Working Group; MZL, marginal zone lymphoma; PS, performance status; R/R, relapsed/refractory. Slide credit: clinicaloptions.com Noy A, et al. ASH 2016. Abstract 1213.

Ibrutinib in R/R MZL (PCYC-1121): Baseline Characteristics Total (N = 63) Median age, yrs (range) 66 (30-92) Age ≥ 65 yrs, n (%) 36 (57) MZL subtype, n (%) Splenic Nodal Extranodal 14 (22) 17 (27) 32 (51) Bulky disease > 6 cm, n (%) Bone marrow involvement, n (%) 21 (33) Baseline cytopenias, n (%) Any cytopenia Hemoglobin ≤ 11 g/dL3 Platelet count ≤ 100,000 per mm3 Absolute neutrophil count ≤ 1500 per mm3 27 (43) 6 (10) 1 (2) LDH, ≥ 350 U/L, n (%) 12 (19) Creatinine clearance < 60 mL/min, n (%) 9 (14) Characteristic Total (N = 63) Prior therapies, median n (range) 2 (1-9) No. prior systemic therapies, n (%) 1 2 ≥ 3 23 (37) 18 (29) 22 (35) Type of prior therapy, n (%) Rituximab monotherapy Rituximab chemoimmunotherapy Radiation Splenectomy ASCT 17 (27) 40 (63) 9 (14) 4 (6) 2 (3) Refractory to most recent therapy, n (%) 14 (22) B symptoms at baseline, n (%) 15 (24) ASCT, autologous stem cell transplantation; LDH, lactate dehydrogenase; MZL, marginal zone lymphoma; R/R, relapsed/refractory. Slide credit: clinicaloptions.com Noy A, et al. ASH 2016. Abstract 1213.

Ibrutinib in R/R MZL (PCYC-1121): Response ORR per IRC assessment: 48% ORR concordance rate (IRC and investigator assessment): 85% Clinical benefit rate (CR + PR + SD) per IRC assessment: 83% Tumor shrinkage in 79% of pts including all 3 MZL subtypes DoR at 18 mos: 62% Median time to response Initial: 4.5 mos Best: 5.2 mos DoR, duration of response; IRC, independent review committee; MZL, marginal zone lymphoma; R/R, relapsed/refractory; SD, stable disease. Slide credit: clinicaloptions.com Noy A, et al. ASH 2016. Abstract 1213.

Ibrutinib in R/R MZL (PCYC-1121): Response Across Pt Subgroups ORR, % (95% CI) Extranodal disease Yes No 36 24 50 (35-66) 46 (28-65) Bone marrow involvement 21 35 62 (41-79) 46 (31-62) Prior regimens 1 2 ≥ 3 22 18 20 50 (31-69) 44 (25-66) 50 (30-70) Prior chemoimmunotherapy 39 46 (32-61) 52 (32-72) Prior rituximab only 16 69 (44-86) Subgroup n ORR, % (95% CI) All pts 60 48 (35-62) MZL subtype Extranodal Splenic Nodal 30 13 17 50 (33-67) 54 (29-77) 41 (22-64) Age < 65 yrs ≥ 65 yrs 24 36 58 (39-76) 42 (27-58) Baseline ECOG PS ≥ 1 32 28 44 (28-61) 54 (36-71) Tumor size (nodal/extranodal) > 6 cm ≤ 6 cm 14 43 50 (27-73) 46 (32-61) Tumor size (nodal) 9 41 56 (27-81) ECOG, Eastern Cooperative Oncology Group; MZL, marginal zone lymphoma; PS, performance status; R/R, relapsed/refractory. Slide credit: clinicaloptions.com Noy A, et al. ASH 2016. Abstract 1213.

Ibrutinib in R/R MZL (PCYC-1121): AEs Median duration of therapy: 11.6 mos Median follow-up: 19.4 mos 38% of pts still on study treatment Reasons for discontinuation: disease progression (32%), AEs (17.5%), withdrawal of consent (6%), investigator decision (6%) AEs Most common AEs: fatigue, diarrhea, anemia, nausea, thrombocytopenia, peripheral edema, cough, arthralgia, dyspnea, upper respiratory infection Leading to dose reductions: 6 pts (10%) Treatment discontinuation: 11 pts (17.5%) Treatment-emergent deaths: 1 pt each PD, cerebral hemorrhage, parainfluenza pneumonia AE, adverse event; MZL, marginal zone lymphoma; PD, progressive disease; R/R, relapsed/refractory. Slide credit: clinicaloptions.com Noy A, et al. ASH 2016. Abstract 1213.

Ibrutinib in R/R MZL (PCYC-1121): Conclusions Ibrutinib monotherapy is active in R/R MZL ORR in total population: 48% Effective across nodal, extranodal, and splenic subgroups AE profile consistent with previous experience Investigators conclude ibrutinib is an effective chemotherapy-free therapeutic option for R/R MZL AE, adverse event; MZL, marginal zone lymphoma; R/R, relapsed/refractory. Slide credit: clinicaloptions.com Noy A, et al. ASH 2016. Abstract 1213.

Go Online for More CCO Coverage of ASH 2016! Short slideset summaries of all the key data Additional CME-certified analyses with expert faculty commentary on all the key studies in: Leukemias Lymphomas/CLL Myeloma/plasma cell disorders MDS and myeloproliferative neoplasms clinicaloptions.com/oncology