Ibrutinib Plus Rituximab in Treatment-Naive Patients With Follicular Lymphoma New Findings in Hematology: Independent Conference Coverage* of ASH 2015, December 5-8, 2015, Orlando, Florida *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. This program is supported by educational grants from Amgen, Celgene Corporation, Incyte, Merck, Seattle Genetics, and Takeda Oncology.

Frontline Ibrutinib Plus Rituximab in FL: Background Rituximab commonly used as frontline treatment in FL Ibrutinib Oral, irreversible BTK inhibitor affecting B-cell adhesion, migration, survival[1] Well tolerated with demonstrated therapeutic potential in R/R FL pts[2,3] Current study evaluates chemotherapy-free combination ibrutinib plus rituximab as frontline therapy[4] FL, follicular lymphoma; R/R, relapsed/refractory. 1. Wang Y, et al. Clin Pharmacol Ther. 2015;97:455-468. 2. Advani, et al. J Clin Oncol. 2013;31:88-94. 3. Bartlett, et al. ASH 2014. Abstract 800. 4. Fowler NH, et al. ASH 2015. Abstract 470.

Frontline Ibrutinib Plus Rituximab in FL: Study Design Multicenter phase II study of combination ibrutinib plus rituximab therapy in previously untreated FL pts Primary endpoint: ORR Secondary endpoints: DoR, PFS, OS, and safety Treatment naive, stage II, III, or IV FL pts with at least 1 measurable lesion ≥ 2 cm; ECOG PS ≤ 2 (N = 60) Ibrutinib 560 mg PO QD + Rituximab 375 mg/m2 IV weekly x 4 Continued until disease progression or toxicity DoR, duration of response; ECOG, Eastern Cooperative Oncology Group; FL, follicular lymphoma; ORR, overall response rate; OS, overall survival; PS, performance status. Slide credit: clinicaloptions.com Fowler NH, et al. ASH 2015. Abstract 470.

Frontline Ibrutinib Plus Rituximab in FL: Baseline Characteristics Ibrutinib + Rituximab (n = 60) Median age, yrs (range) 65 yrs or older, n (%) 58 (32-84) 18 (30) Ann Arbor stage III/IV disease, n (%) 48 (80) FL grade, n (%) Grade 1 Grade 2 Grade 3a 19 (32) 35 (58) 6 (10) FLIPI risk scores, n (%) Low risk (0 - 1) Intermediate risk (2) High risk (≥ 3) 7 (12) 23 (38) 30 (50) ECOG PS, n (%) 1   47 (78) 13 (22) Bulky disease (≥ 5 cm in at least 1 site), n (%) ≥ 7 cm ≥ 10 cm 12 (20) 2 (3) ECOG, Eastern Cooperative Oncology Group; FL, follicular lymphoma; FLIPI, Follicular Lymphoma International Prognostic Index; PS, performance status. Slide credit: clinicaloptions.com Fowler NH, et al. ASH 2015. Abstract 470.

Frontline Ibrutinib Plus Rituximab in FL: Response 100 CR PR SD 50 Improvement From Baseline SPD (Max %) -50 * N = 60 -100 *Response recorded in database is SD; unresolved query FL, follicular lymphoma; SD, stable disease; SPD, sum of the products of the greatest perpendicular diameters. ORR of 82% (49 of 60); CR of 30% Median follow-up: 13.8 mos with a median time to best response of 2.7 mos Median duration of ibrutinib treatment: 12.55 mos Slide credit: clinicaloptions.com Fowler NH, et al. ASH 2015. Abstract 470. Reproduced with permission.

Frontline Ibrutinib Plus Rituximab in FL: DoR and PFS 100 100 90 90 80 80 70 70 60 60 DoR (%) 50 PFS (%) 50 40 40 30 30 20 20 10 10 3 6 9 12 3 6 9 12 15 Mos From Initiation of Study Treatment Mos From Initiation of Study Treatment Pts at Risk, n: Pts at Risk, n: 49 45 34 9 60 56 53 41 12 1 DoR, duration of response; FL, follicular lymphoma. At a median follow-up of 13.8 mos: Median PFS not reached; 12-mo PFS rate of 86% Median OS not reached; 12-mo OS rate of 98% Slide credit: clinicaloptions.com Fowler NH, et al. ASH 2015. Abstract 470. Reproduced with permission.

Frontline Ibrutinib Plus Rituximab in FL: AEs (≥ 20%) Fatigue Diarrhea Nausea Constipation Headache Grade 1/2 Grade 3/4 Cough Maculopapular Rash Vomiting Dry Eye Pyrexia Myalgia Infusion-Related Reaction Dizziness Arthralgia 10 20 30 40 50 60 70 80 90 100 AE, adverse event; FL, follicular lymphoma. Pts (%) Grade 3/4 AEs occurred in 29 pts (48%)  1 pt: fatigue (5%), maculopapular rash (5%), neutropenia (5%), hypertension (3%), and arthritis (3%) 1 death due to Hodgkin’s lymphoma several mos after study discontinuation Slide credit: clinicaloptions.com Fowler NH, et al. ASH 2015. Abstract 470. Reproduced with permission.

Frontline Ibrutinib Plus Rituximab in FL: Additional Safety Outcomes Characteristic, n (%) Ibrutinib + Rituximab (N = 60) Serious AEs (all in 1 pt each) Any Grade 3/4 10 (17) 9 (15) Bleeding events 19 (32) Atrial fibrillation 3 (5) Secondary malignancies 4 (7) Discontinued ibrutinib due to toxicity/intercurrent illness Dose reduction of ibrutinib (560 mg to 420 mg) due to toxicity AE, adverse event; FL, follicular lymphoma. Slide credit: clinicaloptions.com Fowler NH, et al. ASH 2015. Abstract 470.

Frontline Ibrutinib Plus Rituximab in FL: Conclusions Ibrutinib addition to rituximab in treatment-naive FL pts is highly active with 82% ORR and 30% CR Combination chemotherapy-free treatment well tolerated with few grade 3/4 serious AEs AE, adverse event; FL, follicular lymphoma. Slide credit: clinicaloptions.com Fowler NH, et al. ASH 2015. Abstract 470.

Go Online for More CCO Coverage of ASH 2015! Short slideset summaries of all the key data Additional CME-certified analyses with expert faculty commentary on all the key studies in: Acute leukemias/chronic leukemias Myeloma/plasma cell disorders Lymphomas MDS and myeloproliferative neoplasms clinicaloptions.com/oncology