REMARC: Lenalidomide vs Placebo as Maintenance Therapy in Patients With DLBCL Following R-CHOP Induction 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. DLBCL, diffuse large B-cell lymphoma; R-CHOP, rituximab plus cyclophosphamide/doxorubicin/vincristine/prednisone. This activity is supported by educational grants from Amgen, Celgene Corporation, Incyte, Merck, and Seattle Genetics.

REMARC: Lenalidomide Maintenance Therapy Following First-line R-CHOP for DLBCL Rituximab plus CHOP is preferred therapy for DLBCL LNH-98.5 trial observed 10-yr PFS of 36.5% with R-CHOP vs 20.1% with CHOP alone in 399 elderly pts with DLBCL (P < .0001)[1] In this trial, most pts (~ 40% with R-CHOP and ~ 60% with CHOP) relapsed within 2 yrs[1] Studies evaluating addition of various agents to induction and maintenance R-CHOP have not reported evidence of benefit in DLBCL MAIN study of bevacizumab induction (RA-CHOP) found no benefit[2] PRELUDE[3] and PILLAR-2[4] studies of maintenance R-CHOP plus enzastaurin or everolimus found no benefit in 4-yr and 2-yr DFS, respectively Current study assessed safety, efficacy of lenalidomide maintenance therapy following R- CHOP in elderly pts with DLBCL[5] DLBCL, diffuse large B-cell lymphoma; R-CHOP, rituximab plus cyclophosphamide/doxorubicin/vincristine/prednisone. 1. Coiffier B, et al. Blood. 2010;116:2040-2045. 2. Seymour JF, et al. Haematologica. 2014;99:1343-1349. 3. Crump M, et al. J Clin Oncol. 2016;34:2484-2492. 4. Witzig TE, et al. ASCO 2016. Abstract 7506. 5. Thieblemont C, et al. ASH 2016. Abstract 471. Slide credit: clinicaloptions.com

maintenance treatment REMARC: Study Design Multicenter, randomized, double-blind, placebo-controlled phase III study Primary endpoint: PFS, defined as first documented relapse or progression assessed by blinded independent review, or all-cause death Secondary endpoints: safety, OS, conversion from PR to CR, efficacy by R-CHOP response *25 mg/day for 21/28 days. Pts with CrCl < 30 mL/min received 10 mg lenalidomide. Pts aged 60-80 yrs with untreated DLBCL (histologically confirmed CD20+ per WHO 2008 criteria), FL3b, or de novo transformed follicular or indolent lymphoma, no major comorbidities Up to 24-mo maintenance treatment duration Lenalidomide* (n = 323) Placebo* (n = 327) R-CHOP 6-8 cycles Stratified by CR vs PR status after R-CHOP induction CR/PR CrCl, creatinine clearance; DLBCL, diffuse large B-cell lymphoma; R-CHOP, rituximab plus cyclophosphamide/doxorubicin/vincristine/prednisone; WHO, World Health Organization. Slide credit: clinicaloptions.com Thieblemont C, et al. ASH 2016. Abstract 471.

REMARC: Pt Characteristics Lenalidomide (n = 323) Placebo (n = 327) Median age, yrs 70 yrs or older, n (%) 69 154 (48) 68 145 (44) Male, n (%) 183 (57) 180 (55) Response following R-CHOP, n (%) CR PR ORR 251 (78) 69 (21) 320 (99) 244 (75) 83 (25) 327 (100) R-CHOP, rituximab plus cyclophosphamide/doxorubicin/vincristine/prednisone. Slide credit: clinicaloptions.com Thieblemont C, et al. ASH 2016. Abstract 471.

REMARC: Disease Characteristics Histologic Diagnosis Classification, n (%) Lenalidomide (n = 290) Placebo DLBCL NOS 225 (78) 233 (80) FL grade 3b 2 (1) 3 (1) De novo transformed 31 (11) 16 (6) Other* 32 (11) 38 (13) *Includes B-cell lymphoma with features intermediate between DLBCL and Burkitt lymphoma or HD. GCB/ABC Profile,* n (%) Lenalidomide (n = 151) Placebo (n = 167) ABC 63 (42) 58 (35) GCB 59 (39) 79 (47) Unclassified 24 (16) 25 (15) N/A 5 (3) ABC, activated B-cell-like; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; GCB, germinal center B-cell-like; HD, Hodgkin lymphoma; N/A, not available; NOS, not otherwise specified. *Profiled with commercial technology platform in DLBCL NOS only. Slide credit: clinicaloptions.com Thieblemont C, et al. ASH 2016. Abstract 471.

REMARC: Progression-Free Survival Median PFS: NR in lenalidomide arm vs 58.8 mos in placebo arm (HR: 0.708; 95% CI: 0.537-0.933; P = .0135) with a median follow-up of 40 mos Lenalidomide significantly extended PFS in older pts, pts with CR response to R- CHOP, and positive PET scan at randomization Pts aged 70 yrs or older: HR: 0.653; 95% CI: 0.439-0.970 CR response to R-CHOP: HR: 0.722; 95% CI: 0.521-0.999 Positive PET at randomization: HR: 0.592; 95% CI: 0.365-0.959 Lenalidomide trended toward prolonging PFS in GCB-positive DLBCL (P = .0742) but had no significant effect on PFS in ABC positive or unclassified disease No significant differences observed between lenalidomide vs placebo in subgroups by country, sex, or age-adjusted international prognostic index ABC, activated B-cell-like; DLBCL, diffuse large B-cell lymphoma; GCB, germinal center B-cell-like; NR, not reached; R-CHOP, rituximab plus cyclophosphamide/doxorubicin/vincristine/prednisone. Slide credit: clinicaloptions.com Thieblemont C, et al. ASH 2016. Abstract 471.

REMARC: OS and Conversion From PR to CR No significant differences in OS for lenalidomide vs placebo (HR: 1.218; 95% CI: 0.861-1.721; P = .2640) with a median follow-up of 52 mos Similar rates of PR-to-CR conversion during maintenance period among pts with PR response to R-CHOP CR achieved by 23 of 69 (33%) pts receiving lenalidomide vs 24 of 83 (29%) pts receiving placebo (P = .557) Median time to conversion: 5.9 (range: 3.9-26.5) vs 5.6 mos (range: 3.2- 24.8), respectively R-CHOP, rituximab plus cyclophosphamide/doxorubicin/vincristine/prednisone. Slide credit: clinicaloptions.com Thieblemont C, et al. ASH 2016. Abstract 471.

REMARC: Treatment Exposure and Safety Median average dose was 19.8 mg (range: 5.2-25.0) of lenalidomide vs 25.0 mg (range: 5.1-25.0) of placebo D/c due to toxicity occurred in 36% of lenalidomide pts vs 16% of placebo pts ≥ 1 dose reduction due to toxicity in 72% vs 42%, respectively 2 pts receiving placebo died due to toxicity Secondary primary malignancies in 10% of lenalidomide pts vs 13% of placebo pts Hematologic malignancy in 2% per arm Solid tumor (excluding nonmelanoma skin cancer) in 4% vs 6%, respectively Grade 3/4 TEAEs, % Lenalidomide (n = 322) Placebo (n = 323) Neutropenia 56 22 Infection 8 6 Thrombocytopenia 3 1 Venous thromboembolism 0.3 Cutaneous reaction Diarrhea and constipation 2 Hepatic disorder Peripheral neuropathy Cardiac disorders 5 D/c, discontinuation; TEAEs, treatment-emergent adverse events. Slide credit: clinicaloptions.com Thieblemont C, et al. ASH 2016. Abstract 471.

REMARC: Conclusions Lenalidomide significantly prolonged median PFS vs placebo as maintenance therapy after R-CHOP in DLBCL (NR vs 58.8 mos, respectively; P = .0135) No significant effect on OS with a median follow-up of 52 mos Greater rate of grade 3/4 neutropenia and d/c for toxicity observed with lenalidomide vs placebo Investigators concluded that in elderly pts with DLBCL who received first-line R-CHOP, use of lenalidomide maintenance therapy provides clinically meaningful PFS improvement d/c, discontinuation; DLBCL, diffuse large B-cell lymphoma; NR, not reached; R-CHOP, rituximab plus cyclophosphamide/doxorubicin/vincristine/prednisone. Slide credit: clinicaloptions.com Thieblemont C, et al. ASH 2016. Abstract 471.

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