PYRAMID: Frontline R-CHOP ± Bortezomib in Non-GCB DLBCL 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. DLBCL, diffuse large B-cell lymphoma; GCB, germinal center B cell-like; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone. This program is supported by educational grants from Amgen, Celgene Corporation, Incyte, Merck, Seattle Genetics, and Takeda Oncology

PYRAMID: Background In retrospective analyses, non-GCB DLBCL pts display less favorable outcomes with R-CHOP chemotherapy than those with GCB DLBCL[1,2] Non-GCB DLBCL dependent on NF-κB pathways[3-6] Bortezomib: proteasome inhibitor that inhibits NF-κB activation Phase I/II trial showed non-GCB DLBCL pts had similar outcomes to GCB DLBCL when bortezomib was added to R-CHOP[7] Current randomized phase II study in non-GCB DLBCL pts investigates efficacy and safety of frontline R-CHOP vs R-CHOP + bortezomib[8] DLBCL, diffuse large B-cell lymphoma; NF-κB, nuclear factor kappa B; GCB, germinal center B cell; non-GCB, non-germinal center B cell-like; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone. 1. Fu K, et al. J Clin Oncol. 2008;26:4587-4594. 2. Meyer PN, et al. J Clin Oncol. 2011;29:200-207. 3. Davis RE, et al. J Exp Med. 2001;194:1861-1874. 4. Ngo VN, et al. Nature. 2006;441;106-110. 5. Compagno M, et al. Nature. 2009;459:717-721. 6. Bohers E, et al. Leuk Lymphoma. 2015;56:1213-1222. 7. Ruan J, et al. J Clin Oncol. 2011;29:690-697. 8. Leonard JP, et al. ASH 2015. Abstract 811. Slide credit: clinicaloptions.com

Bortezomib 1.3 mg/m2 IV Days 1, 4 + PYRAMID: Study Design Prospective randomized, open-label phase II study Primary endpoint: PFS Secondary endpoints: OS, ORR, CR, toxicity Evaluated response, disease progression by CT and FDG-PET at end of cycles 2 and 6 Follow-up scans every 3 mos until disease progression Treatment-naive, centrally confirmed non-GCB DLBCL by Hans IHC method with measurable disease, ECOG PS 0-2 (N = 183) Bortezomib 1.3 mg/m2 IV Days 1, 4 + R-CHOP* 21 days x 6 cycles (n = 92) R-CHOP* 21 days x 6 cycles (n = 91) *Rituximab 375 mg/m², cyclophosphamide 750 mg/m², doxorubicin 50 mg/m², vincristine 1.4 mg/m² (max 2 mg), all IV Day 1; prednisone 100 mg, PO Days 1-5. CR, complete response; CT, computed tomography; DLBCL, diffuse large B-cell lymphoma; ECOG, Eastern Cooperative Oncology Group; FDG-PET, fluorodeoxyglucose positron emiision tomography; non-GCB, non-germinal center B cell-like; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PS, performance status; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone. Leonard JP, et al. ASH 2015. Abstract 811. Hans CP, et al. Blood 2004;103:275-282. Slide credit: clinicaloptions.com

PYRAMID: Baseline Characteristics (mITT*) VR-CHOP (n = 92) R-CHOP (n = 91) Median age, yrs (range) Age > 65 yrs, % 65 (20-83) 46 62 (24-85) 44 Male, % 49 58 IPI risk group, % Low Low/intermediate High/intermediate High 28 27 34 11 24 25 38 12 ECOG PS, % 1 2 59 40 LDH > ULN, % 54 55 ECOG, Eastern Cooperative Oncology Group; IPI, International Prognostic Index; LDH, lactate dehydrogenase; mITT, modified intent to treat; PS, performance status; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; ULN, upper limit of normal; V, bortezomib. *Central laboratory confirmed non-GCB DLBCL who received ≥ 1 dose of chemotherapy Slide credit: clinicaloptions.com Leonard JP, et al. ASH 2015. Abstract 811.

PYRAMID: Drug Exposure and Response 85% VR-CHOP and 86% R-CHOP pts completed ≥ 6 treatment cycles Median relative dose intensity: > 98% in both arms for all drugs Median duration of follow-up: 34 mos in both arms Characteristic, % VR-CHOP (n = 90) R-CHOP (n = 86) CR 56 49 CR/PR 96 98 Negative FDG-PET at EOT visit 59 53 EOT, end of treatment; FDG-PET, fluorodeoxyglucose positron emission tomography; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; V, bortezomib. Slide credit: clinicaloptions.com Leonard JP, et al. ASH 2015. Abstract 811.

PYRAMID: Survival Outcomes VR-CHOP (n = 92) R-CHOP (n = 91) HR (95% CI) P Value 2-yr PFS rate 82 78 0.73 (0.43-1.24) .611 2-yr PFS rate by IPI risk group Low and Low/Intermediate 89 (n = 51) 90 (n = 45) 0.85 (0.35-2.10) .958 Intermediate/High and High 72 (n = 41) 65 (n = 46) 0.67 (0.34-1.29) .606 2-yr OS rate 93 88 0.75 (0.38-1.45) .763 IPI, International Prognostic Index; PFS, progression-free survival; OS, overall survival; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; V, bortezomib. Slide credit: clinicaloptions.com Leonard JP, et al. ASH 2015. Abstract 811.

PYRAMID: Safety Any grade AE in ≥ 25% pts in either arm Hematologic: neutropenia, thrombocytopenia,‡ anemia Non-hematologic: fatigue,§ nausea,§ peripheral neuropathy,‡ alopecia,§ constipation, insomnia, diarrhea, peripheral edema,‡ decreased appetite Grade ≥ 3 AEs in ≥ 10% pts in either arm Hematologic: neutropenia, thrombocytopenia,‡ anemia,‡ decreased WBC, leukopenia,§ decreased platelet count, febrile neutropenia Nonhematologic: hypokalemia Event, % VR-CHOP (n = 101) R-CHOP (n = 100) Any AE Grade ≥ 3 99 79 100 71 Drug-related AE 95 68 88 55 Serious AE 34 31 AEs leading to discontinuation 6 4 Death < 1* 1† AE, adverse event; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; V, bortezomib; WBC, white blood cell count. *Acute cardiopulmonary arrest (n = 1). †Septic shock (n = 1). ‡More common in VR-CHOP. §More common in R-CHOP. Slide credit: clinicaloptions.com Leonard JP, et al. ASH 2015. Abstract 811.

PYRAMID: Conclusions Similar survival outcomes with VR-CHOP and R- CHOP in treatment-naive pts with non-GCB DLBCL Non-GCB subtype defined by Hans IHC method Investigators suggested that the pt population of the PYRAMID trial may differ from those of previous reports Further subpopulation and gene expression analysis planned by investigators DLBCL, diffuse large B-cell lymphoma; IHC, immunohistochemistry; GCB, germinal center B cell-like; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; V, bortezomib. Slide credit: clinicaloptions.com Leonard JP, et al. ASH 2015. Abstract 811.

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