ALCANZA: Brentuximab Vedotin vs Methotrexate or Bexarotene in Patients With CD30-Positive Cutaneous T-Cell 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. This activity is supported by educational grants from Amgen, Celgene Corporation, Incyte, Merck, and Seattle Genetics.

ALCANZA: Background CTCL: heterogeneous group of TCLs with skin involvement[1,2] Generally chronic with quality of life affected by debilitating pruritus and skin infections MF and pcALCL most common CD30+ CTCLs Current treatments for advanced disease not associated with consistent long-term responses[3] Brentuximab vedotin: anti-CD30 mAb conjugated to monomethyl auristatin E[4] Phase II studies found clinical activity in MF and pcALCL with reasonable safety profile[4,5] Current ALCANZA trial evaluated efficacy and safety of brentuximab vedotin vs methotrexate or bexarotene in treatment-experienced pts with CD30+ CTCL[6] CTCL, cutaneous T-cell lymphoma; mAb, monoclonal antibody; MF, mycosis fungoides; pcALCL, primary cutaneous anaplastic large-cell lymphoma; TCL, T-cell lymphoma. 1. Swerdlow SH, et al. Blood. 2016;127:2375-2390. 2. Rosen ST, et al. Hematology Am Soc Hematol Educ Program. 2006:323-330. 3. Jawed SI, et al. J Am Acad Dermatol. 2014;70:223.e1-17. 4. Duvic M, et al. J Clin Oncol. 2015;33:3759-3765. 5. Kim YH, et al. J Clin Oncol. 2015;33:3750-3758. 6. Kim YH, et al. ASH 2016. Abstract 182. Slide credit: clinicaloptions.com

To maximum of sixteen 21-day cycles ALCANZA: Study Design Open-label, randomized, phase III trial[1] Primary endpoint: ORR4 by independent review Secondary endpoints Rate of CR PFS Symptom burden/pt-reported outcomes (quality-of-life measurement with Skindex- 29[2]) Pts with CD30+ MF or pcALCL*; ≥ 1 prior systemic tx (MF) or prior radiotherapy or ≥ 1 prior system tx (pcALCL); no prior progression on both methotrexate and bexarotene (N = 131) Posttreatment follow-up Brentuximab vedotin 1.8 mg/kg IV Q3W (n = 64) Methotrexate 5-50 mg PO QW or Bexarotene 300 mg/m2 PO daily To maximum of sixteen 21-day cycles MF, mycosis fungoides; ORR4, objective response rate with duration ≥ 4 months; pcALCL, primary cutaneous anaplastic large-cell lymphoma; tx, treatment *Diagnosed by central review of ≥ 1 biopsy (2 for MF), where ≥ 10% neoplastic cells/lymphoid infiltrate CD30+. 1. Kim YH, et al. ASH 2016. Abstract 182. 2. Chren MM, et al. Arch Dermatol. 1997;133:1433-1440. Slide credit: clinicaloptions.com

ALCANZA: Baseline Characteristics of Intent-to-Treat Population Brentuximab Vedotin (n = 64) Methotrexate or Bexarotene Median age, yrs (range) 62 (22-83) 59 (22-83) Male, n (%) 33 (52) 37 (58) ECOG PS 0-1, n (%) 61 (95) 62 (97) Median average baseline CD30 expression, % (range) 33 (3-100) 31 (5-100) MF,* n (%) Early (IA-IIA) Advanced (IIB-IVB)† 48 (75) 15 (31) 32 (67) 49 (77) 18 37) 30 (61) pcALCL, n (%) Skin only Extracutaneous disease 16 (25) 9 (56) 7 (44) 15 (23) 11 (73) 4 (27) Total prior therapies, median (range) Prior systemic therapies 4.0 (0-13) 2.0 (0-11) 3.5 (1-15) 2.0 (1-8) ECOG, Eastern Cooperative Oncology Group; MF, mycosis fungoides; pcALCL, primary cutaneous anaplastic large-cell lymphoma; PS, performance status. *1 pt per arm excluded because of incomplete staging data. †Stage IVB MF only in brentuximab arm (n = 7). Slide credit: clinicaloptions.com Kim YH, et al. ASH 2016. Abstract 182.

ALCANZA: ORR4, PFS, CR, and Change in Symptom Burden Endpoint Brentuximab Vedotin (n = 64) Methotrexate or Bexarotene (n = 64) Difference (95% CI) P Value ORR4, n (%) 36 (56.3) 8 (12.5) 43.8 (29.1 to 58.4) < .0001 CR, n (%) 10 (15.6) 1 (1.6) 14.1 (-4.0 to 31.5) .0046* Median PFS, mos 16.7 3.5 -- < .0001*† Mean max. reduction in Skindex-29 symptom domain, points -27.96 -8.62 -18.9 (-26.6 to -11.2) < .0001* *Adjusted P value from weighted Holm’s procedure. †HR: 0.270 (95% CI: 0.169-0.430). ECOG, Eastern Cooperative Oncology Group; MF, mycosis fungoides; ORR4, objective response rate with duration ≥ 4 months; pcALCL, primary cutaneous anaplastic large-cell lymphoma; PS, performance status. PFS significantly improved for subgroups defined by pt characteristics (baseline ECOG PS of 0, sex, age < 65 yrs, geographical region), disease characteristics (MF and pcALCL, skin involvement, baseline skin tumor score), and treatment (bexarotene and methotrexate) Slide credit: clinicaloptions.com Kim YH, et al. ASH 2016. Abstract 182.

ALCANZA: ORR4 by Disease Type and Stage Pt Group Brentuximab Vedotin Bexarotene or Methotrexate Total, n (%) (N = 64) ORR4, % ORR, % CR, % Total, n (%) (N = 64) ITT 64 (100) 56 67 16 13 20 2 MF 48 (75) 50 65 10 49 (77) Stage IA-IIA II IIIA-IIIB IVA IVB 15 (31) 19 (40) 4 (8) 2 (4) 7 (15) 40 63 100 29 53 68 75 57 7 18 (37) 19 (39) 9 (18) 22 5 NA 28 pcALCL 16 (25) 31 15 (23) 33 Disease involvement Skin only Extracutaneous disease 9 (56) 7 (44) 89 44 14 11 (73) 4 (27) 27 45 9 ITT, intent to treat; NA, not applicable; ORR4, objective response rate with duration ≥ 4 months; pcALCL, primary cutaneous anaplastic large-cell lymphoma. Slide credit: clinicaloptions.com Kim YH, et al. ASH 2016. Abstract 182.

ALCANZA: ORR4 by Key Demographic Subgroups Pt Group, n/n (%) Brentuximab Vedotin Methotrexate or Bexarotene Difference (95% CI) Overall 36/64 (56.3) 8/64 (12.5) 43.8 (29.1 to 58.4) Baseline ECOG PS ≥ 1 29/43 (67.4) 7/21 (33.3) 6/46 (13.0) 2/18 (11.1) 54.4 (37.3 to 71.5) 22.2 (-10.2 to 51.2) Sex Male Female 19/33 (57.6) 17/31 (54.8) 5/37 (13.5) 3/27 (11.1) 44.1 (21.3 to 63.3) 43.7 (18.5 to 64.7) Age < 65 yrs ≥ 65 yrs 20/36 (55.6) 16/28 (57.1) 2/40 (5.0) 6/24 (25.0) 50.6 (29.3 to 68.3) 32.1 (6.9 to 57.4) Region Europe Non-Europe 23/37 (62.2) 13/27 (48.1) 3/35 (8.6) 5/29 (17.2) 53.6 (32.7 to 71.3) 30.9 (4.2 to 53.5) ECOG, Eastern Cooperative Oncology Group; ORR4, objective response rate with duration ≥ 4 months; PS, performance status. Slide credit: clinicaloptions.com Kim YH, et al. ASH 2016. Abstract 182.

ALCANZA: ORR4 by Key Disease and Treatment Subgroups Pt Group, n/n (%) Brentuximab Vedotin Methotrexate or Bexarotene Difference (95% CI) Overall 36/64 (56.3) 8/64 (12.5) 43.8 (29.1 to 58.4) Disease MF pcALCL 24/48 (50.0) 12/16 (75.0) 5/49 (10.2) 3/15 (20.0) 39.8 (19.9 to 56.2) 55.0 (19.7 to 80.4) Treatment Bexarotene Methotrexate 6/38 (15.8) 2/26 (7.7) 40.5 (23.7 to 57.3) 48.6 (26.7 to 67.7) Skin involvement Skin only Skin and extracutaneous 21/31 (67.7) 15/33 (45.5) 5/30 (16.7) 3/34 (8.8) 51.1 (27.3 to 71.0) 36.6 (12.3 to 56.3) Baseline skin tumor score > 0 26/41 (63.4) 10/23 (43.5) 2/38 (5.3) 6/26 (23.1) 58.2 (38.1 to 74.1) 20.4 (-5.5 to 46.3) MF, mycosis fungoides; ORR4, objective response rate with duration ≥ 4 months; pcALCL, primary cutaneous anaplastic large-cell lymphoma. Slide credit: clinicaloptions.com Kim YH, et al. ASH 2016. Abstract 182.

ALCANZA: Safety and Tolerability 4 deaths in brentuximab arm during study period 3 deemed unrelated to study drug (1 each: lymphoma progression, pulmonary embolism, sepsis) 1 pt with T3bN0M1 pcALCL died due to multiple organ dysfunction related to tumor necrosis at visceral disease sites attributed to brentuximab vedotin AE, n (%) Brentuximab Vedotin (n = 66) Methotrexate or Bexarotene (n = 62) Any AE 63 (95) 56 (90) Grade ≥ 3 AE 27 (41) 29 (47) Serious AE 19 (29) 18 (29) AE-related drug discontinuation* 16 (24) 5 (8) Death ≤ 30 days of last study drug dose 4 (6) Death ≤ median 23 mos of follow-up 14 (23) AE, adverse event; pcALCL, primary cutaneous anaplastic large-cell lymphoma. *Brentuximab arm: peripheral neuropathy, n = 9; skin hypersensitivity, n = 3; E coli infection, n = 1; impetigo, n = 1; pulmonary embolism, n = 1; urticaria, n = 1; vertigo, n = 1. Methotrexate or bexarotene arm: maculopapular rash, n = 1; asthenia, n = 1; hematuria, n = 1; hypernatremia, n = 1; neutropenia, n = 1; periorbital infection, n = 1; somnolence, n = 1. Slide credit: clinicaloptions.com Kim YH, et al. ASH 2016. Abstract 182.

ALCANZA: Common Treatment-Emergent AEs Treatment-Emergent AEs Reported in ≥ 15% of Pts,* % Brentuximab Vedotin Methotrexate or Bexarotene Peripheral neuropathy 67 6 Nausea 36 13 Diarrhea 29 Fatigue 27 Vomiting 17 5 Alopecia 15 3 Pruritus Pyrexia 18 Decreased appetite Hypertriglyceridemia 2 18† AE, adverse event. *Drug exposure: median 12 cycles (36 wks) of brentuximab vedotin vs 17 wks of bexarotene or 9 wks of methotrexate. †30% of pts receiving bexarotene experienced elevated triglycerides. Slide credit: clinicaloptions.com Kim YH, et al. ASH 2016. Abstract 182.

ALCANZA: Conclusions Brentuximab vedotin showed significantly longer ORR4 vs methotrexate/bexarotene in pts with CD30+ MF and pcALCL (56.3% vs 12.5%, respectively; P < .0001) Significantly higher rates observed with brentuximab vedotin vs methotrexate/bexarotene for ORR, CR, PFS, and life quality symptom burden Brentuximab vedotin safety profile consistent with previous reports Investigators suggest that brentuximab vedotin may be valuable in managing pts with CD30+ CTCL requiring systemic treatment CTCL, cutaneous T-cell lymphoma; MF, mycosis fungoides; ORR4, objective response rate with duration ≥ 4 months; pcALCL, primary cutaneous anaplastic large-cell lymphoma. Slide credit: clinicaloptions.com Kim YH, et al. ASH 2016. Abstract 182.

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