KEYNOTE-013: Pembrolizumab in Classical Hodgkin’s Lymphoma After Brentuximab Vedotin Failure 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.

KEYNOTE-013: Background Classical Hodgkin’s lymphoma pathologically distinguished by failed immune response Often with 9p24.1 amplification and PD-L1/-L2 overexpression Potentially vulnerable to PD-1 blockade Pembrolizumab: humanized anti–PD-1 monoclonal antibody Approved in NSCLC[1] and melanoma[2] PD-L1 expression on tumor and immune-associated cells potentially predictive of pembrolizumab activity Current study reports data from the classical Hodgkin’s lymphoma expansion cohort of the KEYNOTE-013 phase I study of pembrolizumab in hematologic malignancies[3] NSCLC, non-small-cell lung cancer. 1. Garon EB, et al. N Eng J Med. 2015;372:2018-2028. 2. Robert C, et al. Lancet. 2014;384:1109-1117. 3. Armand P, et al. ASH 2015. Abstract 584. Slide credit: clinicaloptions.com

KEYNOTE-013: Study Design Multicenter, multicohort phase Ib trial of blood cancers cHL, MDS, MM, NHL (DLBCL, FL, PMBL) Primary endpoints: safety, CR Secondary endpoints: OR, DoR, PFS, OS, biomarkers cHL pts with ECOG PS 0/1, previous brentuximab vedotin failure, ASCT failure or ineligibility, adequate organ function, no autoimmune or interstitial lung disease (N = 31) CR Discontinuation permitted ≥ 24 wks Pembrolizumab 10 mg/kg IV Q2W Tx to 24 mos or PD or intolerable toxicity PR or SD PD Discontinuation ASCT, autologous stem cell transplantation; cHL, classical Hodgkin’s lymphoma; DLBCL, diffuse large B-cell lymphoma; DoR, duration of response; ECOG PS, Eastern Cooperative Oncology Group performance status; FL, follicular lymphoma; MDS, myelodysplastic syndrome; MM, multiple myeloma; NHL, non-Hodgkin’s lymphomas; PD, progressive disease; PMBL, primary mediastinal large B-cell lymphoma; SD, stable disease; Tx, treatment. ClinicalTrials.gov. NCT01953692. Armand P, et al. ASH 2015. Abstract 584. Slide credit: clinicaloptions.com

KEYNOTE-013 cHL Cohort: Baseline Characteristics Pembrolizumab (N = 31) Median age, yrs (range) 32 (20-67) Pathology, n (%) Nodular sclerosis Mixed cellularity 30 (97) 1 (3) Previous radiation therapy, n (%) 10 (32) Previous systemic therapy, n (%) 2-4 ≥ 5 14 (45) 17 (55) Previous brentuximab vedotin failure, n (%) 31 (100) ASCT, n (%) Failure Ineligibility/refusal 22 (71) 9 (29) ASCT, autologous stem cell transplantation; cHL, classical Hodgkin’s lymphoma. Slide credit: clinicaloptions.com Armand P, et al. ASH 2015. Abstract 584.

Transplant Ineligibility/Refusal KEYNOTE-013: Efficacy 90% of pts had decreases in target lesion burden Of 20 pts with CR/PR: Still on treatment: n = 7 Discontinued treatment CR: n = 1 PR switched tx: n = 1 AE: n = 1 Allogeneic SCT: n = 3 PD: n = 7 Endpoint, % Total (N = 31) Transplant Failure (n = 22) Transplant Ineligibility/Refusal (n = 9) ORR CR PR 65 16 48 73 14 59 44 22 SD 23 18 33 PD 13 9 DoR ≥ 24 wks Responses occurring by 12 wks 71 80 PFS at 24 wks 69 AE, adverse event; DoR, duration of response; PD, progressive disease; SCT, stem cell transplantation; SD, stable disease; tx, treatment. Slide credit: clinicaloptions.com Armand P, et al. ASH 2015. Abstract 584.

KEYNOTE-013: Safety No grade 4 treatment- related AEs No treatment-related deaths AE-related discontinuations Grade 2 pneumonitis Grade 3 nephrotic syndrome Treatment-Related AEs, % Pembrolizumab (N = 31) Any grade in ≥ 3 pts Gastrointestinal Diarrhea Nausea Endocrine Hypothyroidism Metabolism/nutrition Respiratory Pneumonitis Skin Musculoskeletal 68 36 16 13 19 10 Any grade 3 Increased ALT/AST Colitis Nephrotic syndrome Back pain Joint swelling Axillary pain 3 AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase. Slide credit: clinicaloptions.com Armand P, et al. ASH 2015. Abstract 584.

KEYNOTE-013: Biomarker Assessment Immunohistochemistry 15/16 (94%) PD-L1+ tumor cells 9/10 (90%) PD-L2+ Peripheral blood immunophenotyping Baseline and cycle 7 PB samples (n = 9) evaluable for flow cytometry, all with significant cellular subset changes from baseline Total T cells: P = .008 CD4+ T cells: P = .039 CD8+ T cells: P = .008 NK cells: P = .039 Nanostring analysis Baseline and cycle 7 RNA samples (n = 19) evaluable for signature[1] sequencing in a 794 immune gene platform, all significantly upregulated from baseline after pembrolizumab Expanded immune score: P = .004 TCR score: P = .005 IFN-γ score: P = .017 No single baseline signature or gene predicted response IFN, interferon; NK, natural killer; PB, peripheral blood; TCR, T-cell receptor. 1. Ribas A, et al. ASCO 2015. Abstract 3001. 2. Armand P, et al. ASH 2015. Abstract 584. Slide credit: clinicaloptions.com

KEYNOTE-013: Conclusions Preliminary data in this small classical Hodgkin's lymphoma cohort suggest pembrolizumab treatment after brentuximab vedotin failure is safe and active with durable responses ORR: 65% ORR in transplant failure subgroup: 73% ORR in transplant ineligibility subgroup: 44% DoR ≥ 24 wks: 71% Pembrolizumab treatment increases circulating numbers of T and NK cells, upregulates TCR/IFN-γ signaling Study investigators conclude that further investigation of pembrolizumab for classical Hodgkin's lymphoma is warranted DOR, duration of response; IFN, interferon; NK, natural killer; TCR, T-cell receptor. Slide credit: clinicaloptions.com Armand P, et al. ASH 2015. Abstract 584.

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