1. 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.

2. 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: Robert C, et al. Lancet. 2014;384: Armand P, et al. ASH Abstract 584.
Slide credit: clinicaloptions.com

3. 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. NCT
Armand P, et al. ASH Abstract 584.
Slide credit: clinicaloptions.com

4. 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 Abstract 584.

5. 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 Abstract 584.

6. 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 Abstract 584.

7. 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 Abstract 3001.
2. Armand P, et al. ASH Abstract 584.
Slide credit: clinicaloptions.com

8. 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 Abstract 584.

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