Phase II KEYNOTE-170/KEYNOTE-013 Update: Pembrolizumab in Relapsed/Refractory Primary Mediastinal Large B-Cell Lymphoma Integrating New Malignant Hematology Findings Into Practice: Independent Conference Coverage of ASH 2018* December 1-4, 2018; 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. Supported by educational grants from AbbVie, AstraZeneca, Celgene Corporation, Dova Pharmaceuticals, Incyte, Jazz Pharmaceuticals, Novartis Pharmaceuticals, Pharmacyclics, Seattle Genetics, and Takeda Oncology.

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KEYNOTE-170/KEYNOTE-013 Pembrolizumab in R/R PMBCL: Background R/R PMBCL associated with poor outcomes, few treatment options[1] Genetic abnormalities (eg, activation of NF-kB, JAK/STAT[2]; amplification/translocation of 9p24[3-6]) often lead to overexpression of PD-L1 and PD-L2 in PMBCL May be sensitive to PD-1 blockade Pembrolizumab: humanized IgG4 monoclonal antibody against PD-1 Phase Ib KEYNOTE-013 showed preliminary efficacy, safety of pembrolizumab in PMBCL[1] 41% ORR; 12% CR rate; median DoR not reached Phase II KEYNOTE-170 extends KEYNOTE-013 and adds biomarker analyses[1] Current analysis presents updated safety, efficacy data from KEYNOTE-013 and full KEYNOTE-170 cohort with pembrolizumab in patients with R/R PMBCL DoR, duration of response; PMBCL, primary mediastinal large B-cell lymphoma; R/R, relapsed/refractory. 1. Armand. ASH 2018. Abstr 228. 2. Savage. Blood. 2003;12:3871. 3. Green. Blood. 2010;17:3266. 4. Twa. Blood. 2014;123:2062. 5. Shi. Am J Surg Path. 2014;38:1715. 6. Chen. Clin Can Res. 2013;13:3462. Slide credit: clinicaloptions.com

KEYNOTE-170/KEYNOTE-013 Pembrolizumab in R/R PMBCL: Study Design Phase Ib KEYNOTE-013 R/R PMBCL patients ≥ 18 yrs of age without ASCT* (N = 21) Pembrolizumab 10 mg/kg Q2W (patients 1-10) or 200 mg Q3W (patients 11-21) Treatment up to 2 yrs or until unacceptable toxicity, PD, or study withdrawal Response assessment by PET/CT scan: KEYNOTE-013: Wk 12 then Q8W (10 mg/kg Q2W) or Wks 6, 12 then Q9W (200 mg Q3W), IWG 2007 criteria KEYNOTE-170: Wk 12 then Q12W, IWG 2007 criteria Phase II KEYNOTE-170 R/R PMBCL patients ≥ 18 yrs of age without ASCT,* failed ≥ 2 prior regimens (N = 53) Pembrolizumab 200 mg Q3W Treatment up to 2 yrs or until unacceptable toxicity, PD, or study withdrawal ASCT, autologous stem cell transplantation; DoR, duration of response; IWG, International Working Group; PMBCL, primary mediastinal large B-cell lymphoma; R/R, relapsed/refractory. Primary endpoints: ORR, safety (KEYNOTE-013 only) Secondary endpoints: DoR, PFS, OS, safety (KEYNOTE-170) *Failed, ineligible, or refused. Slide credit: clinicaloptions.com Armand. ASH 2018. Abstr 228. NCT02576990.

KEYNOTE-170/KEYNOTE-013 Pembrolizumab in R/R PMBCL: Patient Characteristics KEYNOTE-013 (N = 21) KEYNOTE-170 (N = 53) Median age, yrs (range) 31 (22-62) 33 (20-61) Female, n % 14 (67) 30 (57) Prior transplant, n (%) 8 (38) 14 (26) Median prior therapies, n (range) 3 (2-9) 3 (2-8) Prior radiation, n (%) 15 (71) 17 (32) Prior rituximab, n (%) 21 (100) 53 (100) PMBCL, primary mediastinal large B-cell lymphoma; R/R, relapsed/refractory. Slide credit: clinicaloptions.com Armand. ASH 2018. Abstr 228.

KEYNOTE-170/KEYNOTE-013 Pembrolizumab in R/R PMBCL: Efficacy Characteristic, n (%) KEYNOTE-013 (N = 21) KEYNOTE-170† (N = 53) KEYNOTE-170‡ OR CR PR 10 (48) 7 (33) 3 (14) 24 (45) 7 (13) 17 (32) 23 (43) 11 (21) 12 (22) SD 5 (24) 5 (9) PD 4 (19) 12 (23) 13 (25) Nonevaluable/ no assessment* 2 (10) Characteristic KEYNOTE-013 (N = 21) KEYNOTE-170 (N = 53) Median duration of follow-up, mos 29.1 12.5 Median time to response, mos 2.7§ 2.8ǁ PFS 12-mo, % Median, mos (range) 47 10.4 (3.4-NR) 38 5.5 (2.8-12.1) OS 65 31.4 (4.9-NR) 58 NR (7.3-NR) NR, not reached; PD, progressive disease; PMBCL, primary mediastinal large B-cell lymphoma; R/R, relapsed/refractory; SD, stable disease. *Insufficient data for response assessment. †Cheson criteria. ‡Lugano criteria. §2 patients converted from PR to CR after 12 mos; 4 patients maintained CR after 2 yrs on treatment (2.3+, 2.5+, 3+, 3.5+ yrs). ǁNo relapses in patients with CR reported at database lock. Slide credit: clinicaloptions.com Armand. ASH 2018. Abstr 228.

KEYNOTE-170/KEYNOTE-013 Pembrolizumab in R/R PMBCL: Safety TRAEs, n (%) KEYNOTE-013 (N = 21) KEYNOTE-170 (N = 53) Any TRAEs 15 (71) 30 (57) Grade 3/4 TRAEs Neutropenia Febrile neutropenia Fatigue Increased ALT Increased AST Hyponatremia C difficile infection Pneumonia Tumor flare VTE 5 (24) 3 (14) 1 (5)* 1 (5) 12 (23) 7 (13) 1 (2) 1 (2)* AEs, n (%) KEYNOTE-013 (N = 21) KEYNOTE-170 (N = 53) Immune-mediated AEs§ Grade 3/4 4 (19) 1 (5)† 6 (11) 1 (2)‡ *Discontinuation. †Myositis. ‡Pneumonitis. §Includes thyroid disease, colitis, myositis, pneumonitis. AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; PMBCL, primary mediastinal large B-cell lymphoma; R/R, relapsed/refractory; TRAE, treatment-related adverse event; VTE, venous thrombotic event Slide credit: clinicaloptions.com Armand. ASH 2018. Abstr 228.

KEYNOTE-170/KEYNOTE-013 Pembrolizumab in R/R PMBCL: Biomarker Analyses Patients with tissue available for biomarker analysis (n = 42) KEYNOTE-013 (n = 5), KEYNOTE-170 (n = 37) IHC membranous staining evaluated and scored by 2 independent pathologists H score by IHC reflects percentage of PD- L1+ cells and relative intensity of staining Range 0-300: 0 = no/low PD-L1+; 100 = ~ 50% cells PD-L1+ PD-L1 H score correlated with magnitude of 9p24 abnormality by FISH (n = 40; P = .038) PD-L1 H score significantly associated with PFS (P = .029) Median PFS for 0, mos: 2.0 (0.1-9.5) Median PFS for 1-99, mos: 6.3 (2.6-11.1) Preselected Cutoffs H Score 1-99 ≥ 100 PD-L1 (n = 42), n (%) 8 (20) 19 (46) 14 (34) PD-L2 (n = 41), n (%) 22 (54) 4 (10) 15 (37) PD-L1/L2* Patients, n (%) ORR, % PFS, mos‡ 5 (12) 0† 1.2 12 (29) 33 4.8 24 (59) 63 11.1 PMBCL, primary mediastinal large B-cell lymphoma; R/R, relapsed/refractory. *Both H scores = 0, at least 1 H score ≥ 100, all others 1-99. †P = .016. ‡P < .001. Slide credit: clinicaloptions.com Armand. ASH 2018. Abstr 228.

KEYNOTE-170/KEYNOTE-013 Pembrolizumab in R/R PMBCL: Conclusions Pembrolizumab results in durable responses in R/R PMBCL Median DoR not yet reached with median follow-up of 29.1 mos (KEYNOTE-013), 12.5 mos (KEYNOTE-170) 12-mo OS > 50%; durable CR in both studies Manageable toxicity profile Biomarker analyses: PD-L1 H score associated with PFS; patients lacking expression of PD-L1/L2 have reduced response to pembrolizumab, worse outcomes Data support receptor-level blockade in R/R PMBCL, per investigators Future studies needed to validate/refine Pembrolizumab received accelerated FDA approval for R/R PMBCL in June 2018 DoR, duration of response; PMBCL, primary mediastinal large B-cell lymphoma; R/R, relapsed/refractory. Slide credit: clinicaloptions.com Armand. ASH 2018. Abstr 228.

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