Nivolumab Anas Younes, M.D. Chief, Lymphoma Service Memorial - - PowerPoint PPT Presentation
New Drugs In Hematology Hodgkin Lymphoma Nivolumab Anas Younes, M.D. Chief, Lymphoma Service Memorial Sloan-Kettering Cancer Center Monday, May 9, 2016 2:10-2:25 p.m immunotherapy modalities Bispecific CAR T Cells Immune Checkpoint Naked
New Drugs In Hematology Monday, May 9, 2016 2:10-2:25 p.m
Anas Younes, M.D. Chief, Lymphoma Service Memorial Sloan-Kettering Cancer Center
Batlevi, C. L. et al. (2015) Novel immunotherapies in lymphoid malignancies
CAR T Cells Bispecific Immune Checkpoint Naked antibodies And ADCs
TCR
CTLA-4 TIM-3 LAG-3 BTLA VISTA OX40 CD137 (4-1BB) CD27 CD28 HVEM Inhibitory Receptors Activating Receptors Blocking Antibodies Agonistic Antibodies
Yamamoto R et al. Blood 2008;111:3220-3224
Expression of PDL1/PDL2 in HL cell lines LMP1 and LMP2A enhanced the transcriptional activity of PDL1/PDL2 LMP1+ PDL1 PDL2 LMP1- PDL1/PDL2 Expression in EBV+ and EBV- cHL
Green M R et al. Blood 2010;116:3268-3277
PD-1L Copy number PD-1L Copy number
9p24.1 amplification EBV Infection
Hodgkin and Reed Sternberg (HRS) Cells
Younes A, ICML, Lugano 2015
9p24.1 Gene amplification EBV Infection
JAK2 PDL1
Hodgkin and Reed Sternberg (HRS) Cells
CD30
PD1 PD-L1 PD-L2
MHC I/II TCR
T cell
Adapted from Stathis & Younes: Ann Oncology 2015
T-Cells T-Cells
PD1
Ansell SM et al. N Engl J Med 2015;372:311-319.
20 40 60 80 100 Change From Baseline, %
Complete remission Partial remission Stable disease Progressive disease
Moskowitz C, et al ASH 2014
Stephen M. Ansell, MD, PhD,1 Philippe Armand, MD, PhD,2 John Timmerman, MD,3 Margaret A. Shipp, MD,2 M. Brigid Bradley Garelick, MD,4 Lili Zhu, MS,5 Alexander M. Lesokhin, MD6
1Mayo Clinic, Rochester, MN, USA; 2Dana-Farber Cancer Institute, Boston, MA, USA; 3Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA; 4Bristol-Myers Squibb, Wallingford, CT, USA; 5Bristol-Myers Squibb, Princeton, NJ, USA; 6Memorial Sloan Kettering Cancer Center, New York, NY, USA
ASH 2015
Age, median (range) 35 (20–54) Histology, n Nodular sclerosing 22 Mixed cellularity 1 Prior autotransplant, n (%) 18 (78) Prior brentuximab vedotin, n (%) 18 (78) Number of prior therapies, median (range) 5 (2–15)
11
Adverse Event cHL (n = 23) Any Grade, n (%) Resolved, %
Gastrointestinal 4 (17) Diarrhea 3 (13) 100 Colitis 1 (4) 100 Hepatic 2 (9) ALT increased 1 (4) 100 AST increased 1 (4) 100 Blood alkaline phosphatase increased 1 (4) Pulmonary 1 (4) Pneumonitis 1 (4) 100 Skin 5 (22) Rash 4 (17) 100 Pruritus 3 (13) 100 Pruritic rash 1 (4) 100 Skin hypopigmentation 1 (4) Endocrine disorders Hyperthyroidism 4 (17) 75 Hypersensitivity/infusion reaction 2 (9) Bronchospasm 1 (4) 100 Infusion-related reaction 1 (4) 100
Patients (n = 23) Percent Change in Tumor Burden CR (22%) PR (65%) SD (13%) 25 –25 –50 –75 –100
On treatment, ongoing response Off treatment without disease progressiona Progressive disease, following response or stable disease
aMaximum clinical benefit, transplant, or toxicity
Ansell et al , ASH 2015
Nivolumab in Patients With Relapsed or Refractory Classical Hodgkin Lymphoma
–100 –50 50 100
Time Since First Treatment Date, Weeks Percent Change From Baseline in Target Lesions/Tumor Burden
6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108 114 On treatment, ongoing response Off treatment without progression Progressive disease, following response or stable disease
First occurrence of new lesion
Ansell et al ASH 2015
Nivolumab in Patients With Relapsed or Refractory Classical Hodgkin Lymphoma
Duration of Response
Median DOR (95% CI): NA (15.5–NA) Time, Months
Probability of Patients in Response 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 3 6 9 12 15 21 24 18
PFS
Ansell et al ASH 2015
Anas Younes, MD1, Armando Santoro, MD2, Margaret Shipp, MD3, Pier Luigi Zinzani, MD4, John M Timmerman, MD5, Stephen Ansell, MD6, Philippe Armand, MD3, Michelle Fanale, MD7, Voravit Ratanatharathorn, MD8, John Kuruvilla, MD9, Jonathon Cohen, MD10, Graham Collins, MD11, Kerry J Savage, MD12, Marek Trneny, MD13, Kazunobu Kato, MD14, Benedetto Farsaci, MD14, Susan M Parker, PhD14, Scott Rodig, MD15, Margaretha GM Roemer, MS3, Azra H Ligon, PhD15, Andreas Engert, MD16
April 14, 2016: FDA Grants Nivolumab Priority Review in Hodgkin Lymphoma
Drug Dose/Sche dule N % ORR % CR ORR in BV treated HL 1st Author Pembrolizumab (humanized IgG4) 10 mg/kg IV Q 2wks 29 66% 21% 66% (n=19) Moskowitz C Nivolumab (Fully human IgG4) 3 mg/kg IV Q 2wks 23 87% 17% 70% (n=16) Ansel SM
Drug Antibody 1st Author (s) Hodgkin Follicular DLBCL T-cell Nivolumab Fully human IgG4 Ansell Lesokin Timmerman 87% (20/23) 40% (4/10) 36% (4/11) 17% (4/23) Pembrolizumab Humanized IgG4 Moskowitz Armand 65% (20/31) Pidilizumab Humanized IgG1 Armand 51% (18/38)
Overall Response Rate (%)
HL B-NHL T-NHL Melanom a NSCL C SCL C TNB C Ovary RC C High PD- L1 Low PD- L1
Urothelia l
MMR deficient MMR proficient
Colorecta l
Gastric Esophageal HNSC C HC C
87 66 28 17 120 556 655 35 129 117 13 1 29 2 394 83 14 4 40 16 27 21 20 26 34 168 39 28 46 38 33 10 18 39 39 23 99 39
No of patients
10 20 30 40 50 60 70 80 90 100 MPDL3280A Pembrolizumab Nivolumab
Batlevi,..and Younes: Nat Rev Clinic Oncol 2016
25 50 75 100
% Response rate
Updated from Betlevi and Younes, Hematology Am Soc Hematol Educ Program. 2013 Smith, K et al : Hodgkin Lymphoma, Hoffan Textbook of Hematology 2015 (In Press)