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 CAR T Cells Bispecific Immune Checkpoint Naked antibodies And ADCs Batlevi, C. L. et al. (2015) Novel immunotherapies in lymphoid malignancies Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2015.187
Therapeutic Activation of Autologous T Cells Targeting Immune Checkpoints Activating Receptors OX40 CD137 (4-1BB) CD27 T cell Inhibitory Receptors VISTA TIM-3 CTLA-4 PD1 Agonistic Antibodies CD28 HVEM LAG-3 BTLA Blocking Antibodies TCR
Expression and gene regulation of PDL-1 (CD273) and PDL-2 (CD274) in Hodgkin Lymphoma Expression of PDL1/PDL2 in HL cell lines LMP1 and LMP2A enhanced the transcriptional activity of PDL1/PDL2 LMP1+ LMP1- PDL1 PDL2 PDL1/PDL2 Expression in EBV+ and EBV- chl Yamamoto R et al. Blood 2008;111:3220-3224
9p24.1 amplification and PD-1L cell-surface expression in HL and MLBCL cell lines. PD-1L Copy number PD-1L Copy number Green M R et al. Blood 2010;116:3268-3277
HRS Cells Express High Levels of PDL-1 Hodgkin and Reed Sternberg (HRS) Cells EBV Infection 9p24.1 amplification JAK2 PDL1 CD30 Younes A, ICML, Lugano 2015
HRS Cells Express High Levels of PDL-1 T cell Hodgkin and Reed Sternberg (HRS) Cells EBV Infection 9p24.1 Gene amplification TCR PD1 JAK2 MHC I/II PD-L1 PD-L2 PDL1 CD30 PD1 HRS T-Cells T-Cells Adapted from Stathis & Younes: Ann Oncology 2015
Nivolumab in Relapsed Hodgkin Lymphoma Ansell SM et al. N Engl J Med 2015;372:311-319.
Change From Baseline, % Pembrolizumab (MK-3475) in Patients With Relapsed Classical Hodgkin Lymphoma 100 80 60 40 20 0-20 -40-60 -80-100 * Complete remission Partial remission Stable disease Progressive disease Moskowitz C, et al ASH 2014
Nivolumab in Patients (Pts) With Relapsed or Refractory Classical Hodgkin Lymphoma Clinical Outcomes From Extended Follow-up of a Phase 1 Study (CA209-039) 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, MD 6 1 Mayo Clinic, Rochester, MN, USA; 2 Dana-Farber Cancer Institute, Boston, MA, USA; 3 Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA; 4 Bristol-Myers Squibb, Wallingford, CT, USA; 5 Bristol-Myers Squibb, Princeton, NJ, USA; 6 Memorial Sloan Kettering Cancer Center, New York, NY, USA ASH 2015
HL Baseline Characteristics Characteristic chl (n = 23) 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
Select Treatment-Related Adverse Events 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) 0 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) 0 Endocrine disorders Hyperthyroidism 4 (17) 75 Hypersensitivity/infusion reaction 2 (9) Bronchospasm 1 (4) 100 Infusion-related reaction 1 (4) 100 All AEs were Grade 1/2 except colitis and pneumonitis which were Grade 3 There were no Grade 4 or Grade 5 AEs and no treatment-related deaths
Percent Change in Tumor Burden Nivolumab in Patients With Relapsed or Refractory Classical Hodgkin Lymphoma 25 SD (13%) Best Response (PR + CR =87%) PR (65%) CR (22%) 0 25 50 75 100 Patients (n = 23) On treatment, ongoing response Off treatment without disease progression a Progressive disease, following response or stable disease a Maximum clinical benefit, transplant, or toxicity Ansell et al, ASH 2015
Percent Change From Baseline in Target Lesions/Tumor Burden Nivolumab in Patients With Relapsed or Refractory Classical Hodgkin Lymphoma Durability of Response 100 50 On treatment, ongoing response Off treatment without progression Progressive disease, following response or stable disease 0 50 100 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108 114 Time Since First Treatment Date, Weeks First occurrence of new lesion Ansell et al ASH 2015
Probability of Patients in Response Nivolumab in Patients With Relapsed or Refractory Classical Hodgkin Lymphoma Duration of Response PFS 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Median DOR (95% CI): NA (15.5 NA) 0 3 6 9 12 15 18 21 24 Time, Months Ansell et al ASH 2015
Nivolumab for classical Hodgkin lymphoma after autologous stemcell transplantation and brentuximab vedotin failure: A phase 2 study Anas Younes, MD 1, Armando Santoro, MD 2, Margaret Shipp, MD 3, Pier Luigi Zinzani, MD 4, John M Timmerman, MD 5, Stephen Ansell, MD 6, Philippe Armand, MD 3, Michelle Fanale, MD 7, Voravit Ratanatharathorn, MD 8, John Kuruvilla, MD 9, Jonathon Cohen, MD 10, Graham Collins, MD 11, Kerry J Savage, MD 12, Marek Trneny, MD 13, Kazunobu Kato, MD 14, Benedetto Farsaci, MD 14, Susan M Parker, PhD 14, Scott Rodig, MD 15, Margaretha GM Roemer, MS 3, Azra H Ligon, PhD 15, Andreas Engert, MD 16 April 14, 2016: FDA Grants Nivolumab Priority Review in Hodgkin Lymphoma
Results of PD1 Blocking Antibodies in Relapsed HL Drug Dose/Sche dule N % ORR % CR ORR in BV treated HL 1 st Author Pembrolizumab (humanized IgG4) Nivolumab (Fully human IgG4) 10 mg/kg IV Q 2wks 3 mg/kg IV Q 2wks 29 66% 21% 66% (n=19) Moskowitz C 23 87% 17% 70% (n=16) Ansel SM
Single Agent Activity of PD1 Blocking Antibodies in Lymphoma Drug Antibody 1 st 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)
B-NHL T-NHL High PD- Low L1 PD- L1 MMR MMR deficient proficient Gastric Esophageal HNSC HC C C Overall Response Rate (%) Single agent activity of PD-1/PD-L1 axis blockade in relapsed/refractory Cancer 100 90 80 70 Hodgkin Lymphoma 60 50 40 B and T NHL MPDL3280A Pembrolizumab Nivolumab 30 20 10 0 No of patients 87 66 28 17 120 556 655 35 129 117 13 1 29 14 2 394 83 4 40 16 27 21 20 26 34 168 39 28 46 38 33 10 18 39 39 23 99 39 HL Melanom a NSCL C SCL C TNB C Ovary RC C Urothelia l Colorecta l Batlevi,..and Younes: Nat Rev Clinic Oncol 2016
% 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) Single agent activity of novel agents in relapsed chl 100 - High response rates - Potentially combinable at full doses 75 CR PR 50 25 0