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 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 Inhibitory Receptors VISTA OX40 TIM-3 CTLA-4 CD137 (4-1BB) T cell PD1 CD27 CD28 Agonistic LAG-3 Blocking Antibodies Antibodies BTLA HVEM 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 PDL1 PDL2 LMP1+ PDL1/PDL2 Expression in EBV+ and EBV- cHL LMP1- 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 9p24.1 Infection amplification JAK2 CD30 PDL1 Younes A, ICML, Lugano 2015
HRS Cells Express High Levels of PDL-1 T cell Hodgkin and Reed Sternberg (HRS) Cells EBV 9p24.1 PD1 TCR Infection Gene amplification PD-L1 MHC I/II PD-L2 JAK2 CD30 PDL1 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.
Pembrolizumab (MK-3475) in Patients With Relapsed Classical Hodgkin Lymphoma 100 80 Complete remission 60 Change From Baseline, % Partial remission 40 Stable disease Progressive disease 20 0 -20 * -40 -60 -80 -100 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, Resolved, % n (%) 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
Nivolumab in Patients With Relapsed or Refractory Classical Hodgkin Lymphoma Best Response (PR + CR =87%) 25 SD (13%) PR (65%) CR (22%) Percent Change in Tumor Burden 0 – 25 – 50 – 75 – 100 Patients (n = 23) On treatment, ongoing response Progressive disease, following response or stable disease Off treatment without disease progression a Ansell et al , ASH 2015 a Maximum clinical benefit, transplant, or toxicity
Nivolumab in Patients With Relapsed or Refractory Classical Hodgkin Lymphoma Durability of Response 100 On treatment, ongoing response Off treatment without progression in Target Lesions/Tumor Burden Percent Change From Baseline Progressive disease, following 50 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
Nivolumab in Patients With Relapsed or Refractory Classical Hodgkin Lymphoma Duration of Response PFS 1.0 Probability of Patients in Response 0.9 0.8 0.7 0.6 0.5 0.4 0.3 Median DOR (95% CI): 0.2 NA (15.5 – NA) 0.1 0.0 0 3 6 9 12 15 18 21 24 Time, Months Ansell et al ASH 2015
Nivolumab for classical Hodgkin lymphoma after autologous stem- cell 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 1 st Author Drug Dose/Sche N % % CR ORR in BV dule ORR treated HL Pembrolizumab 10 mg/kg 29 66% 21% 66% (n=19) Moskowitz C (humanized IV Q 2wks IgG4) Nivolumab 3 mg/kg IV 23 87% 17% 70% (n=16) Ansel SM (Fully human Q 2wks IgG4)
Single Agent Activity of PD1 Blocking Antibodies in Lymphoma 1 st Author (s) Antibody Drug Hodgkin Follicular DLBCL T-cell Fully Ansell Nivolumab human IgG4 Lesokin 87% 40% 36% 17% Timmerman (20/23) (4/10) (4/11) (4/23) Humanized Moskowitz Pembrolizumab IgG4 Armand 65% (20/31) Humanized Armand Pidilizumab IgG1 51% (18/38)
Single agent activity of PD-1/PD-L1 axis blockade in relapsed/refractory Cancer 100 90 Overall Response Rate (%) Hodgkin 80 Lymphoma 70 60 B and T MPDL3280A NHL 50 Pembrolizumab Nivolumab 40 30 20 10 0 13 29 14 No of patients 87 66 28 17 120 556 655 35 129 117 40 16 27 21 20 26 34 168 39 28 46 38 33 10 18 39 39 23 99 39 1 2 394 83 4 MMR proficient Esophageal High PD- Low PD- deficient Gastric MMR L1 L1 HNSC T-NHL B-NHL C HC C HL Melanom NSCL SCL TNB Ovary RC a C C C C Urothelia Colorecta l l Batlevi,..and Younes: Nat Rev Clinic Oncol 2016
Single agent activity of novel agents in relapsed cHL - High response rates - Potentially combinable at full doses 100 75 % Response rate CR PR 50 25 0 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)
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