Nivolumab in Hodgkin Lymphoma Stephen M. Ansell, MD, PhD Professor of Medicine Chair, Lymphoma Group Mayo Clinic
Conflicts of Interest Research Funding from Bristol Myers Squibb Celldex Therapeutics Seattle Genetics Merck Affimed
1. Exhausted intratumoral T-cells are poorly functional A. B. C. D. Yang et al. J Clin Invest 2012;122(4):1271-82.
2. Increased PD-L1 and PD-L2 expression in Hodgkin Lymphoma PD-L1 Negative PD-L1 Positive Ansell et al. N Engl J Med. 2015;372:311-319 Roemer et al. ASH 2015 abstract #176 Moskowitz et al. ASH 2014, abstract 290
Does Immune Checkpoint Blockade work? Blocking PD-1 using nivolumab PD-1 ligands are overexpressed in inflammatory environments and attenuate the immune response via PD-1 on immune effector cells. 1 PD-L1 expressed on malignant cells and/or in the tumor microenvironment suppresses tumor infiltrating lymphocyte activity. 2 IFNγ IFNγR MHC T-cell receptor Tumor cell PD-L1 PD-L2 PD-1 PI3K NFκB Other Shp-2 T cell PD-1 Anti-PD-1 1 Francisco LM et al. J Exp Med 2009;206:3015-29. 2 Andorsky DJ et al. Clin Cancer Res 2011;17:4232-44
Does Blocking PD-1 with nivolumab work? 42 year old female Hodgkin lymphoma 26 year old male Hodgkin lymphoma Courtesy of SM Ansell, Mayo Clinic
Hodgkin Lymphoma Phase 1 data with nivolumab SD (13%) PR (70%) CR (17%) Ansell et al. N Engl J Med. 2015;372(4):311-9.
Percent Change From Baseline in Target Lesions/Tumor Burden Nivolumab - 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, abstract 583
Retreatment With Nivolumab Pretreatment 6 weeks posttreatment Progression when therapy stopped 6 weeks post-second course of therapy Ansell et al. Haematologica 2016; 101(s5): P090
Nivolumab for classical Hodgkin's lymphoma: a multicentre, multicohort, single-arm phase 2 trial (Cohort B). 80 patients failed ASCT and BV 66% ORR Younes et al. Lancet Oncol. 2016 2016 Sep;17(9):1283-94.
Probability of response Duration of Response by Best Response Cohort B: Nivolumab After BV Post-ASCT 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 No. of patients at risk CR PR OR CR OR PR 0 3 6 9 12 15 Months 6 5 5 3 2 0 48 39 31 22 10 0 54 44 36 25 12 0 Database lock Median follow-up, mo (range) Oct 2015 9 (2 12) Apr 2016 15 (2 19) ORR, n (%) 53 (66) 54 (68) Median DOR, mo (95% CI) Median DOCR, mo (95% CI) Median DOPR, mo (95% CI) 8 (7, NR) 5 (NR, NR) 8 (7, NR) 13 (9, NR) NR (5, NR) 13 (8, NR) Timmerman et al. ASH 2016 abstract #1110
Best Overall Response Cohort A: Nivolumab in BV-Naïve Post-ASCT Patients ORR, n (%) 95% CI Cohort A (n = 63) IRRC assessed 43 (68) 55, 79 CR, n (%) 14 (22) PR, n (%) 29 (46) SD, n (%) 13 (21) PD, n (%) 7 (11) Timmerman et al. ASH 2016 abstract #1110
Probability of response Duration of Response by Best Response Cohort A: Nivolumab in BV-Naïve Post-ASCT Patients 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 OR 0 3 6 9 12 15 No. of patients at risk Months CR PR OR 14 13 12 9 3 1 29 24 16 10 3 0 43 37 28 19 6 1 CR PR 18 0 0 0 Durable responses in both complete and partial responders Database lock Jun 2016 Median duration of follow-up, mo (range) Median DOR, mo (95% CI) 14 (1 20) NR (NR, NR) Timmerman et al. ASH 2016 abstract #1110
Nivolumab and Ipilimumab Mechanism of Action CTLA-4 blockade (ipilimumab) PD-1 blockade (nivolumab) APC T-cell interaction Tumor microenvironment Activation (cytokine secretion, lysis, proliferation, MHC migration to tumor) TCR +++ TCR MHC Dendritic B7 +++ cell CD28 T cell T Tumor cell +++ PD-1 PD-L1 B7 cell CTLA-4 --- --- anti-pd-1 anti-ctla-4 PD-1 PD-L2 --- CTLA-4 is expressed on T cells and inhibits T-cell activation 1 Ipilimumab disrupts the CTLA-4 pathway, thus inducing anti-tumor immunity 1 PD-1 expression on tumor-infiltrating lymphocytes is associated with decreased cytokine production and effector function Nivolumab disrupts PD-1 pathway signaling and restores anti-tumor T-cell function 2 4 Ansell et al. ASH 2016 abstract #183
Change from baseline in target lesions tumor burden (%) Nivolumab + Ipilimumab Hodgkin Lymphoma HL (N = 31) ORR, n (%) a 23 (74) Complete response 6 (19) Partial response 17 (55) Stable disease 3 (10) Relapsed or progressive disease Median duration of OR, months (range) 3 (10) NR (0.0+, 13.4+) Transplant naïve b (n = 18) ORR, n (%) 12 (67) 100 75 50 25 0 25 50 75 100 Change in tumor burden, HL Responders (n = 23) Non-responders (n = 8) 0 12 24 36 48 60 72 84 96 Time since first treatment date (weeks) a Response was not reported for 2 (6%) patients with HL btransplant-naïve patients are a subset of the total number of patients with HL; a total of 13 transplant-naïve patients were chemoresistant and 3 were ineligible for the procedure NR = not reached; + = censored value Ansell et al. ASH 2016 abstract #183 15
Nivolumab + Brentuximab vedotin ORR (26/29) = 90% 95% CI: 72.6, 97.8 CmR (18/29) = 62% 95% CI: 42.3, 79.3 a Change in SPD from baseline Deauville score (N=29) 5-Point Score n (%) Total CmR 1 8 (28) 18 (62) 2 6 (21) 3 3 (10) Missing 1 (3) Change in max SUV from baseline PmR 4 6 (21) 8 (28) 5 2 (7) NmR 5 1 (3) 3 (10) PmD 5 2 (7) 2 (7) a Cycle 2 SPD reported for 1 patient Herrera et al. ASH 2016 abstract #1105
BV and Nivolumab is Highly Active Evaluable Patients (n = 12) ORR ORR 12/12 (100%) CR 8/12 (66%) PR 4/12 (34%) 2 of 2 patients with prior BV evaluable= CR Diefenbach et al. ASH 2016 abstract #1106
Conclusions Optimizing immune function is the new therapeutic frontier in Hodgkin lymphoma Immune checkpoint inhibitors such as nivolumab hold real promise in Hodgkin lymphoma. Incorporating promising immunologic agents such as nivolumab into combination approaches will be the next clinical challenge.