Abstract: Cancer cells can exploit the programmed death-1 (PD-1) immune checkpoint pathway to avoid immune surveillance by modulating T-lymphocyte activity. In part, this may occur through overexpression of PD-1 and PD-1 pathway ligands (PD-L1 and PD-L2) in the tumor microenvironment. PD-1 blockade has produced significant antitumor activity in solid tumors, and similar evidence has emerged in hematologic malignancies. Methods In this phase I, open-label, dose-escalation, cohort-expansion study, patients with relapsed or refractory B-cell lymphoma, T-cell lymphoma, and multiple myeloma received the anti–PD-1 monoclonal antibody nivolumab at doses of 1 or 3 mg/kg every 2 weeks. This study aimed to evaluate the safety and efficacy of nivolumab and to assess PD-L1/PD-L2 locus integrity and protein expression. Results Eighty-one patients were treated (follicular lymphoma, n = 10; diffuse large B-cell lymphoma, n = 11; other B-cell lymphomas, n = 10; mycosis fungoides, n = 13; peripheral T-cell lymphoma, n = 5; other T-cell lymphomas, n = 5; multiple myeloma, n = 27). Patients had received a median of three (range, one to 12) prior systemic treatments. Drug-related adverse events occurred in 51 (63%) patients, and most were grade 1 or 2. Objective response rates were 40%, 36%, 15%, and 40% among patients with follicular lymphoma, diffuse large B-cell lymphoma, mycosis fungoides, and peripheral T-cell lymphoma, respectively. Median time of follow-up observation was 66.6 weeks (range, 1.6 to 132.0+ weeks). Durations of response in individual patients ranged from 6.0 to 81.6+ weeks. Conclusion Nivolumab was well tolerated and exhibited antitumor activity in extensively pretreated patients with relapsed or refractory B- and T-cell lymphomas. Additional studies of nivolumab in these diseases are ongoing.

Abstract: Introduction Programmed cell death-1 (PD-1) is an immune checkpoint receptor that inhibits T cell activation upon interaction with its ligands PD-L1 or PD-L2. Increased PD-L1 expression has been reported in various lymphoid malignancies, and may allow these tumors to circumvent host anti-tumor immunity. Nivolumab, a fully human IgG4 monoclonal PD-1 receptor blocking antibody, potentiates T cell activity, and has clinical efficacy in various solid tumors. We hypothesized that nivolumab might also have clinically important anti-tumor activity in patients with lymphoid malignancies. Methods This open-label study enrolled patients with relapsed or refractory lymphoid malignancies including B-cell non-Hodgkin lymphoma (B-NHL), T-cell NHL (T-NHL), multiple myeloma (MM), and classical Hodgkin lymphoma (cHL). Patients were treated using a dose escalation design (1 mg/kg and 3 mg/kg) of nivolumab administered every two weeks for up to two years. Responses were assessed using standard criteria. The primary endpoint was safety; key secondary endpoints included anti-tumor activity and expression of immunomodulatory proteins in tumor biopsies. The preliminary results for the cHL patients will be reported separately. Results Twenty-nine patients with B-NHL, 2 patients with primary mediastinal B-cell lymphoma; 23 patients with T-NHL; 27 patients with MM; and 1 with chronic myelogenous leukemia were enrolled. Patients were heavily pretreated with 67%, 69%, and 78% of MM, B-NHL, and T-NHL patients, respectively, having received ≥ 3 prior treatment regimens. Previous autologous stem cell transplantation was reported for 56% of MM, 14% of B-NHL, and 9% of T-NHL patients. Prior brentuximab treatment was reported in 7% of B-NHL and 26% of T-NHL patients. When this pre-planned interim analysis was performed, six patients had been treated at the 1 mg/kg dose with 2 dose-limiting toxicities (DLTs) occurring in the same patient: grade 3 pneumonia and pneumonitis. At the 3mg/kg dose, seven patients were treated with one patient experiencing two DLTs: grade 3 eosinophilia and diplopia. Additional patients were enrolled in the cohort expansion at 3 mg/kg. Drug-related adverse events (AEs) occurred in 72%, 65%, and 52% of B-NHL, T-NHL, and MM patients, respectively. Serious AEs in B-NHL patients were pneumonitis (7%), acute respiratory distress syndrome, dermatitis, diplopia, enteritis, eosinophilia, mucosal inflammation, pyrexia and vomiting, each occurring in 3%. In the T-NHL patients, serious AEs were pneumonitis, rash, and sepsis, each occurring in 4%, and in MM patients, serious AEs were pneumonitis, myositis, and increased creatine phosphokinase, each occurring in 4%. The incidence and severity of drug related AEs were similar across tumor types. Efficacy results are shown for each tumor type in the table. The overall response rate (ORR) and complete response (CR) rate in patients with B-NHL were 28% and 7%, respectively, including an ORR of 36% in patients with diffuse large B-cell lymphoma (DLBCL), and 40% in patients with follicular lymphoma (FL). In patients with T-NHL, ORR was 17% (no CR), including an ORR of 40% in the 5 patients with peripheral T cell lymphoma. No objective responses were observed in MM. Analysis of PD-L1 expression and correlation to clinical outcome is being performed and will be presented. Conclusions Nivolumab administered at a dose of 3 mg/kg every two weeks was tolerable and the safety profile was similar to that of the agent in solid tumors. Objective responses were observed in DLBCL, FL, mycosis fungoides (MF), and peripheral T cell lymphoma (PTCL). Durable stable disease was observed in relapsed MM. The results of this phase 1 study have led to phase 2 studies in DLBCL and FL, which are ongoing. Table: Efficacy Results Tumor N Complete Response n (%) Partial Response n (%) Stable Disease (SD) n (%) Progression Free Survival Rate at 24 Weeks (%) Diffuse Large B Cell Lymphoma (DLBCL) 11 1 (9) 3 (27) 3 (27) (24) Follicular Lymphoma (FL) 10 1 (10) 3 (30) 6 (60) (68) Other B Cell Lymphoma 8 0 0 5 (63) (38) Primary Mediastinal B Cell Lymphoma 2 0 0 2 (100) (0) Mycosis Fungoides (MF) 13 0 2 (15) 9 (69) (39) Peripheral T Cell Lymphoma (PTCL) 5 0 2 (40) 0 (30) Other T Cell Lymphoma 5 0 0 1 (20) (0) Multiple Myeloma (MM) 27 0 0 18 (67) (15) Chronic Myelogenous Leukemia 1 0 0 1 (100) (100) Disclosures Lesokhin: Bristol-Myers Squibb: Consultancy, Research Funding. Ansell:Bristol-Myers Sqibb: Research Funding. Armand:Merck: Consultancy. Cohen:Celgene: Member, Independent Response Adjudication Committee Other; Onyx: Advisory Board, Advisory Board Other; Bristol-Myers Squibb: Advisory Board, Advisory Board Other, Research Funding; Janssen: Advisory Board, Advisory Board Other. Lebovic:Genentech, Allos, Celgene, Onyx, Millennium: Consultancy, Research Funding, Speakers Bureau. Rodig:Bristol-Myers Squibb: Research Funding. Zhu:Bristol-Myers Squibb: Employment. Grosso:Bristol-Myers Squibb: Employment, Equity Ownership. Kim:Bristol-Myers Squibb: Employment. Shipp:Merck: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding; Janssen R & D: Membership on an entity's Board of Directors or advisory committees. Borrello:Bristol-Myers Squibb: Research Funding. Timmerman:Bristol-Myers Squibb: Research Funding.

Abstract: TPS3113 Background: Programmed death-1 (PD-1) is an immune checkpoint receptor that inhibits T-cell activation upon interaction with its ligands PD-L1 or PD-L2. Increased PD-L1 expression has been reported with various hematologic malignancies and may prevent the host immune response from exerting an antitumor effect on the malignant cells. Nivolumab, a fully human IgG4 monoclonal PD-1 receptor blocking antibody, has demonstrated antitumor activity in pts with solid tumors including melanoma, renal cell carcinoma, and non-small cell lung carcinoma. We hypothesized that nivolumab could also mediate antitumor activity in pts with hematologic malignancies, a significant area of unmet medical need. We describe a phase I study to evaluate the effects of nivolumab in pts with select hematologic malignancies. Methods: This open-label, two-part study will enroll approximately 100 pts. During dose escalation, successive cohorts of pts with relapsed or refractory hematologic malignancies will be treated using a 6+3 escalation design. Pts will receive 1 or 3 mg/kg nivolumab IV every 2 weeks (wks) (the first dose will be followed by a 3-wk evaluation period), for 2 years, with the potential for an additional year of therapy for pts who progress during the follow-up period. Subsequently, 5 tumor-specific cohorts of 16 pts will be enrolled at the maximum tolerated dose (MTD) for multiple myeloma, B-cell lymphoma, T-cell lymphoma, Hodgkin lymphoma/primary mediastinal B-cell lymphoma, and chronic myelogenous leukemia. Response will be assessed at wks 4, 8, 16, 24, and every 16 wks thereafter. The primary study objective is to establish dose limiting toxicities, the MTD, and the recommended phase II nivolumab dose. Secondary objectives are to characterize nivolumab pharmacokinetics, immunogenicity, preliminary antitumor activity, and the potential association between PD-L1 expression on tumor cells and clinical efficacy. Exploratory objectives include investigation of the immunoregulatory effects of nivolumab in peripheral blood, bone marrow, and/or tumor. Pts are currently being enrolled at 3 mg/kg. Clinical trial information: NCT01592370.

Abstract: Introduction: Programmed cell death-1 (PD-1) signaling suppresses the antigen driven activation of T cells upon interaction with its ligands PD-L1 and PD-L2. The PD-1/PD-L1 axis is thought to mediate the resistance of multiple myeloma to conventional therapy (Tamura 2013; Paiva 2015). Nivolumab, a fully human IgG4 monoclonal PD-1 receptor-blocking antibody, has shown clinical activity in a variety of tumor types. Nivolumab has demonstrated a prolonged receptor binding kinetic lasting 〉 100 days that may lead to an efficacy or toxicity signal in the post-treatment period. We therefore evaluated the response of patients with relapsed or refractory multiple myeloma to additional myeloma therapy received within 3 months of the end of nivolumab administration. Methods: The preliminary results of an open-label study that treated patients with relapsed or refractory multiple myeloma using a dose escalation design (1 mg/kg and 3 mg/kg) of nivolumab administered every 2 weeks have been reported previously (NCT01592370, Lesokhin et al., ASH 2014). Here we will report responses and safety data using standard criteria to the next line of therapy received immediately after nivolumab. Results: 8 patients with multiple myeloma from the original open label study were treated at Memorial Sloan Kettering Cancer Center. The disease characteristics and efficacy results are shown in the table. 1 of 8 patients (12.5%) experienced progression while on therapy manifested by development of an isolated plasmacytoma. The patient received radiation and then resumed and completed 97 weeks of therapy with nivolumab. He is currently off therapy without any evidence of disease at 48 weeks after cessation of nivolumab. 3 of 8 patients (37.5%) achieved a partial response to the next line of treatment after nivolumab. 2 of 8 patients (25%) who were exposed and refractory to immunomodulatory drugs (IMiDs) received single-agent, low-dose lenalidomide as the next line of therapy and achieved stable disease lasting approximately 100 days after cessation of nivolumab followed by disease progression. 1 of 8 patients (12.5%) experienced progressive disease despite the next line of therapy, and 1 of 8 patients (12.5%) received an experimental treatment as the next line of therapy and was therefore not evaluable. No new drug-related adverse events occurred in the 3 months after completing treatment with nivolumab. Overall, 6 out of 8 patients derived clinical benefit from post-nivolumab therapy, an unusually high response rate for this population. Conclusions: In a small cohort of patients with relapsed and refractory multiple myeloma, evaluation of response kinetics after cessation of nivolumab supports the notion that long PD-1 receptor binding kinetics may increase the efficacy of subsequent therapy without added toxicity. Larger studies are needed to confirm and expand our findings. Table. Patient Characteristics and Efficacy Age Sex ISS Cytogenetics Prior Lines ASCT IMiD E IMiD R Prot E Prot R Best Response to Nivolumab Next Line of Standard Therapy Best Response to Next Line 52 M 1 S 3 Y Y Y Y Y SD Carfilzomib, Cyclophosphamide, Dexamethasone PR 32 M 1 S 3 Y Y Y Y Y SD None* N/A 80 F 1 S 1 N Y N N N SD Lenalidomide PR 52 F 1 I 3 Y Y Y Y N SD Lenalidomide SD 62 M 1 H 1 Y Y N Y N PD Cyclophosphamide, Bortezomib, Dexamethasone PR 58 M 2 S 5 Y Y Y Y Y PD Lenalidomide SD 57 F 1 S 3 Y Y N Y Y PD None^ N/A 59 F 1 S 3 Y Y Y Y Y PD Lenalidomide, Bortezomib, Dexamethasone PD ISS=international staging system; S=standard cytogenetics; I=intermediate cytogenetics; H=high risk cytogenetics; ASCT=autologous stem cell transplant; IMiD E=IMiD exposed; IMiD R=IMiD refractory; Prot E=proteosome exposed; Prot R=proteosome refractory; PD=progressive disease; SD=stable disease; PR=partial response *Patient completed 97 weeks of nivolumab and continues untreated without any evidence of disease at 48 weeks after cessation of therapy ^Patient received treatment on an experimental protocol Disclosures Funt: Kite Pharma: Equity Ownership. Off Label Use: Nivolumab is FDA approved for use in patients with metastatic melanoma but not in patients with multiple myeloma. . Page:Celgene: Consultancy. Landgren:Bristol-Myers Squibb: Honoraria; Celgene: Consultancy; BMJ Publishing: Consultancy; Bristol-Myers Squibb: Consultancy; BMJ Publishing: Honoraria; Medscape: Consultancy; Medscape: Honoraria; Celgene: Honoraria; International Myeloma Foundation: Research Funding; Onyx: Honoraria; Onyx: Research Funding; Onyx: Consultancy. Borrello:Celgene: Research Funding. Lesokhin:Bristol Myers Squibb: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Aduro: Consultancy; Genentech: Research Funding; Efranat: Consultancy.

Abstract: Introduction: Classical Hodgkin lymphoma (cHL) is characterized by Reed Sternberg (RS) cells surrounded by an extensive but ineffective inflammatory/immune cell infiltrate. Recent studies suggest that Hodgkin RS cells have developed mechanisms that exploit the programmed cell death-1 (PD-1) pathway to evade immune detection. In cHL, chromosome 9p24.1 gain is a frequent structural alteration that increases the gene dosage of the PD-1 ligands, PD-L1 and PD-L2, and their induction via JAK/STAT signaling. Epstein-Barr Virus (EBV) infection also increases the expression of the PD-1 ligands in EBV-positive cHL. Ligand binding to PD-1 receptor-positive activated T cells induces T cell exhaustion, a reversible inhibition of T cell activation and proliferation. Nivolumab (BMS-936558, Bristol-Myers Squibb) is a fully human IgG4 monoclonal PD-1 blocking antibody that potentiates anti-tumor T cell activity, and exhibits clinical efficacy in several solid tumors. We hypothesized that nivolumab may augment anti-tumor activity in patients with relapsed or refractory (R/R) cHL, including those who had failed brentuximab vedotin (BV), and evaluated the PD-1 blocking antibody. These are the first analyses being reported with PD-1 antibody for the treatment of cHL. Methods: Patients with R/R cHL were included as an independent cohort in a dose escalation and cohort expansion phase I study of nivolumab in lymphoma and multiple myeloma (MM). Results for patients with non-Hodgkin lymphoma and MM are reported separately. Patients with cHL received nivolumab 3 mg/kg every 2 weeks until confirmed tumor progression or excessive toxicity. Responses were evaluated using standard criteria. The primary endpoint was safety; key secondary endpoints included anti-tumor activity and expression of immunomodulatory proteins in tumor biopsies. Results: Twenty-three patients were enrolled with R/R cHL. Patients were heavily pre-treated, 87% had received ≥ 3 prior treatment regimens, 78% had prior autologous stem cell transplant (ASCT), and 78% had prior BV treatment. Drug-related adverse events (AEs) of any grade occurred in 78% of patients, the most common of which were rash (22%), decreased platelet count (17%), diarrhea, nausea, pruritus, fatigue, and pyrexia (each at 13%). Drug-related grade 3/4 AEs occurred in 22% of patients. Three patients experienced 1 serious AE each (grade 3 myelodysplastic syndrome [MDS], grade 3 pancreatitis, and grade 2 lymph node pain). The objective response rate (ORR) was 87% (20/23), with 4 patients (17%) achieving a complete response (CR) and 16 (70%) obtaining a partial response (PR). The remaining 3 patients (13%) had stable disease (SD). All 23 patients had a reduction in tumor burden at 1 or more efficacy assessments during treatment with nivolumab (Figure). Among the 18 patients who had previously failed BV, the ORR was 89% (16/18), with 6% (1/18) achieving CR and 83% (15/18) PR. Progression-free survival (PFS) rate at 24 weeks was 86% (95% CI, 62-95%). The median overall survival (OS) has not been reached (range, 21+ to 75+ weeks). Six of 23 patients elected to discontinue study treatment to undergo stem cell transplantation, 2 patients discontinued due to toxicities (MDS and thrombocytopenia in 1 patient; pancreatitis in 1 patient), 4 patients discontinued due to disease progression, and 11 patients continue on study as of June 16, 2014. In a subset of study patients (10/23), PD-L1 and PD-L2 copy numbers in RS cells were assessed using fixed tumor biopsy specimens and a 3-probe fluorescence in situ assay (PD-L1,PD-L2, and control centromeric probe). In all tumors, RS cells had copy gains of PD-L1 and PD-L2, as a result of either polysomy or amplification; these tumors also exhibited increased protein expression of PD-L1. RS cells were also largely positive for pSTAT3, indicative of active JAK/STAT signaling. Conclusions In patients with R/R cHL, nivolumab-mediated PD-1 blockade is safe and tolerable with a safety profile similar to that in solid tumors. The frequent and long-lasting responses in heavily pretreated, R/R patients, including those who have failed BV, highlight the importance of the PD-1 pathway in cHL, and the genetically defined sensitivity to PD-1 blockade in this disease. Based on these results, the FDA granted nivolumab breakthrough status in relapsed cHL and a large, multinational, phase II trial of this therapy is underway. Figure 1 Figure 1. Disclosures Armand: Merck: Consultancy. Off Label Use: Nivolumab was tested for the treatment of hematologic malignancies.. Ansell:Bristol-Myers Squibb: Research Funding. Lesokhin:Bristol-Myers Squibb: Consultancy, Research Funding. Timmerman:Bristol-Myers Squibb: Research Funding. Borrello:Bristol-Myers Squibb: Research Funding. Rodig:Bristol-Myers Squibb: Research Funding. Zhu:Bristol-Myers Squibb: Employment. Grosso:Bristol-Myers Squibb: Employment, Equity Ownership. Kim:Bristol-Myers Squibb: Employment. Shipp:Merck: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding; Janssen R & D: Membership on an entity's Board of Directors or advisory committees.