Preliminary Results of a Phase I Study of Nivolumab (BMS-936558) in Patients with Rel… Page 1 of 7
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`Preliminary Results of a Phase I Study of Nivolumab (BMS-
`936558) in Patients with Relapsed or Refractory Lymphoid
`Malignancies
`Alexander M. Lesokhin, Stephen M. Ansell, Philippe Armand, Emma C. Scott, Ahmad Halwani,
`Martin Gutierrez, Michael M. Millenson, Adam D. Cohen, Stephen J. Schuster, Daniel Lebovic,
`Madhav V. Dhodapkar, David Avigan, Bjoern Chapuy, Azra H. Ligon, Scott J. Rodig, Deepika Cattry,
`Lili Zhu, Joseph F. Grosso, Su Young Kim, Margaret A. Shipp, Ivan Borrello, and John Timmerman
`Blood 2014 124:291;
`
`Article
`
`Info & Metrics
`
`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
`
`http://www.bloodjournal.org/content/124/21/291?sso-checked=true
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`7/30/2019
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`Preliminary Results of a Phase I Study of Nivolumab (BMS-936558) in Patients with Rel… Page 2 of 7
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`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.
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`Preliminary Results of a Phase I Study of Nivolumab (BMS-936558) in Patients with Rel… Page 3 of 7
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`Tumor
`
`Diffuse Large B Cell
`Lymphoma (DLBCL)
`
`N
`
`Complete
`Response
`n (%)
`
`11
`
`1 (9)
`
`Follicular Lymphoma (FL)
`
`10
`
`1 (10)
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`Other B Cell Lymphoma
`
`Primary Mediastinal B Cell
`Lymphoma
`
`8
`
`2
`
`Mycosis Fungoides (MF)
`
`13
`
`Peripheral T Cell
`Lymphoma (PTCL)
`
`Other T Cell Lymphoma
`
`Multiple Myeloma (MM)
`
`Chronic Myelogenous
`Leukemia
`
`5
`
`5
`
`27
`
`1
`
`Table:
`Efficacy Results
`
`Partial
`Response
`n (%)
`
`Stable
`Disease (SD)
`n (%)
`
`Progression Free Survival
`Rate at 24 Weeks (%)
`
`3 (27)
`
`3 (30)
`
`0
`
`0
`
`2 (15)
`
`2 (40)
`
`0
`
`0
`
`0
`
`3 (27)
`
`6 (60)
`
`5 (63)
`
`2 (100)
`
`9 (69)
`
`0
`
`1 (20)
`
`18 (67)
`
`1 (100)
`
`(24)
`
`(68)
`
`(38)
`
`(0)
`
`(39)
`
`(30)
`
`(0)
`
`(15)
`
`(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.
`
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`• ↵* Asterisk with author names denotes non-ASH members.
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`© 2014 by The American Society of Hematology
`
`Potential Articles of Interest
`
`Nivolumab in Patients with Relapsed or Refractory
`Hodgkin Lymphoma - Preliminary Safety, Efficacy and
`Biomarker Results of a Phase I Study
`Philippe Armand et al., Blood, 2014
`
`Nivolumab Combined with Brentuximab Vedotin for
`Relapsed/Refractory Primary Mediastinal Large B-Cell
`Lymphoma: Preliminary Results from the Phase 2
`CheckMate 436 Trial
`Alison J. Moskowitz et al., Blood, 2018
`
`Clinical Outcomes of Anti PD-1 Immunotherapy in
`Patients with Relapsed/Refractory Non Hodgkin
`Lymphomas
`Colleen Dorsey et al., Blood, 2017
`
`A Phase I Study with an Expansion Cohort of the
`Combinations of Ipilimumab, Nivolumab and
`Brentuximab Vedotin in Patients with
`Relapsed/Refractory Hodgkin Lymphoma: A Trial of the
`ECOG-ACRIN Research Group (E4412: Arms G-I)
`Catherine Diefenbach et al., Blood, 2018
`
`Efficacy of Copanlisib Monotherapy in Patients with
`Relapsed or Refractory Marginal Zone Lymphoma:
`Subset Analysis from the CHRONOS-1 Trial
`Martin Dreyling et al., Blood, 2017
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`Teresa Simon et al., Ann Rheum Dis, 2019
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`Juan-Jesus Carrero et al., Heart, 2018
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`Table of Contents
`Volume: 124
`Issue: 21
`Pages: 291
`DOI: https://doi.org/
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