Interim results of brentuximab vedotin in combination with nivolumab in patients with relapsed or refractory Hodgkin lymphoma

Abstract

In this phase 1/2 study, brentuximab vedotin (BV) and nivolumab (Nivo) administered in combination were evaluated as initial salvage therapy in patients with relapsed or refractory (R/R) classical Hodgkin lymphoma (HL). Patients received up to 4 cycles of combination treatment, with BV administered on day 1 and Nivo on day 8 of the first cycle. For cycles 2 to 4, BV and Nivo were both administered on day 1. After study treatment, responses were evaluated by investigators per the 2014 Lugano classification, and patients could proceed to autologous stem cell transplantation (ASCT). Sixty-two patients were enrolled; the complete response rate among all treated patients (n = 61) was 61%, with an objective response rate of 82%. Before ASCT, adverse events (AEs) occurred in 98% of patients, mostly grades 1 and 2. Infusion-related reactions (IRRs) occurred in 44% of patients overall, with 41% of patients experiencing an IRR during at least 1 infusion of BV. Five patients (8%) were treated with systemic steroids for immune-related AEs. A reduction of peripheral T-cell subsets including regulatory T cells was observed after the first dose of BV, and reduced serum levels of thymus- and activation-regulated chemokine concurrent with an increase in proinflammatory cytokines and chemokines were seen after the first BV plus Nivo infusions. The combination of BV plus Nivo was an active and well-tolerated first salvage regimen, potentially providing patients with R/R HL an alternative to traditional chemotherapy. This trial was registered at www.clinicaltrials.gov as #NCT02572167.

Conflict of interest statement

Conflict-of-interest disclosure: K.F., C.A.O., D.T., Q.Z., and M.C. are employees of and receive equity ownership in Seattle Genetics, Inc. A.F.H. received research funding from Seattle Genetics, Bristol-Myers Squibb, MedImmune, Merck, Immune Design, Genentech, and Pharmacyclics. A.J.M. received research funding from Seattle Genetics. N.L.B. received research funding from Seattle Genetics, Janssen, Affimed, ImaginAb, KITE, Forty Seven, Pharmacyclics, Celgene, Bristol-Myers Squibb, AstraZeneca, Genentech, Merck, Millennium, Pfizer, Immune Design, and Novartis. J.M.V. received research funding from Seattle Genetics, Bristol-Myers Squibb, Onyx, Merck, KITE, Janssen, Celgene, Allos Therapeutics, Acerta, Incyte, and US Biotest. R.R., T.A.F., and A.S.L. received research funding from Seattle Genetics. S.M.A. received research funding from Seattle Genetics and Merck. C.H.M. received research funding from Seattle Genetics, Pharmacyclics, and Merck. R.H.A. received research funding from Seattle Genetics, Agensys, Bristol-Myers Squibb, Celgene, Genentech, Infinity, Kura, Merck, Millennium, Regeneron, Janssen, and Pharmacyclics. A.F.H. has consulted for Merck, Genentech, Bristol-Myers Squibb, and Pharmacyclics. N.L.B. has consulted for Seattle Genetics, Gilead, and KITE. R.R. has consulted for Seattle Genetics. C.H.M. has consulted for Seattle Genetics, Celgene, Genentech, and Merck. R.H.A. has consulted for Gilead, Spectrum, Bristol-Myers Squibb, Pharmacyclics, NanoString, Forty Seven, Sutro, and Juno Therapeutics. T.A.F. is a member of a speakers bureau for Seattle Genetics, Pharmacyclics, Johnson & Johnson, AbbVie, and Celgene. The remaining author declares no competing financial interests.

© 2018 by The American Society of Hematology.

Figures

Figure 1.

Percent change in the sum of the product of diameters and maximum percent change in the standard uptake value in efficacy-evaluable patients (n = 60). (A) Sum of the product of diameters (SPD) percent change and (B) maximum standard uptake value (SUV) percent change are calculated as the percent change from the baseline SPD/SUV to the minimum post-baseline SPD/SUV measured before initiation of subsequent anticancer treatment (chemotherapy or radiotherapy, including conditioning regimen for ASCT).

Figure 2.

Therapy after study treatment. Among the 60 patients evaluated for efficacy, 54 patients underwent ASCT, of whom 42 patients did so directly after treatment with BV and Nivo. A total of 17 patients received subsequent salvage therapy, and 1 patient who achieved CR received consolidation radiotherapy after treatment with BV and Nivo. Green boxes indicate response to BV plus Nivo, and blue boxes indicate response to salvage therapy. NE, not evaluable; PD, progressive disease; RT, radiation therapy.

Figure 3.

Flow cytometry results for immunophenotyping T-cell subsets and frequency of T-cell clones in the peripheral blood. (A) T-cell immunophenotyping included Tregs as defined by CD4+CD25+CD127low/−CCR4+; cytotoxic T cells (CTLs) as defined by CD8+; TH2 as defined by CD4+ CXCR3-CCR6-CCR4+; TH17 as defined by CD4+CXCR3-CCR6+CCR4+; T follicular helper (Tfh) CD4+CD45RA-CXCR3-CXCR5+; as well as for plasmablasts CD19+CD20-IgD-CD27+CD38hi. Activated and dividing CD4+ are defined by HLA-Dr and Ki67 expressions, respectively. (B) The frequency of T-cell clones per 100 000 clones is shown relative to baseline during the treatment course. P values were calculated for (A) and (B) using the paired t test (GraphPad Prism) and post hoc Dunn test with Benjamini-Hochberg correction, respectively.

Figure 4.

Longitudinal changes of cytokine levels during the treatment course and intracellular detection of IFN-γ in CD8+effector memory (CD45RA-CCR7−) cells. (A) Average cytokine levels (normalized ratio against baseline) of all patients are depicted by a heat map. Left box highlights proinflammatory monocyte chemokines including MCP-1, MCP-2, and proinflammatory cytokines including interferon-γ (IFN-γ) and INF-α. Middle boxes highlight proinflammatory T-cell chemokines including IFN-induced protein 10 (IP-10), ITAC, Mip-1b, and proinflammatory B-cell activators including BAFF and APRIL. Lower-right box shows cytokines released from RS cells (interleukin [IL]-10, TARC, and IL-6) that have been reported as negative prognostic factors. Levels of (B) IP-10 and TARC during the treatment course were analyzed by best response. Because of the small number of patients, data from C4D1 are excluded from the plots. (C) Intracellular cytokine staining of ex vivo peptide–stimulated T cells. Red box highlights the time point at which the largest separation between peptide antigen and control was observed. Staphylococcal enterotoxin B was used as a positive control, and nonstimulated (NS) was used as a negative control. EBV represents a peptide pool of Epstein-Barr virus–associated peptides, CEFT represents a peptide pool from Cytomegalovirus, Epstein-Barr virus, Influenza, and Tetanus toxin. Stimulation is indicated by red dots, and NS is depicted by blue dots. NR, no response including SD and progressive disease.