Correlation of Target Molecule Expression and Overall Response in Refractory Cutaneous T-Cell Lymphoma Patients Dosed with Mogamulizumab (KW-0761), a Monoclonal Antibody Directed Against CC Chemokine Receptor Type 4 (CCR4)
Authors: Duvic Madeleine , Pinter-Brown Lauren , Foss Francine , Sokol Lubomir , Jorgensen Jeffrey , Ni Xiao , Challagundla Pramoda , Goswami Meghali , Dwyer Karen , Mohamed Nehal , Kim Youn H 
Published: October 2019

Abstract 3697

Introduction:

The CC chemokine receptor 4 (CCR4) is over expressed in most cutaneous T-cell lymphomas (CTCL), and is a potential target for anti-neoplastic therapy in these disorders. Mogamulizumab (KW-0761), a humanized monoclonal antibody with enhanced antibody dependent cellular cytotoxicity has shown promising activity in a Phase 1/2 study in refractory CTCL.

Study Design:

This study assessed the relationship between baseline CCR4 expression levels and tumor response to mogamulizumab in a phase 1/2 study in refractory CTCL. Patients were dosed with mogamulizumab iv as monotherapy, once weekly for four weeks in the first cycle, then every two weeks on subsequent cycles. A global response score was assigned, as a composite of the response in all compartments (skin, lymph nodes, viscera) with response in blood also considered for subjects with significant blood involvement. CCR4 expression levels were determined by both immunohistochemistry (IHC%) on skin biopsy samples and flow cytometric (FC%) analysis of peripheral blood (PB) specimens using the murine parent antibody for mogamulizumab. Logistic regression models were used to assess response as a function of both IHC% and FC%, on IHC% and FC% separately, and with disease type [Mycosis fungoides (MF) or Sezary Syndrome (SS)] in the model.

Results:

Patients were treated with mogamulizumab at 0.1 mg/kg (n=3), 0.3 mg/kg (n=3), or 1.0 mg/kg (n=36). Thirty eight patients (21MF and 17 SS) were evaluable for tumor response and the overall response rate was 37% (29% in MF and 47% in SS). Thirty (30) patients had IHC evaluable skin biopsy specimens at baseline and 28 patients had identifiable PB lymphoma cells by FC in pre-treatment specimens. In all, 35 patient samples were evaluated for CCR4 expression by at least one method. All 28 patients with identifiable PB lymphoma cells were confirmed to be CCR4-positive by FC, and 73% (22/30) of skin biopsy samples showed staining by IHC above background (>5% lymphocytes in skin lesions positive for CCR4). 89% (31/35) of patient samples were positive by at least one method. Logistic regression analyses found no statistical evidence that IHC% or FC% are significant predictors of response, either independently or when disease type is included in the model (p-values >.05 in all cases). Plots of response to mogamulizumab versus CCR4 expression are given below:

Conclusions:

CCR4 was confirmed to be expressed in most of the CTCL patients. Its expression levels had no correlation to response to mogamulizumab in this phase 1/2 study. Further studies with larger sample size are warranted to determine whether measurement of CCR4 expression in diagnostic biopsies may provide clinical utility in predicting mogamulizumab response.

Disclosures:

Duvic: Allos: Membership on an entity's Board of Directors or advisory committees, Research Funding; Biocryst: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Consultancy, Research Funding; Eisai Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau; Eli Lilly and Company: Research Funding; Galderma: Research Funding; Hana Biosciences, Inc.: Research Funding; Hoffman-La Roche, Ltd.: Consultancy; Infinity Pharma: Consultancy; Kyowa Hakko Kirin Pharma, Inc. : Consultancy, Research Funding; Merck & Co., Inc.: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; NAAF: Research Funding; NIH: Research Funding; Novartis Pharma: Consultancy, Research Funding; Pfizer Inc.: Research Funding; Quintiles Pharma: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shape: Consultancy, Research Funding; Sloan-Kettering: Research Funding; Spectrum: Research Funding; Therakos, Inc.: Research Funding; Topotarget: Research Funding; Yaupon Therapeutics, Inc.: Research Funding. Pinter-Brown:Allos Therapeutics: Consultancy; Millenium/Seattle Genetics: Consultancy. Foss:Allos: Consultancy; Celgene: Consultancy; Seattle Genetics: Consultancy; Eisai: Consultancy; Merck: Study Grants Other; Celgene: Study Grants, Study Grants Other. Sokol:Celgene: Honoraria, Speakers Bureau. Ni:Kyowa Hakko Kirin Pharma, Inc: Research Funding. Dwyer:Kyowa Hakko Kirin Pharma, Inc. : Employment. Mohamed:Kyowa Hakko Kirin Pharma, Inc. : Employment. Kim:Allos: Consultancy, Research Funding; Kyowa Kirin Pharma, Inc.: Compensated, Compensated Other, Consultancy, Research Funding; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Consultancy, Research Funding; Emergent: Consultancy; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celegene: Membership on an entity's Board of Directors or advisory committees; Shape: Research Funding; Yaupon: Research Funding.