-Author name in bold denotes the presenting author
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1627 Argx-110 for Treatment of CD70-Positive Advanced Cutaneous T-Cell Lymphoma in a Phase 1/2 Clinical Trial

Program: Oral and Poster Abstracts
Session: 624. Hodgkin Lymphoma and T/NK Cell Lymphoma—Clinical Studies: Poster I
Hematology Disease Topics & Pathways:
antibodies, Biological, Diseases, Therapies, T-Cell Lymphoma, Lymphoid Malignancies
Saturday, December 1, 2018, 6:15 PM-8:15 PM
Hall GH (San Diego Convention Center)

Martine Bagot, MD, PhD1*, Marie Maerevoet, MD2*, Pier Luigi Zinzani, MD3, Fritz Offner, MD4, Franck Morschhauser, MD5*, Jean-Marie Michot, MD6*, Vincent Ribrag, MD7, Maxime Battistella, MD, PhD8*, Helene Moins9*, Angelica Calleri, PhD10*, Stéphane Dalle, MD, PhD11*, Marie Beylot-Barry, MD, PhD12*, Karen Zwaenepoel, PhD13*, Koen De Winnie, PhD14*, Anne Marie-Cardine, PhD15*, Jean-Michel Cayuela, PhD16*, Valentina Tabanelli, MD10*, Giovanna Motta, PhD10*, Federica Melle, PhD10*, Anna Hultberg, PhD17*, Domenica Gandini, MD, PhD17*, Teresa Marafioti, MD18*, Mahan Moshir, MSc17*, Tim Delahaye, MSc17*, Piotr Zabrocki, PhD17*, Karen Silence, PhD19*, Luc Van Rompaey, PhD17*, Armand Bensussan, MD, PhD20*, Hans De Haard, PhD17*, Patrick Pauwels, MD, PhD13*, Nicolas Leupin, MD17 and Stefano A. Pileri, MD, PhD10

1Hôpital Saint Louis, APHP, Inserm U976, Université Paris 7, Paris, France
2Hospital Jules Bordet, Bruxelles, France
3Istituto Di Ematologia, Bologna, Italy
4University Hospital Ghent, Gent, Belgium
5Centre Hospitalier Régional Universitaire De Lille, Nord, France
6Gustave Roussy Cancer Campus, Villejuif, France
7DITEP, Gustave Roussy, Université Paris-Saclay, Villejuif, France
8INSERM U1165, Universite Paris 7, AP-HP Hopital Saint Louis, Paris, FRA
9INSERM UMR-1160, Institut Universitaire D'Hematologie, Paris, FRA
10Unit of Hematopathology, European Institute of Oncology, MILANO, Italy
11Hospices Civils de Lyon, Claude Bernard Lyon 1 University, Lyon, France
12CHU de Bordeaux, Service de Dermatologie; Hôpital Saint-André, Bordeaux, France
13University Hospital Antwerp, Antwerp, Belgium
14University hospital Antwerp, Antwerp, Belgium
15Laboratory of Hematology, University Hospital Saint-Louis, Paris, France
16Laboratory of Hematology, University Hospital Saint-Louis, AP-HP, Paris & GBMHM External Quality Assessment platform, Paris, France
17argenx, Zwijnaarde, Belgium
18Department of Haematopathology, University College London, London, United Kingdom
19argenx, Zwijnaarde, BEL
20University Hospital Saint-Louis, Paris, France

Introduction

Cutaneous T-cell lymphoma (CTCL), a heterogeneous group of rare non-Hodgkin’s lymphomas, is characterized by infiltration of malignant clonally expanded T lymphocytes in the skin and is very challenging to treat at advanced stages. Around 65% of the CTCL cases are mycosis fungoides (MF), which usually starts as indolent disease with accumulation of neoplastic resident memory T lymphocytes in the skin, evolving from patch to plaque and later to tumor stage with poor prognosis. Sézary syndrome (SS) involves erythroderma in the skin, malignant circulating clone, and lymphadenopathy. The CTCL pathogenesis is incompletely understood but suggests a complex interplay between neoplastic T cells and the tumor microenvironment.

Glycoengineered ARGX-110 potently blocks CD70/CD27 signaling, which is thought to inhibit evasion of tumor immune surveillance as well as tumor cell proliferation and survival. The ARGX-110 effector functions, i.e., complement-dependent cytotoxicity (CDC), antibody-dependent cellular phagocytosis (ADCP), and enhanced antibody-dependent cellular cytotoxicity (ADCC), efficiently kill CD70-expressing tumor cells. With only limited expression in normal tissues and strong expression on tumor cells, CD70 is a very attractive target for antibody-based therapy in cancer. The role of CD70 and treatment with ARGX-110 was further investigated as part of a Phase 1/2 study in advanced CTCL patients.

Methods

As part of a non-randomized, open-label, multicenter Phase 1/2 study (NCT01813539), a total of 27 patients with CD70-expressing advanced CTCL of different subtypes and stages were included for determination of the optimal dose, to evaluate exploratory efficacy and safety, and to characterize pharmacokinetics and biomarkers of drug activity (immunohistochemistry [IHC] staining for drug- and disease-related markers, profiling of malignant and non-malignant immune cells by flow cytometry, quantitative polymerase chain reaction [qPCR] and Nanostring). ARGX-110 was administered intravenously at 1 (N=11) or 5 mg/kg (N=16) every three weeks (Q3W). Adverse events were graded according to NCI-CTCAE v. 4.03.

Results

ARGX-110 was safe and well tolerated at both 1 and 5 mg/kg in heavily treated CTCL patients with a median age of 67 years (range: 25-84 years). At cut-off (26th June 2018), a total of 110 treatment-emergent adverse events (TEAE) were reported in 27 patients of which 12 were grade 3-5; 40 events in 18 patients were considered drug-related by the investigator. The most common TEAE was pyrexia (7 events in 5 patients), and infusion-related reactions (IRRs) was the most common drug-related TEAE.

The best response was 1 complete response (CR), 5 partial response (PR), and 7 stable disease (SD) in 26/27 patients evaluable for response, meaning overall response (ORR) in 23% of the patients and disease stabilization in 27% of the patients. The mean duration on the study was around 4.8 months. Two patients were still on the study at cut-off: 1 patient (subcutaneous panniculitis-like T-cell lymphoma, 24 months) with CR and 1 SS patient with PR (6.5 months).

Pharmacokinetics (PK) revealed a mean half-life of 8-12 days, in line with previously published data. The 5 mg/kg dose was chosen as the recommended phase 2 dose (RP2D) based on PK and immunogenicity data. IHC staining for drug- and disease-specific markers showed results in line with clinical reduction of modified Severity Weighted Assessment Tool (mSWAT) and regression from plaque to patch stages. Molecular and cellular profiling indicated a complex interplay between the tumor and the microenvironment, in which CD70/CD27 plays a role.

Conclusions

ARGX-110 was safe and well tolerated at both dose levels (1 and 5 mg/kg) in advanced CD70-expressing CTCL patients. Clinical anti-tumor activity in patients with various types of CTCL was observed after treatment with ARGX-110, indicating ARGX-110 as a safe and promising treatment option for advanced CTCL.

Disclosures: Bagot: Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees; Actelion: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Maerevoet: Karyopharm: Membership on an entity's Board of Directors or advisory committees; takeda: Membership on an entity's Board of Directors or advisory committees, Other: travel grant; roche: Other: travel grant; abbvie: Membership on an entity's Board of Directors or advisory committees, Other: travel grant. Zinzani: SERVIER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astra Zeneca: Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Honoraria, Speakers Bureau; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees. Morschhauser: Janssen: Other: Scientific Lectures; Epizyme: Consultancy; Roche: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees. Michot: Lytix Biopharma: Other: Principal/sub-Investigator of Clinical Trials ; Daiichi Sankyo: Other: Principal/sub-Investigator of Clinical Trials ; MSD: Other: Principal/sub-Investigator of Clinical Trials ; GSK: Other: Principal/sub-Investigator of Clinical Trials ; Janssen: Honoraria, Other: Principal/sub-Investigator of Clinical Trials ; Servier: Other: Principal/sub-Investigator of Clinical Trials ; Sierra Oncology: Other: Principal/sub-Investigator of Clinical Trials ; Eos: Other: Principal/sub-Investigator of Clinical Trials ; Agios: Other: Principal/sub-Investigator of Clinical Trials ; Taiho: Other: Principal/sub-Investigator of Clinical Trials ; Astex: Other: Principal/sub-Investigator of Clinical Trials ; Gamamabs: Other: Principal/sub-Investigator of Clinical Trials ; Gortec: Other: Principal/sub-Investigator of Clinical Trials ; Lilly: Other: Principal/sub-Investigator of Clinical Trials ; Orion: Other: Principal/sub-Investigator of Clinical Trials ; H3 Biomedecine: Other: Principal/sub-Investigator of Clinical Trials ; Pharmamar: Other: Principal/sub-Investigator of Clinical Trials ; Abbvie: Other: Principal/sub-Investigator of Clinical Trials ; Menarini: Other: Principal/sub-Investigator of Clinical Trials ; Kura Oncology: Other: Principal/sub-Investigator of Clinical Trials ; Eisai: Other: Principal/sub-Investigator of Clinical Trials ; Amgen: Other: Principal/sub-Investigator of Clinical Trials ; Blueprint: Other: Principal/sub-Investigator of Clinical Trials ; Astra-Zenenca: Honoraria, Other: Principal/sub-Investigator of Clinical Trials & Non-financial support; Takeda: Other: Principal/sub-Investigator of Clinical Trials ; Celgene: Other: Principal/sub-Investigator of Clinical Trials & Non-Financial Support; Medimmune: Other: Principal/sub-Investigator of Clinical Trials ; Nanobiotix: Other: Principal/sub-Investigator of Clinical Trials ; Rohe: Other: Principal/sub-Investigator of Clinical Trials & Non- Financial support; Pierre Farbe: Other: Principal/sub-Investigator of Clinical Trials ; Debiopharm: Other: Principal/sub-Investigator of Clinical Trials ; Chugai: Other: Principal/sub-Investigator of Clinical Trials ; Sanofi: Other: Principal/sub-Investigator of Clinical Trials ; Genentech: Other: Principal/sub-Investigator of Clinical Trials ; Oncopeptides AB: Other: Principal/sub-Investigator of Clinical Trials ; Aveo Pharmaceuticals: Other: Principal/sub-Investigator of Clinical Trials ; Argen-X: Other: Principal/sub-Investigator of Clinical Trials ; Clovis: Other: Principal/sub-Investigator of Clinical Trials ; Octimet: Other: Principal/sub-Investigator of Clinical Trials ; Nektar Therapeutics: Other: Principal/sub-Investigator of Clinical Trials ; Kyowa: Other: Principal/sub-Investigator of Clinical Trials ; Innate Pharma: Other: Principal/sub-Investigator of Clinical Trials ; Incyte: Other: Principal/sub-Investigator of Clinical Trials ; BMS: Honoraria, Other: Principal/sub-Investigator of Clinical Trials & Non-Financial Support; Novartis: Other: Principal/sub-Investigator of Clinical Trials & Non-Financial Support; Oncoethix: Other: Principal/sub-Investigator of Clinical Trials ; Pfizer: Other: Principal/sub-Investigator of Clinical Trials ; Aduro: Other: Principal/sub-Investigator of Clinical Trials ; Bayer: Other: Principal/sub-Investigator of Clinical Trials ; Boeringer Ingleheim: Other: Principal/sub-Investigator of Clinical Trials ; Merus: Other: Principal/sub-Investigator of Clinical Trials ; Tesaro: Other: Principal/sub-Investigator of Clinical Trials ; Xencor: Other: Principal/sub-Investigator of Clinical Trials ; Gilead: Other: Non-Financial Support; Lysarc: Other: Principal/sub-Investigator of Clinical Trials ; Loxo: Other: Principal/sub-Investigator of Clinical Trials ; Beigene: Other: Principal/sub-Investigator of Clinical Trials ; Exelixis: Other: Principal/sub-Investigator of Clinical Trials ; Forma: Other: Principal/sub-Investigator of Clinical Trials . Ribrag: Incyte Corporation: Consultancy; Amgen: Research Funding; Infinity: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; epizyme: Consultancy, Honoraria; NanoString Technologies: Consultancy, Honoraria; Roche: Honoraria, Other: travel; Servier: Consultancy, Honoraria; pharmamar: Other: travel; argenX: Research Funding; BMS: Consultancy, Honoraria, Other: travel; MSD: Honoraria. Dalle: Kyowa Hakko Kirin Pharmaceutical: Research Funding. Cayuela: Cepheid: Other: financial sponsor to attend John Goldman Conference 2017. Hultberg: argenx: Employment. Gandini: argenx: Employment. Moshir: argenx: Employment. Delahaye: argenx: Employment. Zabrocki: argenx: Employment. Silence: argenx: Consultancy. Van Rompaey: argenx: Employment. De Haard: argenx: Employment. Leupin: argenx: Employment.

*signifies non-member of ASH