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817 Anti-CCR4 Monoclonal Antibody, Mogamulizumab, Demonstrates Significant Improvement in PFS Compared to Vorinostat in Patients with Previously Treated Cutaneous T-Cell Lymphoma (CTCL): Results from the Phase III MAVORIC StudyClinically Relevant Abstract

Hodgkin Lymphoma and T/NK Cell Lymphoma—Clinical Studies
Program: Oral and Poster Abstracts
Type: Oral
Session: 624. Hodgkin Lymphoma and T/NK Cell Lymphoma—Clinical Studies: T-Cell Lymphoma Clinical Studies
Monday, December 11, 2017: 4:30 PM
Bldg A, Lvl 4, Marcus Aud. (Georgia World Congress Center)

Youn H. Kim, MD1, Martine Bagot, MD2*, Lauren Pinter-Brown, MD3*, Alain H. Rook, MD4*, Pierluigi Porcu, MD5*, Steven M. Horwitz, MD6, Sean Whittaker, MD7*, Yoshiki Tokura, MD, PhD8*, Maarten Vermeer, MD, PhD9*, Pier Luigi Zinzani, MD, PhD10, Lubomir Sokol, MD11*, Stephen Morris, MD7*, Ellen Kim, MD4*, Pablo L. Ortiz-Romero, MD12*, Herbert Eradat, MD13*, Julia Scarisbrick, MBChB, FRCP, MD14*, Athanasios Tsianakas, MD15*, Craig Elmets, MD16*, Stephane Dalle, MD, PhD17*, David C. Fisher, MD, PhD18*, Ahmad S. Halwani, MD 19, Brian Poligone, MD, PhD20*, John P. Greer, MD21, Maria Teresa Fierro, MD22*, Amit Khot, MBBS, MD, MRCP, FRCPath, FRACP23, Alison J. Moskowitz, MD6, Karen Dwyer, MBBS, PhD, FRACP24*, Junji Moriya24*, Jeffrey Humphrey, MD24*, Stacie Hudgens25*, Dmitri O. Grebennik, MD24*, Kensei Tobinai, MD, PhD26 and Madeline Duvic, MD27*

1Stanford University, Stanford, CA
2Hôpital Saint Louis, Inserm, Université Paris 7, Paris, France
3UC Irvine, Orange, CA
4University of Pennsylvania, Philadelphia, PA
5Thomas Jefferson University, Philadelphia, PA
6Memorial Sloan Kettering Cancer Center, New York, NY
7Guy's and St Thomas' Hospital, London, United Kingdom
8Hamamatsu University School of Medicine, Hamamatsu, Japan
9Department of Dermatology, Leiden University, Leiden, Netherlands
10Institute of Hematology "Seràgnoli" University of Bologna, Bologna, Italy
11Moffitt Cancer Center, Tampa, FL
12Department of Dermatology, Institute i+12, Hospital 12 de Octubre Medical School, University Complutense Madrid, Madrid, Spain
13UCLA Medical Center, Santa Monica, CA
14University Hospital Birmingham, Birmingham, United Kingdom
15University Hospital Mϋnster, Mϋnster, Germany
16University of Alabama, Birmingham, AL
17Hospices Civils de Lyon, Claude Bernard Lyon 1 University, Lyon, France
18Dana-Farber Cancer Institute, Boston, MA
19Huntsman Cancer Institute, Salt Lake City, UT
20Rochester Skin Lymphoma Center, Fairport, NY
21Vanderbilt University Medical Center, Nashville, TN
22University of Turin, Turin, Italy
23Peter MacCallum Cancer Centre, Melbourne, Australia
24Kyowa Kirin Pharmaceutical Development, Inc., Princeton, NJ
25Clinical Outcome Solutions, Tucson, AZ
26National Cancer Center Hosp., Tokyo, Japan
27MD Anderson Cancer Center, Houston, TX

Introduction: Cutaneous T- cell lymphoma (CTCL) is a rare form of non-Hodgkin lymphoma. Patients with CTCL suffer reduced quality of life from intractable itching and recurrent infections. Advanced stages have a poor prognosis. Mogamulizumab (Moga) is a monoclonal antibody directed against chemokine receptor 4 (CCR4), which is overexpressed on malignant T-cells. In a Phase I-II study in CTCL, Moga demonstrated a tolerable safety profile with a 37% overall response rate (ORR). Based on these results, MAVORIC [NCT01728805], an open-label, multinational, randomized, Phase III study, was initiated to compare Moga to vorinostat (Vor) in previously treated CTCL. This study is the largest randomized trial and the first pivotal trial to use progression-free survival (PFS) as a primary endpoint in CTCL.

Methods: Adult patients with histologically confirmed mycosis fungoides (MF) or Sézary syndrome (SS) who had failed ≥1 systemic therapy were enrolled, stratified by disease type (MF or SS) and stage (IB/II or III/IV), and randomized 1:1 to Moga 1.0 mg/kg (weekly for the first 4-week cycle and then every 2 weeks) or Vor (400 mg daily). Patients randomized to Vor could crossover to Moga upon progression or intolerable toxicity. The primary endpoint was investigator-assessed PFS in the randomized population using the global composite response (based on skin, blood, nodes and viscera) according to the ISCL/EORTC consensus guidelines. Sample size was calculated to provide 90% power to detect a 50% improvement in PFS. Key secondary endpoints included ORR, duration of response (DOR) and quality of life (QoL).

Results: A total of 372 patients were randomized (Intent-to-Treat population) and had the following characteristics (Moga vs Vor): median age 63.5 yrs (25-101) vs 65.0 yrs (25-89); ECOG-PS 0-1, 184 (99%) vs 186 (100%); ECOG-PS 2, 2 (1%) vs 0; stage IB/IIA, 36 (19.4%) vs 49 (26.3%); stage IIB, 32 (17.2%) vs 23 (12.4%); stage III/IV, 118 (63.4%) vs 114 (61.3%); MF, 105 (56.5%) vs 99 (53.2%); SS, 81 (43.5%) vs 87 (46.8%). The median number of prior systemic treatments for both the Moga and Vor arms was 3. According to investigator assessment, treatment with Moga resulted in a significant improvement in PFS compared to Vor (HR 0.53 [95% CI: 0.41, 0.69], p<0.0001) with a median PFS of 7.7 months (95% CI: 5.7, 10.3) for Moga and 3.1 months (95% CI: 2.9, 4.1) for Vor (Figure 1). Improvement in PFS was also demonstrated based on independent review (HR 0.64 [95% CI: 0.49, 0.84], p=0.0007): 6.7 months for Moga and 3.8 months for Vor. Moga was associated with superior PFS in predefined subgroups (Figure 2). Global ORR was significantly improved in the patients randomized to Moga at 28.0% vs 4.8% for Vor (p<0.0001). ORR in predefined subgroups, DOR and response by disease compartment all favored Moga vs Vor (Table 1). Significant improvement in ORR was found with Moga vs Vor in patients with both MF (21.0% vs 7.1%, respectively; p=0.0042) and SS (37.0% vs 2.3%, respectively; p<0.0001). An ORR of 30.1% was observed in Moga treated patients who crossed over from Vor. Patient-reported outcomes, as measured by the Skindex-29 and FACT-G, showed significantly greater symptom reduction and improved functional status in favor of Moga vs Vor in early cycles and throughout treatment (p<0.05). The median dose intensity for Moga was 97.5% vs 95.7% for Vor, supporting adequate treatment in both arms. Treatment exposure was longer with Moga (median 170 vs 84 days for Vor). The most common treatment-emergent adverse events (TEAEs; >20%) that were more frequent (>15% difference) in the Moga vs Vor arm included infusion-related reactions (33.2% vs 0.5%, respectively) and skin eruptions due to drug (23.9% vs 0.5%, respectively). The majority of TEAEs with Moga were mild to moderate in severity (grade I/II, 54.9%; grade III/IV/V, 42.4%). Common TEAEs reported more often with Vor vs Moga included diarrhea (61.8% vs 23.4%), nausea (42.5% vs 15.2%), thrombocytopenia (30.6% vs 11.4%), dysgeusia (29.0% vs 3.3%), and increased blood creatinine (28.0% vs 3.3%).

Conclusions: In this first report of a randomized Phase III study evaluating PFS as primary endpoint in CTCL, Moga, a novel CCR4-targeting antibody therapy, demonstrated significantly superior PFS, ORR, and QoL compared to Vor in patients with previously treated CTCL. The safety profile was consistent with previous reports. This study supports Moga as a valuable new therapeutic option in patients with CTCL.

Disclosures: Kim: Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Research Funding; Soligenix: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Portola: Consultancy, Research Funding; Neumedicine: Research Funding; miRagen: Research Funding; Merck: Research Funding; Medivir: Membership on an entity's Board of Directors or advisory committees; Kyowa-Kirin-Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Consultancy, Research Funding; Horizon Pharma: Consultancy, Research Funding; Forty Seven Inc: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tetralogic: Research Funding; Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees. Bagot: Innate Pharma: Equity Ownership, 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; Kyowa: Membership on an entity's Board of Directors or advisory committees. Horwitz: Kyowa-Hakka-Kirin: Consultancy, Research Funding; Mundipharma: Consultancy; ADCT Therapeutics: Research Funding; Forty-Seven: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; HUYA: Consultancy; Millenium/Takeda: Consultancy, Research Funding; BMS: Consultancy; Seattle Genetics: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Aileron Therapeutics: Research Funding. Whittaker: Celgene: Honoraria; Galderma: Research Funding. Vermeer: Innate Pharma safety board for IPH4102-101: Membership on an entity's Board of Directors or advisory committees. Zinzani: Gilead Sciences: Consultancy; Janssen: Consultancy; Merck: Consultancy; Celgene: Consultancy. Sokol: Spectrum Pharmaceuticals: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy. Kim: Kyowa Kirin Pharmaceutical Development, Inc.: Other: Clinical trials investigator; Solgenix: Other: Clinical trials investigator; Actelion: Consultancy; Cutaneous Lymphoma Foundation: Membership on an entity's Board of Directors or advisory committees; US Cutaneous Lymphoma Consortium: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy. Ortiz-Romero: ACTELION: Consultancy; 4SC: Consultancy; Innate Pharma: Consultancy; Takeda: Consultancy; MEDA: Research Funding. Eradat: Abbvie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Genentech: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding; Novartis: Research Funding; Celgene: Research Funding; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding. Scarisbrick: 4SC: Consultancy; Takeda: Consultancy; Mallinckrodt: Consultancy; Innate Pharma: Consultancy; Actelion: Consultancy. Elmets: NCI: Research Funding; Veterans Administration: Research Funding; California Wine Grape Assn: Research Funding; Solegenix: Research Funding; Idera: Research Funding; Elorac: Research Funding; Ferndale Labs: Consultancy, Research Funding; Astellas Pharma: Research Funding. Dalle: Kyowa Hakko Kirin Pharmaceutical: Research Funding. Fisher: Celgene: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Halwani: Amgen: Research Funding; Pharmacyclics: Research Funding; Takeda: Research Funding; Genetech Inc.: Research Funding; Roche/Genentech Inc.: Research Funding; Seattle Genetics: Research Funding; Bristol Myers Squib: Research Funding; Kyowa Hikko Kirin: Research Funding; AbbVie: Research Funding; Immune Design: Research Funding; Miragen: Research Funding. Poligone: Actelion Pharmaceutical: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy; Kyowa Hakko Kirin: Research Funding; Soligenix: Research Funding. Khot: Celgene: Consultancy; Janssen: Consultancy; Amgen: Other: Travel Grant. Moskowitz: Incyte: Research Funding; Takeda: Honoraria; Bristol Myers-Squibb: Consultancy, Research Funding; ADC Therapeutics: Research Funding; Seattle Genetics: Honoraria, Research Funding. Dwyer: Kyowa Kirin Pharmaceutical Development, Inc.: Employment. Moriya: Kyowa Kirin Pharmaceutical Development, Inc.: Employment. Humphrey: KYOWA KYRIN PHARMACEUTICAL DEVELOPMENT: Employment. Hudgens: Clinical Outcomes Solutions: Consultancy, Research Funding. Grebennik: Kyowa Kirin Pharmaceutical Development, Inc.: Employment. Tobinai: AbbVie: Research Funding; Chugai: Honoraria, Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Zenyaku Kogyo: Honoraria; GlaxoSmithKline: Research Funding; Takeda: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Servier: Research Funding; Janssen: Honoraria, Research Funding; HUYA Bioscience: Honoraria; Daiichi Sankyo Co., Ltd: Consultancy, Honoraria; Mundipharma: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding. Duvic: MDACC: Other: Safety Oversight Committee, Research Funding.

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