Efficacy and Safety of Ublituximab in Combination with Umbralisib (U2) in Patients with Chronic Lymphocytic Leukemia (CLL) By Treatment Status: A Sub-Analysis of the Phase 3 Unity-CLL Study
Authors: Jacobs Ryan , Jurczak Wojciech , Flinn Ian W. , Grosicki Sebastian , Giannopoulos Krzysztof , Wróbel Tomasz , Zafar Syed F. , Cultrera Jennifer L. , Kambhampati Suman , Danilov Alexey V. , Burke John M. , Goldschmidt Jerome , Beach Douglas F. , Huntington Scott F. , Pinilla Ibarz Javier , Sharman Jeff P. , Siddiqi Tanya , Brander Danielle M. , Shadman Mazyar , Pagel John M. , Dlugosz-Danecka Monika , Ghosh Nilanjan , Kolibaba Kathryn S. , Sportelli Peter , Miskin Hari P. , O'Connor Owen A. , Weiss Michael S. , Gribben John G. 
Published: November 2021

Abstract
Background: Umbralisib, a selective PI3Kδ and casein kinase-1epsilon (CK1ε) inhibitor, is pharmacologically distinct from other PI3K inhibitors and is administered orally once daily. Ublituximab is a novel anti-CD20 monoclonal antibody glycoengineered for enhanced antibody-dependent cellular cytotoxicity that targets a unique epitope on CD20. The primary analysis of the randomized, multicenter, Phase 3 UNITY-CLL trial (NCT02612311) demonstrated that the umbralisib+ublituximab (U2) combination prolonged progression-free survival (PFS) compared to chemoimmunotherapy in both treatment-naïve (TN) and previously treated (PT) populations (Gribben et al. 2020). Herein, results are presented for patients treated with U2 by treatment status.
Methods: Patients ≥18 years of age with TN or PT CLL requiring treatment, per iwCLL criteria with adequate organ function and ECOG PS ≤2, were eligible. Patients were initially randomized 1:1:1:1 to receive U2, obinutuzumab+chlorambucil (O+Chl), umbralisib monotherapy, or ublituximab monotherapy. Stratification factors included treatment status (treatment-naïve vs. previously treated) and deletion 17p status.
Umbralisib was administered orally at 800 mg once daily until progression or removal from treatment for other reasons. Ublituximab was administered intravenously at 900 mg on Days 1/2 [split 150/750 mg], 8, and 15 of Cycle 1, Day 1 of Cycles 2 - 6, and on Day 1 every 3 cycles after Cycle 6. The primary endpoint was independent review committee (IRC)-assessed PFS of U2 compared to O+Chl. Key secondary endpoints included IRC-assessed overall response rate (ORR), complete response, undetectable minimal residual disease (uMRD), duration of response, and safety, assessed from the first dose until 30 days after the last dose of study medication. While the primary analysis reported results for the pooled intent-to-treat population, the current analysis focuses on outcomes in patients treated with U2 by treatment status.

Results: At data cut-off date of May 1, 2020, U2-treated patients had a median follow-up of 35.27 months. Of the 210 patients treated with U2, 119 were TN and 91 were PT. TN patients had a median age of 68 years (39 - 88 years) and 63% were male. Median PFS for U2 in TN patients was 38.5 mos (95% CI, 33.2, NE) with an estimated 24-mo PFS rate of 76.6%. IRC-assessed ORR was 84.0% (95% CI, 77.5%-90.6%). The median duration of exposure to umbralisib and ublituximab was 26.5 and 29.5 mos, respectively. In TN patients, AEs of special interest (AESI) of grade ≥3 included: neutropenia (24.1%), diarrhea (13.8%), ALT increased (12.1%), AST increased (7.8%), non-infectious colitis (2.6%), infusion-related reaction (IRR, 0.9%), and pneumonitis (0.9%). Discontinuation of either study drug due to these grade ≥3 AESI occurred in 5.2% (neutropenia), 2.6% (diarrhea), 3.4% (ALT increase), 1.7% (AST increase), 1.7% (colitis), 0.9% (IRR), and 0.9% (pneumonitis) of patients.
PT patients had a median of 2 prior (1 - 9) lines of therapy, the median age was 65 years (43 - 87 years) and 65.9% were male. Median PFS was 19.5 mos (95% CI, 14.6-27.7) with an estimated 24-mo PFS rate of 41.3%. The IRC-assessed ORR was 82.4% (95% CI, 74.6%-90.2%). Among 14 patients previously treated with ibrutinib, the ORR was 57%. The median duration of exposure to umbralisib and ublituximab were 15.6 mos and 14.6 mos, respectively. In PT patients, AESI of grade ≥3 included: neutropenia (40.0%), diarrhea (10.0%), IRR (3.3%), ALT increase (3.3%), AST increase (2.2%), and non-infectious colitis (2.2%). Discontinuation of either study drug due to these grade ≥3 AESI occurred in 1.1% (ALT increase), 1.1% (AST increase), and 1.1% (colitis) of patients.
Conclusions: U2 demonstrated a tolerable safety profile in both the TN and PT populations. These results mark the first randomized Phase 3 trial of a PI3K in TN CLL, establishing a new mechanism of action in this setting.

Disclosures
Jacobs: Genentech: Consultancy; Jannsen: Speakers Bureau; TG Therapeutics: Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding, Speakers Bureau; Verastem: Consultancy; AbbVie: Consultancy, Speakers Bureau; SecuraBio: Consultancy, Speakers Bureau; TeneoBio: Research Funding; MEI Pharma: Research Funding; Adaptive Biotechnologies: Consultancy; ADC Therapeutics: Consultancy. Jurczak: Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Research Funding; Morphosys: Research Funding; Mei Pharma: Research Funding; Merck: Research Funding; Loxo Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Epizyme: Research Funding; Debbiopharm: Research Funding; Celgene: Research Funding; Celtrion: Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding. Flinn: ArQule: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Loxo: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Infinity Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Agios: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Seagen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding; Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Celgene: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Curis: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Juno Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Incyte: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Verastem: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Forma Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forty Seven: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Great Point Partners: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Karyopharm Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Genentech: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AstraZeneca: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Novartis: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Takeda: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Calithera Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Portola Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; IGM Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; TG Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Roche: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Rhizen Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Teva: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Trillium Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Triphase Research & Development Corp.: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Century Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Hutchison MediPharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Vincerx Pharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Sarah Cannon Research Institute: Current Employment; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Seagen: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Unum Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute, Research Funding; Johnson & Johnson: Current holder of individual stocks in a privately-held company; Seattle Genetics: Research Funding. Giannopoulos: Sandoz: Consultancy, Honoraria; Pfizer: Honoraria; Teva: Honoraria; Karyopharm: Consultancy, Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Bei-Gene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Astra-Zeneca: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; TG Therapeutics: Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Polish Myeloma Consortium, Next Generation Hematology Association: Membership on an entity's Board of Directors or advisory committees; Sanofi-Genzyme: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding. Wróbel: Novartis: Honoraria, Speakers Bureau; BMS: Honoraria; Roche: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; BeiGene: Honoraria. Cultrera: Beigene: Research Funding. Danilov: Gilead Sciences: Research Funding; Bristol-Meyers-Squibb: Honoraria, Research Funding; Takeda Oncology: Research Funding; TG Therapeutics: Consultancy, Research Funding; Abbvie: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Rigel Pharm: Honoraria; Bayer Oncology: Consultancy, Honoraria, Research Funding; Astra Zeneca: Consultancy, Honoraria, Research Funding; SecuraBio: Research Funding; Genentech: Consultancy, Honoraria, Research Funding. Burke: Kymera: Consultancy; Adaptive Biotechnologies: Consultancy; Beigene: Consultancy, Speakers Bureau; Epizyme: Consultancy; AbbVie: Consultancy; MorphoSys: Consultancy; Verastem: Consultancy; Bristol Myers Squibb: Consultancy; Kura: Consultancy; Roche/Genentech: Consultancy; AstraZeneca: Consultancy; SeaGen: Consultancy, Speakers Bureau; X4 Pharmaceuticals: Consultancy. Goldschmidt: Ontada: Current Employment; Blue Ridge Cancer Care: Current Employment; Amgen: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; TG Therapeutics: Honoraria; G1 Therapeutics: Honoraria, Speakers Bureau. Beach: TG Therapeutics: Speakers Bureau. Huntington: TG Therapeutics: Research Funding; DTRM Biopharm: Research Funding; AbbVie: Consultancy; AstraZeneca: Consultancy, Honoraria; Flatiron Health Inc.: Consultancy; Bayer: Honoraria; Servier: Consultancy; Genentech: Consultancy; Novartis: Consultancy; Thyme Inc: Consultancy; SeaGen: Consultancy; Pharmacyclics: Consultancy, Honoraria; Celgene: Consultancy, Research Funding. Pinilla Ibarz: Sellas: Other: ), patents/royalties/other intellectual property; AbbVie, Janssen, AstraZeneca, Takeda: Speakers Bureau; AbbVie, Janssen, AstraZeneca, Novartis, TG Therapeutics, Takeda: Consultancy, Other: Advisory; MEI, Sunesis: Research Funding. Sharman: TG Therapeutics: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy; BeiGene: Consultancy; AstraZeneca: Consultancy; Centessa: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy; Lilly: Consultancy; AbbVie: Consultancy. Siddiqi: AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Juno therapeutics: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; BeiGene: Other: DSM Member, Speakers Bureau; PCYC: Speakers Bureau; Jannsen: Speakers Bureau; Dava Oncology: Honoraria; ResearchToPractice: Honoraria. Brander: Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AstraZeneca: Research Funding; ArQule: Research Funding; DTRM: Research Funding; Ascentage: Research Funding; Genentech: Consultancy, Research Funding; Novartis: Research Funding; TG Therapeutics: Consultancy, Research Funding; AbbVie: Consultancy, Other: informCLL registry steering committee, Research Funding; Verastem: Consultancy; MEI Pharma: Research Funding; LOXO: Research Funding; NCCN: Other: panel member; ArQule/Merck: Consultancy; Juno Therapeutics/Celgene/Bristol Myers Squibb: Research Funding; BeiGene: Research Funding; Pfizer: Consultancy, Other: Biosimilars outcomes research panel. Shadman: Abbvie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, Beigene, Bristol Myers Squibb, Morphosys, TG Therapeutics, Innate Pharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, Eli Lilly, Adaptimmune , Mustang Bio and Atara Biotherapeutics: Consultancy; Mustang Bio, Celgene, Bristol Myers Squibb, Pharmacyclics, Gilead, Genentech, Abbvie, TG Therapeutics, Beigene, AstraZeneca, Sunesis, Atara Biotherapeutics, GenMab: Research Funding. Pagel: AstraZeneca: Consultancy; Gilead: Consultancy; Pharmacyclics/AbbVie: Consultancy; Incyte/MorphoSys: Consultancy; Actinium Pharmaceuticals: Consultancy; Kite, a Gilead Company: Consultancy; MEI Pharma: Consultancy; Epizyme: Consultancy; BeiGene: Consultancy. Dlugosz-Danecka: Janssen: Consultancy, Research Funding; Roche: Consultancy, Research Funding, Speakers Bureau; Servier: Consultancy, Speakers Bureau; Acerta Pharma: Research Funding; AbbVie: Research Funding; Macrogenics: Research Funding; Beigene: Research Funding; MEI Pharma: Research Funding; Incyte Corp.: Research Funding; Takeda: Research Funding. Ghosh: Janssen: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Speakers Bureau; Karyopharma: Consultancy, Honoraria; Genentech: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Epizyme: Honoraria, Speakers Bureau; Genmab: Consultancy, Honoraria; Adaptive Biotech: Consultancy, Honoraria; AbbVie: Honoraria, Speakers Bureau. Kolibaba: TG Therapeutics: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Atara Biotechm: Consultancy; McKesson Specialty Health: Consultancy; Sunitomo Dainippon Pharma: Consultancy; Tolero Pharma: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Sportelli: TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Miskin: TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. O'Connor: Mundipharma: Consultancy; Nomocan: Consultancy; Kymera: Consultancy, Current equity holder in publicly-traded company; TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company; Dren: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Myeloid Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Weiss: TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Gribben: Takeda: Honoraria; Novartis: Honoraria; Morphosys: Honoraria; Gilead/Kite: Honoraria; BMS: Honoraria; Abbvie: Honoraria; AZ: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; TG Therapeutics: Honoraria.