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Safety and Efficacy of Cusatuzumab in Combination with Venetoclax and Azacitidine (CVA) in Patients with Previously Untreated Acute Myeloid Leukemia (AML) Who Are Not Eligible for Intensive Chemotherapy;An Open-Label, Multicenter, Phase 1b Study
Blood ; 138:369, 2021.
Article in English | EMBASE | ID: covidwho-1582289
ABSTRACT

Background:

Acute myeloid leukemia (AML) is driven by aberrant leukemic stem cells (LSCs) that initiate and sustain malignancy. To circumvent resistance to therapy, combination therapies with additive mechanisms of action are needed. CD70, a tumor necrosis factor receptor ligand, and its receptor CD27 are expressed on LSCs and AML blasts, but not on hematopoietic stem cells. Cusatuzumab, a high-affinity humanized monoclonal anti-CD70 antibody, kills CD70-expressing cells by Fc domain-mediated effector functions and is a potent inhibitor of CD70-CD27 signaling. Here we report initial results of a study of cusatuzumab in combination with the current standard of care therapy, venetoclax plus azacitidine (CVA), in patients with untreated AML (de novo or secondary) ineligible for intensive chemotherapy due to age ≥75 years or medical comorbidities.

Methods:

The primary objective of this open label, multicenter, phase 1b study was to assess safety and tolerability of CVA. Key secondary objectives included response rate per ELN 2017 criteria and time to response. Patients received cusatuzumab 10 or 20 mg/kg IV on Day 3 and Day 17, a 3-day ramp-up of venetoclax (100, 200, and 400 mg PO) followed by 400 mg daily dosing, and azacitidine 75 mg/m 2 SC or IV on Days 1-7 of each 28-day cycle.

Results:

Based on data through Jul 9, 2021, 44 patients enrolled with median age 75 years (range 32-89), 36.4% had secondary AML, 40.9% had an ECOG performance status of 2, and ELN risk was favorable, intermediate and adverse in 18.2%, 20.5% and 61.4%, respectively. All patients received 20 mg/kg cusatuzumab except for 3 patients who received a starting dose of 10 mg/kg with the option to escalate to 20 mg/kg. Of these 3 patients, 1 escalated to 20 mg/kg. At a median follow-up of 29.1 weeks, the median number of treatment cycles was 4.0 (range 1.0-11.0). Grade 3 or above TEAEs were reported in 97.7% of patients;the most common (reported in ≥10%) were neutropenia (68.2%), thrombocytopenia (65.9%), febrile neutropenia (36.4%), anemia (34.1%), leukopenia (29.5%), sepsis (27.3%), and lymphopenia (15.9%). Treatment-emergent serious adverse events (SAEs) were reported in 75% of patients;the most common (reported in at least ≥5%) were febrile neutropenia (27.3%), sepsis (22.7%), COVID-19 (6.8%), and thrombocytopenia (6.8%). Treatment-emergent SAEs of grade ≥3 were reported in 72.7% of the patients. Infusion-related reactions (IRRs) were reported for 11.4% of patients with 2.3% at grade ≥3. Six (13.6%) patients discontinued treatment due to AEs, and 5 (11.4%) TEAEs resulted in death. The mortality rate within 30 days from start of treatment was 4.5%. Table 1 summarizes best response to study treatment. In the intent-to-treat analysis set (n=44) complete remission (CR) rate was 45.5%, while CR + CR with partial hematologic recovery (CRh) + CR with incomplete hematologic recovery (CRi) was 77.3%;MLFS was observed in 11.4% of patients. Of 34 responders (defined as CR, CRi or CRh), 47% were MRD negative by flow cytometry at or after achievement of response. Median time to first response for patients who achieved CR, CRh or CRi was 4.21 (3.0-25.0) weeks. Best response rates in the post-hoc response evaluable analysis set (n=42) that excluded two patients who died before the first disease evaluation were CR in 47.6%, CR + CRh + CRi in 81.0% and MLFS in 11.9% of patients (Table 1). The majority (97.1%) of responders experienced at least one cycle delay in administration of CVA post response.

Conclusions:

Cusatuzumab administered in combination with venetoclax and azacitidine to elderly patients with untreated AML was generally well tolerated and demonstrated a safety profile consistent with that previously reported with venetoclax-azacitidine, with the addition of generally manageable IRRs. Response rates support an additive effect of cusatuzumab to the standard of care with potential for improved clinical outcomes. However, further clinical trials are needed for validation of these initial results. HK and GB contributed equally to this publ cation. [Formula presented] Disclosures Roboz AstraZeneca Consultancy;Janssen Research Funding;Bristol Myers Squibb Consultancy;Jasper Therapeutics Consultancy;Agios Consultancy;Novartis Consultancy;Amgen Consultancy;Blueprint Medicines Consultancy;Janssen Consultancy;Helsinn Consultancy;Daiichi Sankyo Consultancy;Glaxo SmithKline Consultancy;Celgene Consultancy;Jazz Consultancy;MEI Pharma - IDMC Chair Consultancy;Mesoblast Consultancy;Actinium Consultancy;AbbVie Consultancy;Astex Consultancy;Bayer Consultancy;Astellas Consultancy;Roche/Genentech Consultancy;Pfizer Consultancy;Otsuka Consultancy. Aribi Seagen Consultancy. Brandwein Astellas Honoraria;Jazz Honoraria;Amgen Honoraria;Taiho Honoraria;BMS/Celgene Honoraria;Pfizer Honoraria;Abbvie Honoraria;University of Alberta Current Employment. Döhner Astellas Consultancy, Honoraria, Research Funding;AstraZeneca Consultancy, Honoraria;Berlin-Chemie Consultancy, Honoraria;Amgen Consultancy, Honoraria, Research Funding;Abbvie Consultancy, Honoraria, Research Funding;Agios Consultancy, Honoraria, Research Funding;Celgene Consultancy, Honoraria, Research Funding;GEMoaB Consultancy, Honoraria;Helsinn Consultancy, Honoraria;Janssen Consultancy, Honoraria;Jazz Consultancy, Honoraria, Research Funding;Novartis Consultancy, Honoraria, Research Funding;Oxford Biomedicals Consultancy, Honoraria;Pfizer Research Funding;Roche Consultancy, Honoraria;Gilead Consultancy, Honoraria;Bristol Myers Squibb Consultancy, Honoraria, Research Funding;Astex Consultancy, Honoraria;Ulm University Hospital Current Employment. Fiedler Jazz Pharmaceuticals Consultancy, Other support for meeting attendance;Abbvie Consultancy, Honoraria;Morphosys Consultancy;Celgene Consultancy;Pfizer Consultancy, Research Funding;Novartis Consultancy;ARIAD/Incyte Consultancy;Amgen Consultancy, Other support for meeting attendance, Patents & Royalties, Research Funding;Servier Consultancy, Other support for meeting attendance;Daiichi Sankyo Consultancy, Other support for meeting attendance;Stemline Consultancy. Gandini argenx Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Geddes University of Calgary Current Employment;Taiho Consultancy, Membership on an entity's Board of Directors or advisory committees;Jazz Consultancy, Membership on an entity's Board of Directors or advisory committees;Pfizer Consultancy, Membership on an entity's Board of Directors or advisory committees;Novartis Consultancy;BMS Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Celgene Consultancy, Membership on an entity's Board of Directors or advisory committees;Amgen Consultancy;Paladin Consultancy;Janssen Research Funding;Geron Research Funding;Abbvie Membership on an entity's Board of Directors or advisory committees, Research Funding. Hou University of Pittsburgh Medical Center Hillman Cancer Centers Current Employment;AbbVie Honoraria;AstraZeneca Honoraria;Karyopharm Honoraria;Chinese American Hematology Oncology Network Membership on an entity's Board of Directors or advisory committees. Howes Janssen R&D, part of Johnson & Johnson Current Employment;Johnson & Johnson Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Hultberg argenx Current Employment, Patents & Royalties. Huselton University of Rochester Current Employment. Jacobs Argenx BV Current Employment, Current equity holder in publicly-traded company;University of Antwerp Ended employment in the past 24 months. Kane Janssen R&D, part of Johnson & Johnson Current Employment, Current equity holder in publicly-traded company. Lech-Marańda Takeda Membership on an entity's Board of Directors or advisory committees;AbbVie Membership on an entity's Board of Directors r advisory committees;Novartis Membership on an entity's Board of Directors or advisory committees;Roche Membership on an entity's Board of Directors or advisory committees;Janssen-Cilag Membership on an entity's Board of Directors or advisory committees;Amgen Membership on an entity's Board of Directors or advisory committees;Sanofi Membership on an entity's Board of Directors or advisory committees;Gilead Membership on an entity's Board of Directors or advisory committees, Research Funding. Louwers argenx Current Employment, Patents & Royalties Patents (no royalties). Nottage Janssen R&D, part of Johnson & Johnson Current Employment;Johnson & Johnson Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Platzbecker Novartis Honoraria;AbbVie Honoraria;Janssen Honoraria;Celgene/BMS Honoraria;Geron Honoraria;Takeda Honoraria. Rampal Pharmaessentia Consultancy;BMS/Celgene Consultancy;Abbvie Consultancy;Sierra Oncology Consultancy;Incyte Consultancy, Research Funding;Blueprint Consultancy;Disc Medicine Consultancy;Jazz Pharmaceuticals Consultancy;Constellation Research Funding;Kartos Consultancy;Stemline Consultancy, Research Funding;CTI Consultancy;Novartis Consultancy;Memorial Sloan Kettering Current Employment. Salman Janssen Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Shah Janssen R&D, part of Johnson & Johnson Current Employment. Stuart Clinical Drug Development Consultants LLC Current Employment;Argenx Consultancy;Cleave Therapeutics Consultancy;Triphase Accelerator Corp Consultancy;IgM Biosciences Consultancy;Revolution Medicines Consultancy;Jiya CorpConsultancy;Geron Corp Current holder of individual stocks in a privately-held company. Subklewe Janssen Consultancy;Pfizer Consultancy, Speakers Bureau;Takeda Speakers Bureau;Klinikum der Universität München Current Employment;MorphoSys Research Funding;Novartis Consultancy, Research Funding, Speakers Bureau;Roche Research Funding;Seattle Genetics Consultancy, Research Funding;Miltenyi Research Funding;Gilead Consultancy, Research Funding, Speakers Bureau;Amgen Consultancy, Research Funding, Speakers Bureau;BMS/Celgene Consultancy, Research Funding, Speakers Bureau. Sumbul argenx Current Employment. Wang Takeda Consultancy, Honoraria, Other Advisory board;Jazz Pharmaceuticals Consultancy, Honoraria, Other Advisory Board;Astellas Consultancy, Membership on an entity's Board of Directors or advisory committees;Stemline Therapeutics Consultancy, Honoraria, Other Advisory board, Speakers Bureau;AbbVie Consultancy, Membership on an entity's Board of Directors or advisory committees;Kite Pharmaceuticals Consultancy, Honoraria, Other Advisory Board;GlaxoSmithKline Consultancy, Honoraria, Other Advisory Board;Genentech Membership on an entity's Board of Directors or advisory committees;BMS/Celgene Membership on an entity's Board of Directors or advisory committees;DAVA Oncology Consultancy, Speakers Bureau;Kura Oncology Consultancy, Honoraria, Other Advisory board, steering committee, Speakers Bureau;Novartis Consultancy, Honoraria, Other Advisory Board;Mana Therapeutics Consultancy, Honoraria;Pfizer Consultancy, Honoraria, Other Advisory Board, Speakers Bureau;Rafael Pharmaceuticals Other Data safety monitoring committee;Gilead Consultancy, Honoraria, Other Advisory board;Daiichi Sankyo Consultancy, Honoraria, Other Advisory board;PTC Therapeutics Consultancy, Honoraria, Other Advisory board;Genentech Consultancy;MacroGenics Consultancy. Wierzbowska Jazz Research Funding;Pfizer Honoraria;Janssen Honoraria, Membership on an entity's Board of Directors or advisory committees;Novartis Honoraria, Membership on an entity's Board of Directors or advisory committees;Astellas Honoraria, Membership on an entity's Board of Directors or advisory comm ttees;Abbvie Honoraria, Membership on an entity's Board of Directors or advisory committees;BMS Honoraria. Yao Statagize LLC Current Employment;Puma Biotechnology, Inc. Ended employment in the past 24 months;Argenx Consultancy. Yee Astex Membership on an entity's Board of Directors or advisory committees, Research Funding;Janssen Research Funding;TaiHo Membership on an entity's Board of Directors or advisory committees;Otsuka Membership on an entity's Board of Directors or advisory committees;Onconova Research Funding;Pfizer Membership on an entity's Board of Directors or advisory committees;Tolero Research Funding;Novartis Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Paladin Membership on an entity's Board of Directors or advisory committees;MedImmune Research Funding;AbbVie Honoraria;Bristol-Myers Squibb/Celgene Membership on an entity's Board of Directors or advisory committees;Shattuck Labs Membership on an entity's Board of Directors or advisory committees;Forma Therapeutics Research Funding;Takeda Membership on an entity's Board of Directors or advisory committees;Geron Research Funding;Genentech Research Funding;F. Hoffmann La Roche Membership on an entity's Board of Directors or advisory committees, Research Funding;Jazz Research Funding. Kantarjian Immunogen Research Funding;Astra Zeneca Honoraria;KAHR Medical Ltd Honoraria;Astellas Health Honoraria;Pfizer Honoraria, Research Funding;NOVA Research Honoraria;Ascentage Research Funding;Precision Biosciences Honoraria;Novartis Honoraria, Research Funding;Aptitude Health Honoraria;Ipsen Pharmaceuticals Honoraria;Jazz Research Funding;Daiichi-Sankyo Research Funding;BMS Research Funding;Amgen Honoraria, Research Funding;AbbVie Honoraria, Research Funding;Taiho Pharmaceutical Canada Honoraria. Borthakur Protagonist Consultancy;Ryvu Research Funding;Astex Research Funding;GSK Consultancy;Novartis Consultancy, Membership on an entity's Board of Directors or advisory committees;Takeda Membership on an entity's Board of Directors or advisory committees;University of Texas MD Anderson Cancer Center Current Employment;ArgenX Membership on an entity's Board of Directors or advisory committees.
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Full text: Available Collection: Databases of international organizations Database: EMBASE Language: English Journal: Blood Year: 2021 Document Type: Article

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Full text: Available Collection: Databases of international organizations Database: EMBASE Language: English Journal: Blood Year: 2021 Document Type: Article