Pivekimab sunirine (IMGN632), a novel CD123-targeting antibody-drug conjugate, in relapsed or refractory acute myeloid leukaemia: a phase 1/2 study.

Autor:	Daver NG; MD Anderson Cancer Center, Houston, Texas, USA. Electronic address: ndaver@mdanderson.org., Montesinos P; Hospital Universitari i Politècnic La Fe, Valencia, Spain., DeAngelo DJ; Dana-Farber Cancer Institute, Boston, MA, USA., Wang ES; Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA., Papadantonakis N; University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, AL, USA., Todisco E; Istituto Europeo di Oncologia, Milan, Italy., Sweet KL; Moffitt Cancer Center, Tampa, FL, USA., Pemmaraju N; MD Anderson Cancer Center, Houston, Texas, USA., Lane AA; Dana-Farber Cancer Institute, Boston, MA, USA., Torres-Miñana L; Hospital Universitari i Politècnic La Fe, Valencia, Spain., Thompson JE; Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA., Konopleva MY; Albert Einstein College of Medicine, Bronx, NY, USA., Sloss CM; ImmunoGen, Waltham, MA, USA., Watkins K; ImmunoGen, Waltham, MA, USA., Bedse G; ImmunoGen, Waltham, MA, USA., Du Y; ImmunoGen, Waltham, MA, USA., Malcolm KE; ImmunoGen, Waltham, MA, USA., Zweidler-McKay PA; ImmunoGen, Waltham, MA, USA., Kantarjian HM; MD Anderson Cancer Center, Houston, Texas, USA.
Jazyk:	angličtina
Zdroj:	The Lancet. Oncology [Lancet Oncol] 2024 Mar; Vol. 25 (3), pp. 388-399.
DOI:	10.1016/S1470-2045(23)00674-5
Abstrakt:	Background: Pivekimab sunirine (IMGN632) is a first-in-class antibody-drug conjugate comprising a high-affinity CD123 antibody, cleavable linker, and novel indolinobenzodiazepine pseudodimer payload. CD123 is overexpressed in several haematological malignancies, including acute myeloid leukaemia. We present clinical data on pivekimab sunirine in relapsed or refractory acute myeloid leukaemia. Methods: This first-in-human, phase 1/2 dose-escalation and dose-expansion study enrolled participants aged 18 years or older at nine hospitals in France, Italy, Spain, and the USA with CD123+ haematological malignancies (Eastern Cooperative Oncology Group performance status of 0-1); participants reported here were in a cohort of participants with acute myeloid leukaemia who were refractory to or had relapsed on one or more previous treatments for acute myeloid leukaemia. The 3 + 3 dose-escalation phase evaluated two dosing schedules: schedule A (once every 3 weeks, on day 1 of a 3-week cycle) and fractionated schedule B (days 1, 4, and 8 of a 3-week cycle). The dose-expansion phase evaluated two cohorts: one cohort given 0·045 mg/kg of bodyweight (schedule A) and one cohort given 0·090 mg/kg of bodyweight (schedule A). The primary endpoints were the maximum tolerated dose and the recommended phase 2 dose. Antileukaemia activity (overall response and a composite complete remission assessment) was a secondary endpoint. The study is ongoing and registered with ClinicalTrials.gov, NCT03386513. Findings: Between Dec 29, 2017, and May 27, 2020, 91 participants were enrolled (schedule A, n=68; schedule B, n=23). 30 (44%) of schedule A participants were female and 38 (56%) were male; 60 (88%) were White, six (9%) were Black or African American, and two (3%) were other races. Pivekimab sunirine at doses of 0·015 mg/kg to 0·450 mg/kg in schedule A was administered in six escalating doses with no maximum tolerated dose defined; three dose-limiting toxicities were observed (reversible veno-occlusive disease; 0·180 mg/kg, n=1 and 0·450 mg/kg, n=1; and neutropenia; 0·300 mg/kg, n=1). Schedule B was not pursued further on the basis of comparative safety and antileukaemia findings with schedule A. The recommended phase 2 dose was selected as 0·045 mg/kg once every 3 weeks. At the recommended phase 2 dose (n=29), the most common grade 3 or worse treatment-related adverse events were febrile neutropenia (three [10%]), infusion-related reactions (two [7%]), and anaemia (two [7%]). Treatment-related serious adverse events occurring in 5% or more of participants treated at the recommended phase 2 dose were febrile neutropenia (two [7%]) and infusion-related reactions (two [7%]). Among 68 participants who received schedule A, one death (1%) was considered to be treatment-related (cause unknown; 0·300 mg/kg cohort). At the recommended phase 2 dose, the overall response rate was 21% (95% CI 8-40; six of 29) and the composite complete remission rate was 17% (95% CI 6-36; five of 29). Interpretation: Pivekimab sunirine showed single-agent activity across multiple doses, with a recommended phase 2 dose of 0·045 mg/kg once every 3 weeks. These findings led to a phase 1b/2 study of pivekimab sunirine plus azacitidine and venetoclax in patients with CD123-positive acute myeloid leukaemia. Funding: ImmunoGen. Competing Interests: Declaration of interests NGD reports consultancy for Agios, Astellas, KITE, AbbVie, Gilead, Jazz, Daiichi Sankyo, BMS, ImmunoGen, Syndax, Novartis, Shattuck Labs, Trillium, Genentech, Stemline/Menarini, Celgene, Amgen, Pfizer, Servier, and Arog; and research funding from Astellas, Trovagene, FATE Therapeutics, Novimmune, KITE, Hanmi Pharm, AbbVie, Gilead, Daiichi Sankyo, BMS, ImmunoGen, Glycomimetics, Trillium, Genentech, Amgen, Pfizer, and Servier. PM reports consultancy for Daiichi Sankyo and Celgene; membership on an entity's Board of Directors or advisory committees for Daiichi Sankyo, AbbVie, Celgene, Novartis, Karyopharm, Incyte, Janssen, Pfizer, and Teva; research support from Daiichi Sankyo, Celgene, Novartis, Karyopharm, Janssen, Pfizer, and Teva; being on a speaker's bureau for Daiichi Sankyo, Celgene, Novartis, Incyte, Janssen, Pfizer and Teva; and research funding from Novartis, Janssen, Pfizer, and Teva. DJD reports research funding from AbbVie, Glycomimetics, and Novartis; and consultancy for Novartis, Amgen, Blueprint, Gilead Sciences, Incyte, Jazz Pharmaceuticals, Pfizer, Servier, and Takeda. ESW reports being on an advisory board or consulting for AbbVie, BMS, CTI Biopharma, Daiichi Sankyo, Genentech, GSK, Johnson & Johnson, Kite, Kura, Novartis, Rigel, Sellas, and Sumitomo Pharma; a speaker role for Astellas, Kura, and Pfizer; being on a data monitoring committee for AbbVie and Gilead; and being on a research committee for Gilead. NPa reports being on an advisory board for CTI Biopharma and Cambium Oncology; consultancy for CTI Biopharma; and research funding from Gilead, ONO Pharma, and AbbVie. ET reports consultancy for AbbVie, Janssen, and Jazz Pharmaceuticals; and being on an advisory board for AbbVie, Janssen, and Jazz Pharmaceuticals. KLS reports consultancy for Bristol Myers Squibb, Gilead, Jazz Arog, Pfizer, BerGenBio, Astellas, Novartis, Curis, Mablytics, Daiichi Sankyo, and Nkarta; and research funding from Jazz and Incyte. NPe reports consultancy for MustangBio, AbbVie, Celgene, Stemline Therapeutics, Novartis, and Incyte; research funding from MustangBio, Samus, AbbVie, Cellectis, Stemline Therapeutics, Novartis, Plexxikon, Daiichi-Sankyo, SagerStrong, Affymetrix, and Incyte; and honoraria from AbbVie, Celgene, and Stemline Therapeutics. AAL received research funding from AbbVie and Stemline Therapeutics; and consulting fees from Cimeio Therapeutics, IDRx, Jnana Therapeutics, N-of-One, and Qiagen. JET reports research funding from Bristol Myers Squibb and Novartis. MYK reports research funding from Allogene, Daiichi, Gilead, ImmunoGen, MEI Pharma, Precision Biosciences, Sanofi, Ablynx, Genentech, Cellectis, AbbVie, Stemline Therapeutics, Forty-Seven, and AstraZeneca; consultancy for Gilead, MEI Pharma, Sanofi, Janssen, Vincerx, Genentech, AbbVie, Stemline Therapeutics, and AstraZeneca; honoraria from BAKX Therapeutics, Genentech, AbbVie, and Stemline Therapeutics; and equity ownership, patents & royalties from Reata Pharmaceuticals. CMS, KW, GB, YD, KEM, and PAZ-M are employees of ImmunoGen. HMK reports honoraria from Pfizer, Takeda, Amphista, Amgen, Ascentage, Astellas, Agios, Biologix, Curis, Ipsen Biopharmaceuticals, KAHR, Medical LabCorp, Shenzhen Target, Stemline, Novartis, and AbbVie; and research funding from Jazz Pharma, BMS, Amgen, Ascentage, Agios, ImmunoGen, Cyclacel, Daiichi-Sankyo, Novartis, and AbbVie. LT-M declares no competing interests. (Copyright © 2024 Elsevier Ltd. All rights reserved.)
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