Abstract
Background: Pevonedistat is a first-in-class inhibitor of NEDD8-activating enzyme that catalyzes the rate-limiting step of protein neddylation, a critical step in the degradation of cellular proteins that occurs upstream of the proteasome. The combination of azacitidine plus pevonedistat has resulted in high response rates and durable remissions in both myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), particularly in secondary AML (s-AML). Preclinical studies suggest that pevonedistat synergizes with venetoclax through neutralization of Mcl-1, providing rationale for the triplet combination of azacitidine, venetoclax and pevonedistat.
Methods: In this phase I/II study, adult patients (pts) with newly diagnosed s-AML, including pts with therapy-related AML (t-AML) or AML with MDS-related changes, who were unsuitable for intensive chemotherapy were eligible. Pts were required to have a performance status ≤2, total bilirubin ≤ upper limit of normal (ULN), ALT/AST ≤2.5 x ULN, and creatinine clearance ≥30 mL/min. In cycle 1, pts received azacitidine 75 mg/m 2 SC/IV on days 1-7, venetoclax on days 1-28, and pevonedistat 20 mg/m 2 IV on days 1, 3 and 5 on a 28-day schedule. Venetoclax dose ranged from 200mg to 400mg daily during the phase I dose escalation. For cycles 2 and beyond, venetoclax was given on days 1-21.
Results: Between 3/2019 and 5/2021, 28 pts were treated (3 pts at venetoclax 200mg daily and 25 pts at 400mg daily). Baseline characteristics are shown in Table 1. The median age was 74 years (range, 61-80), and 12 pts (43%) were ≥75 years of age. The study population was enriched with pts with poor-risk features, including 19 pts (68%) with adverse-risk cytogenetics, 14 (50%) with prior hypomethylating (HMA) or chemotherapy exposure for preceding hematologic malignancy, and 8 (29%) with TP53 mutation.
The overall response rate (CR+CRi+MLFS) was 71%, and the CR+CRi rate was 64%. Thirteen pts (46%) achieved CR as best response, 5 (18%) achieved CRi, and 2 (7%) achieved MLFS. Among the 18 pts who achieved CR/CRi, 8 (44%) achieved MRD negativity by multiparameter flow cytometry. Responses were observed across subgroups, including in 8/14 pts (57%) with prior HMA/chemotherapy exposure, 6/8 pts (75%) with TP53 mutation, 12/19 pts (63%) with poor-risk cytogenetics, and 8/9 pts (89%) without non-poor-risk cytogenetics.
With a median follow-up of 13.4 months (range 0.4 to 26.3+ months), the median overall survival (OS) was 8.2 months, and the median relapse-free survival was 7.5 months (Figure 1). The median OS for pts with poor-risk and non-poor cytogenetics was 7.9 and 18.0 months, respectively; for pts with and without prior HMA/chemotherapy exposure was 6.2 and 8.9 months, respectively; and for pts with inv(3) AML, TP53-mutated AML, and non-inv(3)/non-TP53-mutated AML was 3.8, 8.9, and 18.0 months, respectively. Four pts (14% of the entire cohort, 20% of responding pts) proceed to hematopoietic stem cell transplantation (HSCT), 3 of whom are still alive and 1 with inv(3) who relapsed post-HSCT and died from progressive AML.
The combination was overall well-tolerated with myelosuppression as expected with the combination of HMA plus venetoclax in AML. The median number of cycles received was 2 (range, 1-13 cycles). Non-hematologic grade ≥3 adverse events occurring in ≥2 pts included infection or neutropenic fever in 18 pts (61%), hypophosphatemia in 8 pts (29%), hyperglycemia, hyperbilirubinemia and ALT/AST elevation in 3 pts each (11%), and pneumonitis, acute kidney injury, hypokalemia and vomiting in 2 pts each (7%). One pt developed multiorgan failure on cycle 1, day 1 of therapy, with transaminase elevation, hyperbilirubinemia, renal failure and hyperferritinemia; this pt recovered with holding therapy and supportive care. Hypophosphatemia, which has previously been reported with pevonedistat, was easily managed with oral or intravenous phosphorus supplementation. The 4-week and 8-week mortality rates were 7% and 14%, respectively.
Conclusions: The combination of azacitidine, venetoclax and pevonedistat was safe and effective in a very poor-risk population of pts with s-AML, half of whom had prior HMA or chemotherapy exposure for antecedent hematologic malignancy. A randomized study evaluating azacitidine and venetoclax ± pevonedistat (NCT04266795) is ongoing and will help to clarify the potential role of pevonedistat in the frontline treatment of AML.
Short: AstraZeneca: Consultancy; Jazz Pharmaceuticals: Consultancy; NGMBio: Consultancy; Astellas: Research Funding; Novartis: Honoraria; Takeda Oncology: Consultancy, Research Funding; Amgen: Consultancy, Honoraria. Alvarado: Daiichi-Sankyo: Research Funding; Jazz Pharmaceuticals: Research Funding; FibroGen: Research Funding; BerGenBio: Research Funding; MEI Pharma: Research Funding; Sun Pharma: Consultancy, Research Funding; CytomX Therapeutics: Consultancy; Astex Pharmaceuticals: Research Funding. Konopleva: KisoJi: Research Funding; Ascentage: Other: grant support, Research Funding; AstraZeneca: Other: grant support, Research Funding; Agios: Other: grant support, Research Funding; Ablynx: Other: grant support, Research Funding; Cellectis: Other: grant support; Forty Seven: Other: grant support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; Calithera: Other: grant support, Research Funding; Sanofi: Other: grant support, Research Funding; Stemline Therapeutics: Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Yilmaz: Pfizer: Research Funding; Daiichi-Sankyo: Research Funding. Jain: Genentech: Honoraria, Research Funding; Cellectis: Honoraria, Research Funding; Precision Biosciences: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Research Funding; Pfizer: Research Funding; Adaptive Biotechnologies: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Aprea Therapeutics: Research Funding; Janssen: Honoraria; Incyte: Research Funding; Servier: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Fate Therapeutics: Research Funding; Beigene: Honoraria; TG Therapeutics: Honoraria; Pharmacyclics: Research Funding; AbbVie: Honoraria, Research Funding. Borthakur: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ryvu: Research Funding; ArgenX: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Astex: Research Funding; University of Texas MD Anderson Cancer Center: Current Employment; GSK: Consultancy; Protagonist: Consultancy. DiNardo: ImmuneOnc: Honoraria, Research Funding; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Foghorn: Honoraria, Research Funding; Forma: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Novartis: Honoraria; Agios/Servier: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Research Funding; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding. Daver: Astellas: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; Glycomimetics: Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; FATE Therapeutics: Research Funding; Amgen: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Trovagene: Consultancy, Research Funding; Hanmi: Research Funding; Novimmune: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Issa: Syndax Pharmaceuticals: Research Funding; Novartis: Consultancy, Research Funding; Kura Oncology: Consultancy, Research Funding. Pemmaraju: MustangBio: Consultancy, Other; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Aptitude Health: Consultancy; Samus: Other, Research Funding; Plexxicon: Other, Research Funding; Sager Strong Foundation: Other; CareDx, Inc.: Consultancy; Cellectis S.A. ADR: Other, Research Funding; Daiichi Sankyo, Inc.: Other, Research Funding; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Springer Science + Business Media: Other; Pacylex Pharmaceuticals: Consultancy; Celgene Corporation: Consultancy; Roche Diagnostics: Consultancy; DAVA Oncology: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; LFB Biotechnologies: Consultancy; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Incyte: Consultancy; Affymetrix: Consultancy, Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Clearview Healthcare Partners: Consultancy; Blueprint Medicines: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy. Sasaki: Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding. Ravandi: AstraZeneca: Honoraria; Jazz: Honoraria, Research Funding; Taiho: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Honoraria, Research Funding; Novartis: Honoraria; Prelude: Research Funding. Kadia: Genfleet: Other; Cure: Speakers Bureau; Genentech: Consultancy, Other: Grant/research support; Amgen: Other: Grant/research support; Dalichi Sankyo: Consultancy; Jazz: Consultancy; Novartis: Consultancy; Liberum: Consultancy; Aglos: Consultancy; Pfizer: Consultancy, Other; AbbVie: Consultancy, Other: Grant/research support; Pulmotech: Other; BMS: Other: Grant/research support; Astellas: Other; Sanofi-Aventis: Consultancy; AstraZeneca: Other; Cellonkos: Other; Ascentage: Other. Andreeff: Breast Cancer Research Foundation: Research Funding; Aptose: Consultancy; Daiichi-Sankyo: Consultancy, Research Funding; Karyopharm: Research Funding; Novartis, Cancer UK; Leukemia & Lymphoma Society (LLS), German Research Council; NCI-RDCRN (Rare Disease Clin Network), CLL Foundation; Novartis: Membership on an entity's Board of Directors or advisory committees; Glycomimetics: Consultancy; Senti-Bio: Consultancy; Oxford Biomedica UK: Research Funding; Syndax: Consultancy; AstraZeneca: Research Funding; ONO Pharmaceuticals: Research Funding; Amgen: Research Funding; Reata, Aptose, Eutropics, SentiBio; Chimerix, Oncolyze: Current holder of individual stocks in a privately-held company; Medicxi: Consultancy. Bose: Pfizer: Research Funding; Constellation Pharmaceuticals: Research Funding; Novartis: Honoraria; Sierra Oncology: Honoraria; Kartos Therapeutics: Honoraria, Research Funding; Blueprint Medicines: Honoraria, Research Funding; CTI BioPharma: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Incyte Corporation: Honoraria, Research Funding; Astellas: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding. Kantarjian: Ipsen Pharmaceuticals: Honoraria; Amgen: Honoraria, Research Funding; Precision Biosciences: Honoraria; Astellas Health: Honoraria; Astra Zeneca: Honoraria; Immunogen: Research Funding; Daiichi-Sankyo: Research Funding; KAHR Medical Ltd: Honoraria; Aptitude Health: Honoraria; Pfizer: Honoraria, Research Funding; Ascentage: Research Funding; NOVA Research: Honoraria; BMS: Research Funding; Jazz: Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Taiho Pharmaceutical Canada: Honoraria. Cortes: Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Bio-Path Holdings, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sun Pharma: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Bristol Myers Squibb, Daiichi Sankyo, Jazz Pharmaceuticals, Astellas, Novartis, Pfizer, Takeda, BioPath Holdings, Incyte: Consultancy, Research Funding.
