A phase 1/2 study of azacitidine, venetoclax and pevonedistat in newly diagnosed secondary AML and in MDS or CMML after failure of hypomethylating agents

Abstract

Background Pevonedistat is a first-in-class, small molecular inhibitor of NEDD8-activating enzyme that has clinical activity in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Preclinical data suggest synergy of pevonedistat with azacitidine and venetoclax. Methods This single-center, phase 1/2 study evaluated the combination of azacitidine, venetoclax and pevonedistat in older adults with newly diagnosed secondary AML or with MDS or chronic myelomonocytic leukemia (CMML) after failure of hypomethylating agents. Patients received azacitidine 75 mg/m2 IV on days 1–7, venetoclax at maximum dose of 200-400 mg orally on days 1–21 (AML cohort) or days 1–14 (MDS/CMML cohort) and pevonedistat 20 mg/m2 IV on days 1, 3 and 5 for up to 24 cycles. The primary endpoints for the phase 2 portion of the study were the CR/CRi rate in the AML cohort and the overall response rate (CR + mCR + PR + HI) in the MDS/CMML cohort. Findings Forty patients were enrolled (32 with AML and 8 with MDS/CMML). In the AML cohort, the median age was 74 years (range 61–86 years), and 27 patients (84%) had at least one adverse risk cyto-molecular feature, including 15 (47%) with a TP53 mutation or MECOM rearrangement; seventeen patients (53%) had received prior therapy for a preceding myeloid disorder. The CR/CRi rate was 66% (CR 50%; CRi 16%), and the median overall survival (OS) was 8.1 months. In the MDS/CMML cohort, 7 patients (87%) were high or very high risk by the IPSS-R. The overall response rate was 75% (CR 13%; mCR with or without HI 50%; HI 13%). The most common grade 3–4 adverse events were infection in 16 patients (35%), febrile neutropenia in 10 patients (25%) and hypophosphatemia in 9 patients (23%). In an exploratory analysis, early upregulation of NOXA expression was observed, with subsequent decrease in MCL-1 and FLIP, findings consistent with preclinical mechanistic studies of pevonedistat. Upregulation of CD36 was observed, which may have contributed to therapeutic resistance. Conclusions The triplet combination of azacitidine, venetoclax and pevonedistat shows encouraging activity in this very poor-risk population of patients with AML, MDS or CMML. Trial registration ClinicalTrials.gov (NCT03862157).

Unmet Horizons: Assessing the Challenges in the Treatment of TP53-Mutated Acute Myeloid Leukemia

“…Novel targeted therapies incorporated into combination regimens have also been explored in the TP53 mut AML setting. Pevonedistat (PEVO)-an inhibitor of the NEDD8activating enzyme (NAE)-seems to exert antiproliferative effects on LCs, and preclinical data supports synergistic effects with AZA and VEN [55][56][57]. A phase 1b study of unfit, treatment-naïve AML patients treated with PEVO and AZA showed improved responses with an ORR of 50%, with TP53 mut patients achieving a CR and partial response (PR) rate of 80% [55].…”

“…Based on these results, a phase 2 study consisting of TP53 mut AML patients was conducted, but failed to show enhanced CRR rates and was prematurely terminated [56]. Intriguingly, a phase 1/2 study evaluating the efficacy of combined PEVO, AZA, and VEN in ND secondary AML reported a CR/CRi rate of 64%, but a dreadful 1-year OS of 0% in TP53 mut patients, contrary to a median OS of 18 months in TP53 wt patients [57]. Moreover, the DOR differed significantly among these patients [57].…”

“…Intriguingly, a phase 1/2 study evaluating the efficacy of combined PEVO, AZA, and VEN in ND secondary AML reported a CR/CRi rate of 64%, but a dreadful 1-year OS of 0% in TP53 mut patients, contrary to a median OS of 18 months in TP53 wt patients [57]. Moreover, the DOR differed significantly among these patients [57]. These conflicting results may be attributable to the different VAF of patients, since the second study included only TP53 mut patients with a VAF of >30%.…”

Deciphering the role of neddylation in tumor microenvironment modulation: common outcome of multiple signaling pathways

“…When tested in combination with azacitidine and venetoclax in a phase 1/2 trial, the study targeted older adults recently diagnosed with secondary AML, MDS, or chronic myelomonocytic leukemia (CMML) and assessed their response rates to the specified drug combination [ 192 ]. Notably, an impressive complete remission or incomplete hematological recovery (CR/CRi) rate of 66% was observed in the AML cohort, whereas the MDS/CMML cohort demonstrated a robust overall response rate of 75%, signaling the potency of this drug combination [ 192 ]. However, the prevalence of common adverse events, such as infection and febrile neutropenia, must be considered [ 192 ].…”

“…Notably, an impressive complete remission or incomplete hematological recovery (CR/CRi) rate of 66% was observed in the AML cohort, whereas the MDS/CMML cohort demonstrated a robust overall response rate of 75%, signaling the potency of this drug combination [ 192 ]. However, the prevalence of common adverse events, such as infection and febrile neutropenia, must be considered [ 192 ]. Moreover, the research findings suggest potential molecular alterations that may contribute to the development of therapeutic resistance.…”