To the Editor

There is a critical unmet need for novel treatment options that can improve outcomes in patients with acute myeloid leukemia (AML) or higher-risk myelodysplastic syndromes (MDS). Pevonedistat (MLN4924; TAK-924) is an investigational small-molecule inhibitor of neural precursor cell expressed, developmentally downregulated 8 (NEDD8)-activating enzyme (NAE) [1,2,3]. Upregulation of the NEDD8 cascade is associated with cancer pathogenesis, making it a compelling target for drug development [4, 5]. Pevonedistat forms an adduct with NAE, preventing activation of the cascade and ultimately leading to substrate accumulation and cell death. A phase 1b study of pevonedistat and azacitidine combination treatment conducted in Western patients aged ≥ 60 years with untreated AML showed that the combination was well tolerated and exhibited clinical activity, with an objective response rate (ORR) of 50% [6]. The recommended phase 2/3 dose (RP2/3D) of pevonedistat for co-administration with azacitidine was determined to be 20 mg/m2.

Pharmacokinetics (PK) can differ between Asian and Western patients. We conducted an open-label phase 1/1b dose escalation/expansion study (NCT02782468) to assess the safety/tolerability and PK of pevonedistat as a single agent or in combination with azacitidine in East Asian patients with AML or higher-risk MDS, and to determine the RP2/3D for combination treatment in this population. Full study design and methods are provided in Additional file 1.

A total of 23 patients were enrolled in Japan, South Korea and Taiwan (n = 12/4/7). Ten patients received single-agent pevonedistat 25 mg/m2 or 44 mg/m2 (n = 3/7), and 13 patients received pevonedistat 10 mg/m2 or 20 mg/m2 (n = 3/10) plus azacitidine 75 mg/m2. Patient demographics and disease characteristics are shown in Additional file 1: Table S1. At data cut-off, 5 patients remained on combination treatment, while 18 had discontinued study treatment, primarily due to progressive disease (PD; n = 9) or adverse events (AEs; n = 6).

Safety

All 23 patients experienced at least one grade ≥ 3 treatment-emergent AE (TEAE). The safety profile of pevonedistat with/without azacitidine in East Asian patients (summarized in Table 1) was comparable to that in Western patients [6, 7], with the most common TEAEs including constipation, nausea, and anemia (Additional file 1: Table S2).

Table 1 Overall summary of TEAEs (safety population)
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Only one of twenty evaluable patients experienced DLTs: One patient receiving pevonedistat 20 mg/m2 plus azacitidine experienced grade 3 atrial fibrillation and grade 3 tumor lysis syndrome. The RP2/3D of pevonedistat in combination with azacitidine was therefore determined to be 20 mg/m2.

Pevonedistat PK

Pevonedistat PK data (summarized in Additional file 1: Table S3) showed that systemic exposure increased in an approximately dose-proportional manner over the 10–44 mg/m2 dose range. There was minimal accumulation following multiple-dose administration, consistent with the mean terminal disposition phase half-life (T1/2z) of approximately 8 h. Clearance rates were comparable for pevonedistat as a single agent and when co-administered with azacitidine, suggesting that co-administration has no clinically meaningful effects on pevonedistat exposure. These findings were consistent with previous analyses of pevonedistat PK in Western patients (Additional file 1: Table S4) [6,7,8,9].

Antitumor activity

Treatment duration and responses for the 19 evaluable patients are illustrated in Fig. 1a. ORRs were 0% in the single-agent pevonedistat arm (N = 8) and 45% in the pevonedistat plus azacitidine arm (N = 11; Additional file 1: Table S5). The median duration of response in the 5 responding patients, all of whom had AML, was 4.8 months (range 1–14 months) at data cut-off. The majority of patients with MDS (N = 6) had stable disease (n = 4), while one achieved marrow complete remission (mCR) and one had PD (Additional file 1: Table S5). Changes from baseline in myeloblast count in patients with AML and MDS are shown in Fig. 1b, c.

Fig. 1
figure 1

Treatment responses in the response-evaluable populationa (N = 19): a Swimmer plot showing responses and duration of treatmentb; Best percentage change from baseline in myeloblast count in b patients with AMLc and c patients with MDSd. AE, adverse event; AML, acute myeloid leukemia; CB, clinical benefit; CR, complete remission; CRi, complete remission with incomplete blood count recovery; HSCT, hematopoietic stem cell transplant; mCR, marrow complete remission; MDS, myelodysplastic syndromes; PD, progressive disease; PR, partial remission; SD, stable disease. aAll patients who received at least one dose of study drug, had a baseline disease assessment, and had at least one post-baseline disease assessment. bFor patients who were ongoing treatment at data cut-off and who therefore did not have a date of last visit, their date of last assessment was used to determine bar length. TP53 mutation status is indicated for the 4 patients with available data. Mutation status was unknown in the remaining patients. cTwo patients with AML in the single-agent pevonedistat 44 mg/m2 dose cohort and one patient with AML in the pevonedistat 10 mg/m2 combination arm dose cohort were excluded due to insufficient bone marrow aspirate blast data. The patient with AML with a decrease in blast count and stable disease had an abnormal cytogenetic finding at screening; stable disease was recorded on cycle 1 day 15 on November 27, 2017, and lasted to the end of study on December 7, 2017. The patient discontinued the study to initiate a hematopoietic stem cell transplant. dOne patient with MDS in the pevonedistat 20 mg/m2 combination arm dose cohort was excluded due to insufficient bone marrow aspirate blast data

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In summary, the safety and PK profiles of pevonedistat in East Asian patients were consistent with those seen in Western patients. Clinical activity was demonstrated, with an ORR of 45% in East Asian patients with AML treated with pevonedistat plus azacitidine. The RP2/3D for pevonedistat in combination with azacitidine was 20 mg/m2, the same as that previously determined in Western patients [6]. This supports use of the same treatment regimens in Western and East Asian patients in future global trials, which may help expedite access to pevonedistat-based treatment in Asia.