Can Pevonedistat Improve Azacitidine’s Activity in Older Patients With AML?

Adding pevonedistat, a first-in-class inhibitor of the NEDD8-activating enzyme (NAE), to azacitidine led to responses in patients with acute myeloid leukemia (AML), according to results from a phase Ib trial published in Blood. In this population of treatment-naïve older patients with AML, half of the participants responded to therapy.

Based on preclinical studies, in which pevonedistat had synergistic activity with azacitidine, Ronan T. Swords, MD, PhD, assistant professor of medicine at the Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, and co-authors evaluated the safety and tolerability of this combination in 64 patients (median age = 75 years; range = 61-89 years) with previously untreated AML.

All participants were at least 60 years old and were considered unlikely to benefit from standard induction therapy (defined as age ≥75 years, presence of antecedent myelodysplastic syndromes, adverse cytogenetic risk, or Eastern Cooperative Oncology Group performance status score of 2). Those with concurrent illness or known infection were excluded from the study.

“The advantages of this study are that it was performed across 10 sites, that the participants’ median age was 75 years, and that their median marrow blast percentage was 38.5 percent,” Peter D. Emanuel, MD, said when asked for comments on the study’s findings. “The latter is important because it indicates that these were not patients with minimal AML or smoldering AML, but that it was bona fide AML.” Read more from Dr. Emanuel in “Perspectives” at the end of this article.

To determine the maximum tolerated dose (MTD) of pevonedistat in combination with azacitidine (the study’s primary objective), the drug was administered via 60-minute intravenous infusion on days one, three, and five of a 28-day cycle, beginning at 20 mg/m2 and escalating to 30 mg/m2. Azacitidine was administered either subcutaneously or intravenously on days one through five and days eight and nine at a fixed dose of 75 mg/m2.

Treatment continued until disease progression or unacceptable toxicity (defined as grade ≥3 pevonedistat-related adverse events [AEs]).

In the dose-finding portion of the study, six patients started at the pevonedistat 20 mg/m2 dosing and three of these patients increased to 30 mg/m2. At the 30 mg/m2 dose level, two of the three patients experienced a dose-limiting toxicity (DLT; 1 persistent grade 2 bilirubin elevation and 1 reversible grade 4 aspartate transaminase elevation), so the MTD was set at 20 mg/m2.

In the MTD expansion cohort (n=55), two additional patients experienced DLTs (grade ≥3 transaminase elevation) and were successfully retreated with a reduced dose of pevonedistat. Both patients remained on study without further hepatic toxicity, the authors reported.

Patients received a median of four treatment cycles (range = 1-37 cycles), and 23 of 64 patients (36%) received at least six cycles of therapy. As seen in the TABLE, the most common treatment-emergent AEs were constipation, fatigue, nausea, and anemia. Fifty-three patients (83%) experienced grade ≥3 AEs, the most frequent of which were anemia and febrile neutropenia.

“The nature and frequency of the toxicities typically observed for azacitidine monotherapy (fatigue, gastrointestinal toxicity, myelosuppression, and subcutaneous injection-site pain) did not change significantly with the addition of pevonedistat in this study,” the researchers noted.

Treatment-related febrile neutropenia led to two patient withdrawals. There were 11 on-study deaths, because of progressive disease or disease-related events – all of which were considered unrelated to study therapy.

Based on these results, the authors stated that the recommended phase II dose of pevonedistat in this combination is 20 mg/m2.

Preliminary analyses of disease response (a secondary study objective) showed that half of the intent-to-treat population responded to the pevonedistat plus azacitidine combination, including:

  • 20 complete remissions (CRs)
  • 5 CRs with incomplete peripheral count recovery
  • 7 partial remissions

In the 23 patients receiving at least six cycles of therapy, 19 (83%) responded. “Most responding patients achieved responses within two cycles of therapy (63%), and almost all the responses reported occurred within four cycles of therapy (91%),” the authors observed.

Molecular analyses, another secondary objective of the study, revealed that six of the eight patients with TP53-mutated disease responded to treatment. Though the numbers were small, “The timing and frequency of responses suggest potential benefit from the addition of pevonedistat to a standard regimen of single-agent azacitidine,” the authors concluded.

The findings of this early-phase trial are limited by its small patient population, lack of a comparator arm, and open-label design.

The research was supported by Takeda Pharmaceuticals.

The authors report financial support from Celgene, the manufacturer of azacitidine.

Reference

Swords RT, Coutre S, Maris MB, et al. Pevonedistat, a first-in-class NEDD8-activating enzyme inhibitor, combined with azacitidine in patients with AML. Blood. 2018;131:1415-24.

TABLE. Most Common All-Cause Adverse Events (AEs)
All-grade AEs (≥25%) Grade ≥3 AEs (≥15%) Serious AEs (≥10%)
Constipation 31 (48%) 1 (2%) 0
Fatigue 27 (42%) 2 (3%) 0
Nausea 27 (42%) 0 0
Anemia 25 (39%) 19 (30%) 1 (2%)
Decreased appetite 19 (30%) 0 0
Febrile neutropenia 19 (30%) 19 (30%) 16 (25%)
Thrombocytopenia 18 (28%) 15 (23%) 1 (2%)
Pyrexia 16 (25%) 2 (3%) 4 (6%)
Neutropenia 15 (23%) 13 (20%) 0
Vomiting 15 (23%) 0 0
Pneumonia 14 (22%) 11 (17%) 9 (14%)

“Over the last several years, we have shifted away from attempting to treat older patients with AML with intensive chemotherapy regimens, because even if a remission was obtained, it was typically short-lived. So, a focus on enhancing the efficacy of either azacitidine or decitabine is a worthwhile endeavor.

From a scientific standpoint, the development of this potential new therapeutic agent makes great sense: Pevonedistat targets the E3 ubiquitin ligases, which direct the degradation of specific substrates through the proteasome. This ultimately leads to anti-proliferative effects in AML.

The overall response rate of 50 percent is impressive, but I do not believe that the results will be immediately practice-changing, especially since this agent is still investigational. Additional trials should include a randomized trial with an azacitidine-alone arm.  Or, as the authors suggest, combinations of this agent with other therapeutics.”

Peter D. Emanuel, MD
Director, Winthrop P. Rockefeller Cancer Institute
Professor of Medicine, Division of Hematology/Oncology
Kent Westbrook, MD Endowed Director’s Chair
University of Arkansas for Medical Sciences
Little Rock, AR

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