ASH Clinical News ACN_4.7_FULL_ISSUE_DIGITAL | Page 22

Written in

Featured research from recent issues of Blood
PAPER SPOTLIGHT

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 treatmentnaïve 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 ” on opposite page .
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 / m 2 and escalating to 30 mg / m 2 . Azacitidine was administered either subcutaneously or intravenously on days one through five and days eight and nine at a fixed dose of 75 mg / m 2 .
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 / m 2 dosing and three of these patients increased to 30 mg / m 2 . At the 30 mg / m 2 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 / m 2 .
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 / m 2 .
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 %)
20 ASH Clinical News June 2018