Mikkael A. Sekeres, MD, highlights findings from a phase 2 study that evaluated the combination of pevonedistat and azacitidine in higher-risk MDS, CML, and LB AML, and the next steps for research.
Mikkael A. Sekeres, MD
Pevonedistat plus azacitidine showed encouraging clinical activity in terms of event-free survival (EFS) and overall survival (OS) versus azacitidine monotherapy in patients with higher-risk myelodysplastic syndrome (MDS) and low-blast acute myelogenous leukemia (LB AML), according to Mikkael A. Sekeres, MD, who added that no notable safety differences were observed between the 2 treatment arms.
In the randomized, open-label, international, multicenter, phase 2 trial (NCT02610777), investigators evaluated the combination of pevonedistat and azacitidine versus azacitidine alone in patients with higher-risk MDS, chronic myelomonocytic leukemia (CMML), and LB AML. The primary end point of the trial was EFS, defined as the time to death or transformation to AML in higher-risk MDS/CMML or death in LB AML. Key secondary objectives included OS and overall response rate.
“Pevonedistat is a novel NEDD8-activating enzyme inhibitor that works on the cellular processes to induce apoptotic cell death,” Sekeres explained. “This occurs in cells such as blast, which play a critical role in the diagnosis of AML, MDS, and CMML.”
In the analysis, a total of 120 patients were randomized 1:1 to receive 20 mg/m2 of intravenous (IV) pevonedistat on days 1, 3, and 5 in combination with 75 mg/m2 of IV or subcutaneous azacitidine (n = 58) on days 1-5, 8, and 9, or azacitidine monotherapy (n = 62) on the same schedule in 28-day cycles.
Results showed that the median EFS was 21.0 months with pevonedistat plus azacitidine versus 16.6 months with azacitidine monotherapy in the intent-to-treat population (HR, 0.665; 95% CI, 0.423-1.047; P = .060) and the median OS was 21.8 months versus 19.0 months, respectively (HR, 0.802; 95% CI, 0.512-1.256; P = .334).
When analyzed by subgroup, patients with higher-risk MDS experienced a median EFS of 20.2 months with the combination versus 14.8 months with azacitidine alone (HR, 0.539; 95% CI, 0.292-0.995; P = .045). In this group, the median OS was 23.9 months versus 19.1 months, respectively (HR, 0.701; 95% CI, 0.386-1.273; P = .240).
Moreover, in the subgroup of patients with LB AML, the median OS was 23.6 months versus 16.0 months in the combination and monotherapy arms, respectively (HR, 0.494; 95% CI, 0.220-1.109; P = .081). Notably, due to the definition of EFS in the study, OS was equivalent to EFS in this group of patients.
Lastly, in patients with higher-risk CMML, the median EFS was 21.0 months in the combination arm versus not evaluable (NE) in the monotherapy arm (HR, 4.302; 95% CI, 0.791-23.407; the median OS in this subgroup was 21.7 months versus NE, respectively (HR, 7.519; 95% CI, 1.362-41.510; P = .010).
Regarding safety, the most common any-grade adverse effects (AEs) that occurred in at least 25% of patients in either arm and were consistent with prior data. These AEs included pyrexia (38% with combination vs 40% with monotherapy), cough (38% vs 34%, respectively), constipation (36% vs 47%), nausea (34% vs 45%), neutropenia (34% vs 29%), diarrhea (33% vs 27%), anemia (31% vs 45%), febrile neutropenia (26% vs 29%), and fatigue (21% vs 40%).
In an interview with OncLive, Sekeres, the vice-chair for Clinical Research and the director of the Leukemia Program at Cleveland Clinic Taussig Cancer Institute, further highlighted findings from a phase 2 study that evaluated the combination of pevonedistat and azacitidine in higher-risk MDS, CML, and LB AML, and the next steps for research.
OncLive: Why are new novel therapies being sought in this space?
Sekeres: Patients with higher-risk MDS, CMML, or [LB] AML, are offered a couple of different types treatment options. One is intensive induction chemotherapy, which has a high treatment-related mortality rate and is often viewed as burdensome to older patients with comorbidities and the second is less-intensive therapies. [The latter is] usually comprised of a backbone of a hypomethylating agent, such as azacitidine.
With azacitidine alone,the chance of response is somewhere around 35% and the duration of response is often measured in months, [and that equates to] approximately 6-8 months. We've been evaluating the addition of other agents to the azacitidine backbone to see whether we can improve outcomes in this patient population.
Could you provide some background on the phase 2 study that evaluated the addition of pevonedistat to azacitidine in this patient population? What were the findings?
We randomized patients to receive either azacitidine monotherapy, which is the standard, or azacitidine in combination with pevonedistat.This population was comprised of patients who were diagnosed with these conditions. The median age was 72 years and the majority of patients had higher-risk MDS. Another 36 patients had AML and the remainder had higher-risk CMML. We were very happy to see that the rates of AEs, including serious AEs, did not seem to [significantly] differ between the treatment arms.
The primary end point of the trial was EFS, and this favored the combination of pevonedistat and azacitidine at 21 months compared with 16.6 months for those patients who received azacitidine monotherapy, with a trend toward significance. The study wasn't powered to see any difference in OS, although numerically it did favor the combination at 22 months versus 19 months for azacitidine. When looking at the patients with higher-risk MDS, the median EFS was 20 months [with the combination] versus 15 months for those who received azacitidine alone, which was a significant difference. The median OS was 24 months for those who received the combination therapy versus 19 months for those who were given single-agent azacitidine.
If we instead focus on those patients who had LB AML, the median OS was, again, approximately 24 months for those who received the combination versus only 16 months for those who received monotherapy, with a trend toward significance.
We concluded from this trial that the combination was tolerable, meaning that the safety profiles didn't differ [with the addition of pevonedistat]. Additionally, there appears to be a strong signal of activity for the combination in terms of improving EFS and, for patients who had LB AML, an improvement in OS, compared with azacitidine monotherapy.
What are the next steps of this research?
In the study, there was some benefit observed in the patients with higher-risk MDS and LB AML. This study has transitioned from a randomized phase 2 study to a phase 3 study to determine whether the benefits of the combination remain consistent in these select patient populations.