Pevonedistat/Azacitidine Shows Favorable Activity in Higher-Risk MDS/CMML, Low-Blast AML

The combination of pevonedistat and azacitidine led to a trend toward improved event-free survival (EFS) and a numerical improvement in overall survival (OS) versus azacitidine alone in patients with higher-risk myelodysplastic syndrome (MDS)/chronic myelomonocytic leukemia (CMML), and low-blast acute myelogenous leukemia (LB AML), according to findings from a phase 2 study (NCT02610777) that were presented during the 2020 ASCO Virtual Scientific Program.

The median EFS was 21.0 months with pevonedistat and azacitidine versus 16.6 months with azacitidine alone in the intent-to-treat (ITT) population, translating to approximately a 34% reduction in the risk of death or transformation to AML (HR, 0.665; 95% CI, 0.423-1.047; P = .076). The median OS was 21.8 months and 19.0 months, respectively (HR, 0.802; 95% CI, 0.512-1.256; P = .334).

“Patients with high-risk MDS/CMML or low-blast AML who are ineligible for high-intensity therapy or transplant need novel combination therapies that improve outcomes with an acceptable safety profile,” lead study author Lionel Ades, MD, of Hôpital Saint-Louis in Paris, France, said in a virtual presentation during the meeting.

Attempts to enhance the effects of azacitidine monotherapy with other therapies have been limited by toxicity. Pevonedistat, a first small-molecule inhibitor of the NEDD8-activating enzyme (NAE), binds to and inhibits NAE, disrupting cell proliferation and survival. In a phase 1b trial (NCT01814826), pevonedistat demonstrated promising clinical activity and tolerability in patients with acute myeloid leukemia.

In the global, open-label, multicenter, proof-of-concept study, patients with higher-risk MDS/CMML or LB AML were randomized to 20 mg/m² of intravenous (IV) pevonedistat on days 1, 3, and 5 plus 75 mg/m² of IV or subcutaneous (SC) azacitidine (n = 58) on days 1 to 5, 8, and 9, or azacitidine alone (n = 62) on the same schedule in 28-day cycles. Eligible patients had to have been ineligible for allogeneic stem cell transplant and could not have received prior hypomethylating agents.

Patients were stratified by risk according to the Revised International Prognostic Scoring System (IPSS-R) for MDS/CMML, and LB AML.

EFS, defined as the time to death or transformation to AML in higher-risk MDS/CMML or death in LB AML, served as one of the coprimary end points. OS, originally a secondary end point, became a coprimary end point according to a regulatory recommendation after enrollment. Due to the statistical design of the trial, the study was not powered to detect a difference in OS, said Ades. Objective response rate (ORR) remained a secondary end point.

Baseline patient demographics and disease characteristics were well balanced between arms, said Ades. Patients had a median age of 72.5 years (range, 34-91), and the majority were male (69%). Most patients in the combination and azacitidine-alone arms had a diagnosis of higher-risk MDS (n = 32; n = 35, respectively), followed by higher-risk CMML (n = 9; n = 8) and LB AML (n = 17; n = 19).

“There were slightly more patients with very-high risk MDS in the azacitidine arm compared with the pevonedistat plus azacitidine arm, due to changes in diagnosis or IPSS-R classification after screening and before randomization” said Ades.

Patients received a median of 13 cycles of treatment in the combination arm versus 8.5 in the azacitidine-alone arm. The median dose intensity of azacitidine was maintained at 96.9% in the combination arm versus 98.2% in the azacitidine-alone arm.

According to a prespecified subgroup analysis of the ITT population, all patients except those with intermediate-risk disease (n = 29; HR 1.890; 95% CI, 0.552-6.467) and an ECOG performance status of 2 (n = 5; HR, 3.348; 95% CI, 0.336-33.362) benefited from the combination.

In patients with higher-risk MDS, the median EFS was also prolonged with the combination versus azacitidine alone. Here, the median EFS was 20.2 months in the combination arm versus 14.8 months in the azacitidine-alone arm (HR, 0.539; 95% CI, 0.292-0.995; P =.045). The median OS was also numerically longer, at 23.9 months and 19.1 months, respectively (HR, 0.701; 95% CI, 0.386-1.273; P = .240).

The combination favored all patients with higher-risk MDS with the exception of females (n = 18; HR, 1.027; 95% CI, 0.290-3.639) and patients with intermediate IPSS-R risk (n = 20; HR, 1.071; 95% CI, 0.282-4.067).

In patients with LB AML, OS trended toward improvement with the combination of pevonedistat and azacitidine versus azacitidine alone, at 23.6 months versus 16.0 months, respectively (HR, 0.494; 95% CI, 0.220-1.109; P = .081).

Patients with higher-risk CMML did not derive EFS or OS benefit from the combination of pevonedistat and azacitidine. The median EFS was 21.0 months in the combination arm and not estimable (NE) in the azacitidine-alone arm (HR, 4.302; 95% CI, 0.791-23.407). The median OS was 21.7 months and not estimated, respectively (HR, 7.519; 95% CI, 1.362-41.510; P = .010).

The small sample size and exclusion of patients with proliferative disease among other factors may have contributed to this finding and therefore prevent definitive conclusions from being made, said Ades.

Among 108 response-evaluable patients, the ORR was 70.9% in the combination arm, consisting of a 40.0% complete response (CR) rate, 5.5% CR rate with incomplete bone marrow recovery (CRi), a 5.5% partial response (PR) rate, and a 20% hematologic improvement (HI) rate. The ORR in the azacitidine-alone arm was 60.4%, which consisted of a 30.2% CR rate, 7.5% CRi rate, 7.5% PR rate, and a 15.1% HI rate.

The median duration of response (DOR) was 20.6 months (95% CI, 10.71-34.60) in the combination arm versus 13.1 months (95% CI, 12.62—NE) in the azacitidine-alone arm.

According to a subgroup analysis, patients with higher-risk MDS (n = 59) and higher-risk CMML (n = 17)who received the combination experienced a higher ORR versus azacitidine alone, respectively at 79.3% versus 56.7% and 77.8% versus 75.0%, respectively. Patients with LB AML (n = 32) experienced an ORR of 52.9% versus 60.0%, respectively.

In patients with higher-risk MDS, the median DOR was 34.6 months (95% CI, 11.53-34.60) versus 13.1 months (95% CI, 12.02—NE) in the combination and azacitidine-alone arms, respectively. The rate of transfusion independence was 69.2% with the combination versus 50.0% with azacitidine alone.

The most common any-grade AEs occurring in at least 25% of patients in either arm were consistent with prior data with pevonedistat and the known safety profile of azacitidine, said Ades. These included pyrexia, cough, constipation, nausea, neutropenia, diarrhea, anemia, febrile neutropenia, and fatigue.

The percentage of patients with grade 3 or higher AEs, serious AEs, and AEs requiring dose modification were comparable between arms. Ninety patients in the combination arm developed grade 3 or higher AEs versus 87 patients in the azacitidine-alone arm. Serious AEs were reported in 69 and 63 patients in the combination and azacitidine-alone arms, respectively. AEs leading to treatment discontinuation were reported in 17 and 21 patients, respectively.

The most common grade 3 or higher AEs occurring in at least 10% of patients in the combination and azacitidine-alone arms, respectively, included neutropenia (33% vs 27%), febrile neutropenia (26% vs 29%), decreased neutrophil count (21% vs 10%), anemia (19% vs 27%), thrombocytopenia (19% vs 23%), and pneumonia (12% vs 10%).

The proportion of on-study death was numerically lower in the combination arm (n = 9) versus the azacitidine-alone arm (n = 16).

Given the promising activity that was reported in the phase 2 trial, a randomized phase 3 trial (NCT03268954), which has fully accrued, will evaluate the combination versus azacitidine alone in patients with higher-risk MDS/CMML and LB AML, concluded Ades.

Ades L, Watts JM, Radinoff A, et al. Phase II study of pevonedistat (P) + azacitidine (A) versus A in patients (pts) with higher-risk myelodysplastic syndromes (MDS)/chronic myelomonocytic leukemia (CMML), or low-blast acute myelogenous leukemia (LB AML) (NCT02610777). J Clin Oncol. 2020;38(suppl 15; abstr 7506). doi:10.1200/JCO/2020.38.15_suppl.7506

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