The phase III PANTHER trial, which evaluated pevonedistat plus azacitidine vs azacitidine alone in higher-risk myelodysplastic syndromes, chronic myelomonocytic leukemia, and low–blast count acute myeloid leukemia (AML) failed to meet its primary endpoint of event-free survival,1 though lessons were learned that are applicable in the clinic, said lead investigator Mikkael A. Sekeres, MD, Professor of Medicine and Chief of the Division of Hematology, Sylvester Comprehensive Cancer Center of the University of Miami Miller School of Medicine.
“In a post hoc analysis, we saw an encouraging and significant overall survival benefit with the combination for patients with higher-risk myelodysplastic syndrome who received at least four cycles—and particularly six or more—of the treatment, underscoring the need to keep patients on azacitidine-based therapy long enough to appreciate a benefit,” he said.
Mikkael A. Sekeres, MD
Older patients with higher-risk myelodysplastic syndrome, chronic myelomonocytic leukemia, or AML with 20% to 30% marrow blasts typically receive single-agent hypomethylating agents. Median response duration and survival for these patients are poor, and many patients with myelodysplastic syndrome transform to secondary AML, where prognosis is “particularly dismal,” Dr. Sekeres noted.
“Novel hypomethylating agent–based combination therapies that improve survival, delay transformation, and increase depth and duration of response vs single-agent hypomethylating agents, without additional toxicity or myelosuppression, are needed,” he said
The hope was that pevonedistat might be a good component of such a regimen. It is a first-in-class agent that inhibits the NEDD8-activating enzyme, thereby preventing protein ubiquitination upstream of the proteasome and resulting in cell-cycle disruption and apoptotic tumor cell death. In preclinical models of AML, pevonedistat and azacitidine were synergistic.
A randomized proof-of-concept phase II study previously showed this combination improved outcomes, vs azacitidine alone, in patients with higher-risk myelodysplastic syndrome, chronic myelomonocytic leukemia, or low-blast AML not previously treated with a hypomethylating agent. In higher-risk myelodysplastic syndrome, the combination achieved a response rate of 79% and a median event-free survival of 20.2 months vs 14.8 months with single-agent azacitidine.2 The nonsignificant improvement in overall survival for the combination in the randomized phase II setting was 4 months.
The phase III trial reported by Dr. Sekeres at the ASH meeting evaluated pevonedistat plus azacitidine in the first-line setting in higher-risk myelodysplastic syndrome/chronic myelomonocytic leukemia or AML with 20% to 30% blasts.
The 454 patients, who had received no previous hypomethylating agent, included 324 with higher-risk myelodysplastic syndrome, 27 with chronic myelomonocytic leukemia, and 103 with low-blast AML. Baseline mutations in the myelodysplastic syndrome group for the respective combination and azacitidine monotherapy arms were primarily ASXL1 (41% and 39%), TET2 (30% and 26%), TP53 (29% and 26%), RUNX1 (26% and 33%), SRSF2 (27% and 21%), and DNMT3A (21% and 16%). Most patients were considered to have very-high or high-risk disease.
Patients were randomly assigned to pevonedistat at 20 mg/m2 on days 1, 3, and 5 plus azacitidine at 75 mg/m2 on days 1 to 5, 8, and 9 of a 28-day cycle, or azacitidine alone, indefinitely. The primary endpoint was event-free survival. Event-free survival and overall survival were tested sequentially in the higher-risk myelodysplastic syndrome cohort and the intent-to-treat population using separate hierarchical testing procedures, with subsequent overall survival testing in the AML cohort.
Main Efficacy Outcome
In the intent-to-treat population, median event-free survival was 17.7 months in the combination arm and 15.7 months in the single-agent arm (P = .557); median overall survival was 20.3 and 16.8 months, respectively (P = .181); and response rates were 28% and 32%, respectively.
More distinction between the arms was seen, however, in the subset with higher-risk myelodysplastic syndrome, where the combination yielded a median event-free survival of 19.2 months vs 15.6 with azacitidine alone (hazard ratio [HR] = 0.887; P = .431) and median overall survival of 21.6 months vs 17.5 months, respectively (HR = 0.785; P = .092). No distinctions between the arms were observed in the other subsets.
Drilling down further into the higher-risk myelodysplastic syndrome cohort, the study identified an overall survival benefit for patients with platelet counts < 100,000 cells/m2 (HR = 0.720; 95% confidence interval = 0.522–0.993).
More Treatment Yielded Better Results
Encouragingly, an increasing number of treatments was associated with better overall survival in both arms: receipt of at least three cycles yielded an event-free survival rate of 79% with the combination and 80% with azacitidine alone, and a median overall survival of 23.8 months and 20.6 months (HR = 0.714; P = .021). With at least six cycles, median overall survival was 27.1 months and 22.5 months, respectively (HR = 0.626; P = .008). Dr. Sekeres reported.
Treatment was discontinued by 22.4% given the combination and 22.7% of those given azacitidine monotherapy. This was due to toxicity in 13.7% and 9.2% and disease progression in 2.5% and 3.1%. The median number of cycles was nine for the combination and eight for azacitidine. The median azacitidine dose intensity was 98% in each arm.
Takeaways for the Clinic and Trial Design
Dr. Sekeres said that although the PANTHER trial is negative, its findings add to those derived from a previous combination trial that showed the importance of keeping patients on hypomethylating agents: the phase II/III North American Intergroup Study S1117, which evaluated azacitidine as a single agent and in combination with lenalidomide or vorinostat.3
With a median follow-up of 23 months, the objective response rate, the primary endpoint, was 38% with azacitidine, 49% with azacitidine plus lenalidomide (P = .14 vs azacitidine), and 27% with azacitidine plus vorinostat (P = .16 vs azacitidine). A nonsignificant overall survival difference of 4 months, however, was observed.
“As in the PANTHER trial, the study showed no difference in outcomes, but we saw that patients discontinued the combination prematurely or dose-reduced significantly more often with the combinations than with azacitidine monotherapy,” he said.
“We used that information to build the pevonedistat trial, with strict language about not dose-reducing or dose-delaying. Because of that, patients remained on treatment for a median of 8 to 9 months. They had a much higher complete response rate with monotherapy (32%), probably because they stayed on the treatment long enough to initiate a response. PANTHER showed that if you keep patients on azacitidine monotherapy or azacitidine-based combinations for a long time, they can do well.”
Additionally, Dr. Sekeres said his work on the Intergroup and PANTHER trials has convinced him that “powering studies to show a median overall survival difference of 6, 8, or 10 months is unrealistic for therapies that are not targeted in a population that is heterogeneous.” Instead, he suggested the aim should be “incremental benefit,” as is seen in trials of most other malignancies. For PANTHER and the Intergroup studies, the combinations yielded an absolute survival benefit of 4 months in the higher-risk myelodysplastic syndrome cohorts.
Longitudinal clonal evolution studies are ongoing to identify treatment effects on specific clones.
DISCLOSURE: Dr. Sekeres has served on the Board of Directors or advisory committees with Novartis, Takeda/Millennium, and Bristol Myers Squibb.
1. Sekeres M, Girshova L, Doronin V, et al: Pevonedistat + azacitidine versus azacitidine alone as first-line treatment for patients with higher-risk myelodysplastic syndromes/chronic myelomonocytic leukemia or acute myeloid leukemia with 20% to 30% marrow blasts: The randomized phase 3 PANTHER trial (NCT03268954). 2021 ASH Annual Meeting & Exposition. Abstract 242. Presented December 11, 2021.
2. Sekeres MA, Watts J, Radinoff A, et al: Randomized phase 2 trial of pevonedistat plus azacitidine versus azacitidine for higher-risk MDS/CMML or low-blast AML. Leukemia 35:2119-2124, 2021.
3. Sekeres MA, Othus M, List AF, et al: Randomized phase II study of azacitidine alone or in combination with lenalidomide or with vorinostat in higher-risk myelodysplastic syndromes and chronic myelomonocytic leukemia: North American Intergroup Study SWOG S1117. J Clin Oncol 35:2745-2753, 2017.