Summary
While the last few years have seen the arrival of new drugs for patients with acute myeloid leukemia (AML), including targeted drugs and immunotherapies, there is still an unmet need for novel drugs for patients with this disease (and its precursor, myelodysplastic syndrome [MDS]).
Patients who are older and/or too frail or sick to be eligible for allogeneic stem cell transplant (because they may not be able to tolerate the procedure) are left with limited treatment options, particularly patients with higher-risk MDS.
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Original Article
Phase II Trial Data for Pevonedistat Drug Combination Encouraging
Oncology Times
By Sarah DiGiulio
While the last few years have seen the arrival of new drugs for patients with acute myeloid leukemia (AML), including targeted drugs and immunotherapies, there is still an unmet need for novel drugs for patients with this disease (and its precursor, myelodysplastic syndrome [MDS]).
Patients who are older and/or too frail or sick to be eligible for allogeneic stem cell transplant (because they may not be able to tolerate the procedure) are left with limited treatment options, particularly patients with higher-risk MDS.
So encouraging data from the phase II trial of the novel drug pevonedistat used in combination with azacitidine are welcome. Pevonedistat is a first-in-class NEDD8-activating enzyme (NAE) inhibitor. The NEDD8 pathway is thought to be a critical one in the cancer cell replication and proliferation process; pevonedistat treatment disrupts cell-cycle progression and cell survival leading to cell death in some cancers, including leukemias.
Patients with higher-risk MDS, higher-risk chronic myelomonocytic leukemia (CMML), or low-blast AML who received the drug combination responded to the treatment regimen at slightly higher rates compared with azacitidine treatment alone—with trends toward longer overall survival and event-free survival, too. The trial results were presented at the 2020 ASCO Annual Meeting (Abstract 7506).
“It’s exciting to see such encouraging results in the Pevonedistat-2001 trial, particularly in higher-risk MDS, an aggressive type of MDS associated with poor prognosis, diminished quality of life, and higher chance of transformation to AML,” Lionel Adès, MD, PhD, a physician at Hôpital Saint-Louis in Paris and a primary investigator of the new study, said in a press release. “Adding pevonedistat to the current standard of care in higher-risk MDS doubled complete remission rates, increased the duration of response, and improved long-term outcomes with a safety profile similar to azacitidine alone, which may address a significant need for people living with this disease.”
Though, it’s worth noting that this trial was a proof-of-concept study intended to show clinical activity for this drug combination. A phase III trial is ongoing.
Study Details
This trial included 120 patients with higher-risk MDS, higher-risk CMML, or low-blast AML who were ineligible for allogeneic stem cell transplant and had not previously been treated with hypomethylating agents. Overall survival was the primary endpoint; event-free survival was one the secondary endpoints.
The patients received a median of 13 cycles of the drug combination or a median of 8.5 cycles of azacitidine alone.
The data showed the following results:
- Median overall survival was 21.8 months for the patients taking pevonedistat plus azacitidine and 19 months for patients taking azacitidine alone.
- Event-free survival was 21 months for the patients taking the drug combination versus 16 months for those taking azacitidine alone.
Just looking at the subgroup of 67 patients with higher-risk MDS, the data showed:
- Median overall survival for patients taking the drug combination was 23.9 months versus 19.1 months for those taking just azactidine.
- Median event-free survival for patients taking the drug combination was 20.2 months compared with 14.8 months for those taking just azacytidine.
- The overall response rate for patients taking the drug combination was 79.3 percent versus 56.7 percent among patients just taking azacitidine.
Data about safety showed that the safety profile for the pevonedistat-azacitidine combination was similar to that of azacitidine alone, and did not lead to increased myelosuppression.
The most common adverse effects (grade 3 or higher) for patients in either arm were neutropenia, febrile neutropenia, decreased neutrophil count, anemia, thrombocytopenia, and pneumonia. Among patients taking the drug combination, five individuals died during the study period versus 10 patients taking just azacitidine.
The new data are encouraging, said Guido Marcucci, MD, Chair and Professor in the Department of Hematologic Malignancies Translational Science and Director of the Gehr Family Center for Leukemia Research at City of Hope, who was not an investigator in this clinical trial but was a consultant in the development of pevonedistat.
He cautions, however, that this trial was not designed to be adequately powered to answer questions about whether the pevonedistat-azacitidine combination was better than azacitidine alone for any of these groups of patients. The ongoing phase III trial will better help answer that question, Marcucci told Oncology Times in an interview.
“This study was done particularly as a proof-of-concept that the combination is feasible, it’s not toxic, and [it] provides some clinical response,” he said.
It was interesting—even though it was not the primary endpoint—that event-free survival for patients with MDS was significantly higher among patients taking the drug combination versus azacitidine alone, Marcucci noted. For patients with MDS, one of the events that can happen, in addition to lapsed disease, is the transformation of MDS into AML. So if the combination works better to prevent more patients with MDS from progressing to AML, that finding would be an important one, he said.
But more data from more patients in the phase III trial will be needed to tease out those details and show the true size of that effect.
Beyond the results of the phase III trial, Marcucci noted that, if those data are also positive, he will look forward to additional trials down the line that use this drug combination (pevonedistat plus azacitidine) in a more complex combination with other molecular-targeting therapies. In that way, he said the goal of the phase III trial is to establish this pevonedistat-azacitidine combination therapy not only as a more effective treatment, but a building block to continue to increase efficacy of treatments even further.
The data is also important because while there has been a significant number of new drugs for AML in the past few years, the case is quite different for patients with MDS.
“The drugs that are available for MDS patients are still very limited, so the approach that we can take for the treatment of these patients is very limited as well. So one more drug that could be effective in MDS is very significant.”
Sarah DiGiulio is a contributing writer.