Pevonedistat Shows Promising Partner Potential for HMAs in Higher-Risk MDS

Joshua F. Zeidner, MD

For patients with higher-risk myelodysplastic syndrome (MDS), an unmet need remains for new agents or combinations to improve upon rates of complete remission (CR) observed with hypomethylating agents (HMAs) alone, according to Joshua F. Zeidner, MD, who added that the addition of pevonedistat to azacitidine has shown promise in this specific subset.

“We really have not had any new agents for patients with higher-risk MDS available [since the advent of HMAs] decades ago. We have all been yearning for novel therapies and combinations that can really improve patient survival and responses to HMAs alone,” Zeidner said. “It is an evolving area, and I’m very hopeful that not only will we find new combinations that will be effective for MDS, but we will be able to pinpoint which subgroups of patients will be able to respond to different therapies. I hope that we may even have a menu of options available. That way, we can select based on specific genomic factors and other patient characteristics and we will not treat patients with a one-size-fits-all approach, such as azacitidine alone.”

The NEDD8-activating enzyme inhibitor pevonedistat was evaluated in the phase 2 Pevonedistat-2001 trial (NCT02610777) in combination with azacitidine vs azacitidine alone in patients with higher-risk MDS, low-blast acute myeloid leukemia (AML), and CMML. Results showed that in the subgroup of patients with higher-risk MDS, the combination yielded a median event-free survival (EFS) of 20.2 months vs 14.8 months with azacitidine alone (HR, 0.539; 95% CI, 0.292-0.995; P = .045). The median overall survival in the investigative and control arms was 23.9 months vs 19.1 months, respectively. Additionally, those with higher-risk MDS were found to be more likely to achieve a response with pevonedistat plus azacitidine vs azacitidine alone, at 79.3% vs 56.7%, respectively.

“We eagerly await more data and a subsequent randomized phase 3 trial, known as PANTHER or PEVINEDISTAT-3001 [NCT03268954] to hopefully answer the question of whether pevonedistat improves outcomes in addition azacitidine vs azacitidine alone,” Zeidner noted.

In an interview with OncLive^®, Zeidner, associate professor of medicine, chief of Leukemia Research, and associate chief of research, Hematology, at the University of North Carolina Lineberger Comprehensive Cancer Center, discussed the role that HMAs have played in the MDS treatment landscape and shared data reported with promising emerging agents like pevonedistat that can be combined with HMAs to improve outcomes for certain patient subsets.

OncLive^®: What is the current role of hypomethylating agents in the treatment of patients with MDS?

Zeidner: Patients with MDS are essentially divided into 2 different risk groups: those with low-risk, and those with higher-risk MDS. We typically stratify our patients based on the Revised International Prognostic Scoring System [RIPSS], and the RIPSS has 5 different risk groups: very low, and low, which are both categorized as the lower-risk subgroup, and then intermediate, high, and very-high risk. Of course, high, and very-high are part of the higher-risk subgroup, but intermediate can occasionally be elucidated as a low- or a higher-risk subgroup, depending on other patient characteristics.

Those with higher-risk MDS are treated with HMAs as first-line treatment, and this could either be azacitidine or decitabine. Azacitidine has shown a survival advantage compared with other treatment regimens for patients with higher-risk MDS and that is currently the standard of care. However, several promising agents that are being explored in combination with HMAs, and we are eagerly awaiting to see whether that can change the treatment paradigm.

What are some of the unmet needs in this space, and what efforts with HMA are being made to address these areas?

A multitude of unmet needs exist in MDS. First and foremost [we need to develop] better frontline therapies for those with higher-risk disease. HMAs, particularly azacitidine, are known to have a complete remission [CR] rate of approximately 15% to 20%. In higher-risk MDS, about half of patients will achieve some clinical benefit [from these agents], with hematologic improvements, and so forth. [However,] only approximately 20% of these patients will achieve a CR. This is paramount for younger patients, or those who are fit to undergo an allogeneic stem cell transplant. We strive to achieve the best overall response prior to transplant. If we can find combinations or agents that improve overall complete remission rates, then that would be a huge benefit to our patients.

One of the other big unmet needs is deciphering which patients are going to respond durably to HMAs. In other words, we need to find biomarkers of response to these agents. Several studies are exploring genomic and epigenetic factors, but we really do not have a good way of identifying which patients are going to do well on HMAs. We understand some core risk subgroups that probably do not do as well with these agents, and those patients, unfortunately, do not respond very well to any therapies that we have available for MDS. Those are the TP53-mutant subgroups and some other subgroups. However, if we can find better predictive biomarkers of response, that would be a huge benefit to the field.

Lastly, I would say the biggest unmet need in MDS is in those who either do not respond to HMAs, or who respond and subsequently relapse. We really do not have any effective second-line agents [available for our patients with] higher-risk MDS that we know are effective. As such, those patients, unfortunately, have dismal outcomes. Finding better treatment [options] for the refractory and relapsed patient population is a huge unmet need.

Could you speak to the goal of transfusion independence with these agents?

Azacitidine leads to a hematologic improvement of approximately 50% in patients with higher-risk MDS, and a proportion of those patients may become transfusion independent. Transfusion independence is really a critical goal for patients because they feel better when they are transfusion independent, and they do not have to come in as frequently for lab work and transfusions.

As such, transfusion independence is a goal that most patients strive to achieve. It is particularly relevant for older patients, or those who may not be candidates for allogeneic stem cell transplant. For those patients, our goal is to maximize quality of life and improve survival, so there is no question that transfusion independence is an important goal.

You mentioned that those with higher-risk MDS represents a population with an unmet need. What are some of the data that have read out regarding the use of pevonedistat in these patients?

Pevonedistat is an interesting agent; it is a first-in-class NEDD8-activating enzyme inhibitor that works on the neddylation pathway, which ultimately leads to proteasomal degradation of certain proteins. Pevonedistat blocks that pathway and prevents the proteasomal degradation of key proteins that are implicated in cell survival. The agent has been investigated in combination with azacitidine in patients with higher-risk MDS and in those with acute myeloid leukemia [AML].

Most recently, a randomized phase 2 trial [NCT02610777] examined azacitidine plus pevonedistat vs azacitidine alone in patients with higher-risk MDS, chronic myelomonocytic leukemia, and AML. The results [from the trial] were published in Leukemia, and several presentations have been delivered over the past several years. Ultimately, the study was powered, initially, to show an improvement in event-free survival [EFS] with the pevonedistat combination. However, during this study, based on some feedback from other advisors, the primary end point was changed to overall survival [OS]. Nonetheless, among the entire patient population, no significant improvement in survival or EFS [was observed], although some trends indicated that pevonedistat had a favorable impact.

Recently, at the 2020 ASH Annual Meeting & Exposition, findings [with the combination] were presented specifically in the high-risk MDS subgroup, and there did appear to be an advantage from an EFS and ORR standpoint with the addition of pevonedistat to azacitidine.

What are the safety data that have been reported with this combination?

Pevonedistat is a very well-tolerated intravenous agent…To date, the addition of pevonedistat [to azacitidine] does not seem to increase toxicity compared with azacitidine alone. It is a well-tolerated agent, and it allows patients to potentially be treated for subsequent cycles, without having to stop early for toxicity or other reasons. It is a very promising agent, but again, we are eagerly awaiting more data to see where it fits in our treatment armamentarium.

Could you speak to the data that were presented at EHA this year regarding MDS transformation to AML?

We know that patients with higher-risk MDS, particularly those who are treated with a HMA as a first-line therapy and ultimately transform to AML, have dismal outcomes. Several studies have shown a median OS ranging from 4 to 6 months in patients who subsequently develop AML after receiving prior treatment with a HMA for MDS. We do not have known effective therapies for patients with newly diagnosed AML, who have subsequently been exposed to HMAs for MDS; this is, in part, because many of our AML treatments also include HMAs, and once a patient progresses on an HMA, they are likely to become resistant [to these agents].

A recent abstract presented during the 2021 European Hematology Association Congress looked at the outcomes of patients with MDS who had exposure to azacitidine and those who did not. Ultimately, once those patients transformed to AML, they had worse outcomes vs those with MDS who do not transform to AML. These data really corroborate with what we have seen in other studies: Once transformation to AML occurs in a [patient with] MDS, that subgroup has poor outcomes, and it behooves us to find combinations and treatments that delay or prevent transformation to AML.

Reference

1. 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. 2021;35(7):2119-2124. doi:10.1038/s41375-021-01125-4