Pevonedistat Plus HMAs Provides a Promising Strategy in Higher-Risk MDS

Supplements And Featured Publications, Emerging Treatments and Clinical Challenges in Myelodysplastic Syndromes: ASCO 2021 and EHA 2021 Updates, Volume 1, Issue 1

Daniel Pollyea, MD, MS, discusses the current management of patients with higher-risk myelodysplastic syndrome, the data noted so far with pevonedistat in this paradigm, and other therapies positioned to improve outcomes for this patient population.

The clinical efficacy demonstrated with the investigational, first-in-class, NEDD8-activating enzyme inhibitor pevonedistat in combination with the hypomethylating agent (HMA) azacitidine offers a “glimmer of hope” for patients with higher-risk myelodysplastic syndrome (HR-MDS) where treatment options are limited and outcomes remain poor, said Daniel Pollyea, MD, MS.

“At the moment, we have no therapies beyond HMA monotherapy for patients [with HR-MDS]. Having anything on the market that we can use that is better [than single-agent HMAs] will be very welcome. [An FDA approval for pevonedistat] would have a very significant effect on the landscape,” said Pollyea.

Findings from the randomized phase 2 Pevonedistat-2001 study (NCT02610777) demonstrated a median event-free survival (EFS) of 21 months with the combination of pevonedistat and azacitidine compared with 16.6 months with azacitidine alone (P = .076) at a median follow-up of 21.4 months and 19 months, respectively, in patients with HR-MDS/chronic myelomonocytic leukemia and low-blast acute myelogenous leukemia (AML).1

The median overall survival (OS) was 21.8 months with pevonedistat vs 19 months with azacitidine monotherapy (P = .334).

Based on these data, the FDA granted pevonedistat a breakthrough therapy designation for the treatment of patients with HR-MDS.2

In an interview with OncLive®, Pollyea, clinical director of Leukemia Services at the University of Colorado and the UCHealth Blood Disorders and Cell Therapies Center, discussed the current management of patients with HR-MDS, the data noted so far with pevonedistat in this paradigm, and other therapies positioned to improve outcomes for this patient population.

OncLive®: What is the current role of HMAs in the treatment of patients with MDS?

Pollyea: [HMAs] are the standard of care for patients with newly diagnosed and relapsed MDS. They are also [standard] for [patients with] lower- and higher-risk disease. [HMAs] are really the only therapy that we have for almost all patients with MDS, and the efficacy we get from this [mode of] treatment is pretty disappointing.

They are therapies that don’t work very well and are all we have for the entire treatment landscape of MDS. We are very excited to improve upon responses.

How do transfusions offer support to patients with MDS? Can patients achieve transfusion independence?

Transfusion is a very important element of supportive care for patients with MDS. It is something that makes patients feel better. It can be lifesaving or life-extending, while also improving quality of life [QOL].

[Transfusions] are a supportive care resource that is a principle of the management of MDS. However, patients don’t love getting transfusions. Blood transfusions in particular take quite a long time. It [requires] a lot of time spent at a facility. So, a goal of many therapies is to reduce or free a person from the need for transfusions. When this happens, [we see] a very significant improvement with respect to QOL and other metrics. [Transfusion independence] is often a major goal, as it should be, of effectively treating patients with MDS.

What unmet needs require attention in HR-MDS?

In MDS, the entire disease is an unmet need. For a newly diagnosed patient with high-risk disease, we have very few effective therapies [available]. A patient who has progressed on HMAs essentially doesn’t have any conventional options and outcomes are very poor. Those are both major unmet needs.


We do have a therapy with respect to luspatercept-aamt [Reblozyl], which is FDA approved for some patients with lower-risk MDS. That [population] is probably less of an urgent need vs these other clinical scenarios, such as high-risk, newly diagnosed, or HMA-failure MDS populations. A lot of work needs to be done in this disease.

What therapies appear promising for patients with high-risk MDS?

There are several glimmers of hope. We are very excited about where the field is going.

Venetoclax [Venclexta] paired with azacitidine [demonstrated] very promising early-phase data for patients with newly diagnosed HR-MDS. There is now a phase 3 study ongoing to [further evaluate this combination]. We also have some preliminary data that have been presented for [venetoclax/azacitidine] in the setting of patients with HMA-failure MDS that are quite promising. I hope that is something that is pursued.

In terms of other therapies, we have pevonedistat for patients with high-risk, newly diagnosed MDS. That [agent] showed promising preliminary results, and [is the subject of] a confirmatory study that is ongoing. We are very excited to hear more about that agent.

We also have magrolimab, which is a CD47-directed antibody. That [agent] is showing some very promising preliminary results in patients with MDS.

Those are just 3 of the therapies that are the furthest along, but there is a lot to be excited about. As we learn more about this disease, how it works, and what its weaknesses are, we will be able to continue to have success targeting some of the vulnerabilities of MDS.

What efficacy data have been observed with pevonedistat?

The data that we have seen are quite promising from the randomized study of pevonedistat plus azacitidine vs azacitidine [alone] in patients with HR-MDS. The primary end point was EFS. We need more time, data, and patients, but it looks like [EFS] is an end point that [pevonedistat] might be able to meet.

The safety profile looks to be very tolerable, which is always an important principle for patients with MDS who often poorly tolerate aggressive therapies.

Some of the other metrics around that study, such as the response rate and duration of response, also look really promising. Pevonedistat is something we all have our eyes on and are very excited to hear more about the final results of the randomized study. We are very hopeful that [those data] will be positive.

Some subgroup analyses showed that higher-risk patients may have [derived] more benefit [from pevonedistat compared with lower-risk patients]. That is quite promising. Perhaps [pevonedistat has utility] even in AML. There were some cohorts of patients that were between 20% and 30% blasts, meaning they had gone beyond MDS and into AML. Those types of analyses are also quite promising.

We will have to see what the near future holds, but there is a lot to be excited about.

How do you anticipate the field will incorporate pevonedistat in the context of HMAs if it receives FDA approval?

Everything that we have seen [tells us] that [pevonedistat will be used] in conjunction with HMAs. We would need a lot more work to show that we don’t need an HMA at all, but currently, most of the studies that have been done have combined [pevonedistat] with an HMA. For now, we are stuck with HMAs as the backbone, but [HMAs] provide a lot of benefit. It will be some time until we get to a point where we can say that we don’t need HMAs at all.

References

  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
  2. Takeda announces US FDA breakthrough therapy designation granted for pevonedistat for the treatment of patients with higher-risk myelodysplastic syndromes (HR-MDS). News release. Takeda. July 30, 2020. Accessed July 14, 2021. https://bit.ly/39IYsDS.