David Sallman, MD, discusses the role of hypomethylating agents in the treatment of patients with higher-risk myelodysplastic syndrome, the promise of pevonedistat in this population, the hunt for biomarkers of response to treatment, and remaining areas of unmet need to address with future efforts.
The addition of pevonedistat to the hypomethylating agent (HMA) azacitidine could represent a new standard-of-care option in the frontline treatment of patients with higher-risk myelodysplastic syndromes (MDS), pending positive data from the phase 3 PANTHER trial (NCT03268954), according to David Sallman, MD.
The trial will evaluate whether the combination will improve event-free survival (EFS) over azacitidine alone in the first-line treatment of patients with higher-risk MDS, chronic myelomonocytic leukemia (CMML), or low-blast acute myelogenous leukemia (AML).
“If the trial is positive, then it is a new standard. If not, then it would be a very unclear path forward. Based on the response rates to date, we are all very optimistic that the trial should be positive,” Sallman said. “Many of us have [previously] shown that complete remission [CR] rates are quite concordant with overall survival [OS] in these patient groups. As long as the CR rate is somewhat similar…then I would be very optimistic that this trial would be a positive study.”
In an interview with OncLive®, Sallman, an assistant member in the Department of Malignant Hematology at Moffitt Cancer Center, discussed the role of HMAs in the treatment of patients with higher-risk MDS, the promise of pevonedistat in this population, the hunt for biomarkers of response to treatment, and remaining areas of unmet need to address with future efforts.
Sallman: HMAs, such as azacitidine or decitabine, are the gold standard therapies for patients with higher-risk MDS. This is really based on the phase 3 AZA-001 trial [NCT00071799] that is now dating back quite a while but had a median OS of about 24 months, and an overall response rate [ORR] ranging [from] 40% to 50%, with about 20% of patients experiencing a CR. This has been established as the frontline standard of care since about 2006.
Real-world data show a median OS of 17 months to 18 months [in this population], and half of patients are not experiencing any response [to treatment]. The challenge is, once a HMA fails [a patient] with higher-risk MDS, they then have a median OS of approximately 6 months. No approved, or near approved, agents are available [for use] in the second-line setting. Targetable mutations do not occur, for the most part, in this population, either. With an average OS of less than 2 years, less than half of patients achieving a response [to treatment], and no good salvage options [available] outside of allogeneic transplant, there is a huge unmet need to optimize frontline therapy. [HMAs are] our standard of care, but it is quite an inadequate standard.
As far as the emerging landscape, the HMA combination landscape [in the frontline treatment of these patients] is as exciting as anything in all malignant hematology. Now, at least 3 doublets, if not as many as 5 doublets, [have emerged] and they are looking quite transformative compared with azacitidine alone—at least from a response perspective.
As far as the goal of improving OS in these patients, all these drugs are [under evaluation] in large, randomized phase 3 trials to definitively prove [whether that benefit is being achieved]. [Data from the] early, phase 1b/2 studies have been very encouraging. We are all very hopeful that multiple new doublet options [will be available] soon. We are already thinking about next steps, [which will likely entail] looking at what triplet combinations are best to evaluate in the frontline [setting for these patients]. To effectively figure this out, we need to consider safety, toxicity, cost, and efficacy.
Many patients with higher-risk MDS are transfusion dependent at baseline. They can be transfusion dependent [regarding] blood, platelets, or both, and the frequency can be as bad as twice weekly, or somewhat infrequent. More than half, or approximately 70% to 80%, of patients are transfusion dependent, with an average transfusion burden of 2 to 3 packed red blood cell units per month. However, there is a lot of variability with that. When [a patient] achieves a complete remission, by definition, [they] have achieved transfusion independence; that [occurs] in the [realm of at least] 15% to 20% [of patients] with standard treatment.
A greater percentage of patients do achieve improved hemoglobin and platelets—approximately 30% at baseline, and up to 40% could achieve that with standard HMA therapy. However, this is one of our key secondary end points because this ties the patients to the center; this is correlative with quality of life and survival, as well. The percentage of patients who achieve transfusion independence, or a high improvement of hemoglobin or platelets, is one of the most meaningful metrics for treatment. At the same time, it also speaks to the toxicity. If some treatment induces responses, but you see significant cytopenia with the combination, then that is probably less favorable—especially when we are thinking about indefinite therapy, at least in transplant-ineligible patients.
Data with this agent were reported during the 2020 ASH Annual Meeting and some have also been published. A randomized phase 2 trial looked at a relatively small cohort, [with approximately] 30 patients in both arms. Half [of the patients received] azacitidine plus pevonedistat, and the other half received azacitidine [alone]. This was a mixed cohort, so although we are focused on [those with] higher-risk MDS, [the study] did include others who had CMML, which is a disease subset with unmet need, as well as oligoblastic AML, which is essentially [just crosses] the threshold [between] MDS [and] AML.
The big thing to focus on is the response rates [reported with the combination]. Patients experienced an ORR of approximately 80%, and about 50% achieved a true CR by International Working Group criteria. This is at least double what we would expect to see in this patient population historically. Secondly, [we should note] the durability of these responses. The median duration of response [DOR] was dramatically longer [with the] combination vs azacitidine alone. [Investigators] looked at preliminary survival, which I am always a little cautious of in a non–placebo-controlled study that has a relatively small numbers of patients. Their EFS, which is a bit of a controversial topic for our patients, was technically statistically significant, [with a] P value of .045. [The EFS] was 20 months vs 15 months [in the investigative and control arms, respectively]. The [trial] was not powered to look at differences in median survival, but it was approximately 24 months in the combination arm vs around 19 months [in the control arm], which is what we expect with azacitidine therapy.
[This data look] favorable, but with small cohorts, [we must] be cautious. What is clear is that response rates are dramatically higher [with the combination]. However, we always must be a little cautious when phase 2 trials go to randomized phase 3 studies. Importantly, when we look at the toxicity profile [of the combination] vs azacitidine alone, there was no [new safety signals]. No organ toxicity, no significant increase in any adverse effect [AE] or severe AE [was observed]. It almost looked like [the patients] were receiving azacitidine alone. [Additionally, it should be mentioned that] the schedule [for the regimen] is quite easy [to administer]; it is just [given on] days 1, 3, and 5; this overlaps with the days that patients are already receiving azacitidine. Overall, the safety [of the combination] looks good, the response rates look really good, and the survival end points are too preliminary [to draw any concrete conclusions].
We are all eagerly awaiting data from PANTHER. [The trial] has a primary end point of EFS. Again, [that is] a little bit controversial, but if [results are] positive, then this is a new standard of care for patients with higher-risk MDS and would clearly be utilized in all cases over azacitidine alone. It looks like [the regimen] should be quite readily able to be rolled out to the community. Logistically, there are no unique [effects] that you need to monitor for, from a cytopenia perspective. Overall, [the regimen has been shown to be] quite well tolerated, but we need those [phase 3] data to read out.
This continues to be a big question. [We need to] further understand the mechanism of action [of pevonedistat]. This [agent] probably has a multitude of mechanisms, and even if you ask key opinion leaders in the field, there is a lot of uncertainty of what the exact mechanism of action is. We know [the agent’s] target, this NEDD8-activating enzyme, but it ultimately leads to multiple substrates accumulating, which then leads to cell cycle arrest and apoptosis. [It is important to understand] what exactly is occurring in patients that leads to this synergy. Ideally, when patients lose a response, [we need to understand] what the resistance mechanisms [to the agent] are.
[In terms of] subsets, we would love for a greater molecular profiling of these patients. Some of those data were recently presented. They show that in patients on the combination treatment, there was less progression of any mutation. [However], it does not really speak [to whether certain] molecular subsets experience a better or worse response [to treatment]. One big subset for which we want to know more about response rates, durability of response, and survival [benefit achieved with the combination] is patients with TP53-mutant [disease]. One big paradigm shift, both in elderly [patients with] AML and high-risk MDS, is thinking about whether patients have TP53-mutated disease or not. We may very well have specific therapies, both on and off trial, [that are] focused on that patient group [in the future]. We would love to see that.
We would also like to see what the depth, or quality, of remission is. We have never talked about minimal residual disease [MRD] in MDS because we never had treatments that could [achieve negativity]. With these new combinations, MRD may be the most critical biomarker for us to look at; [it could potentially help us to decide whether] one treatment is better than another [for a patient].
Are there other biomarkers—either clinical, molecular, or others—that may [indicate which] patients [will] have better or worse responses? Ideally, in the larger phase 3 study, some of those [questions will be answered in the] data [that] will read out. These are critical questions. We have multiple doublets, [but] as we go on to [investigate] triplets, what groups should we think [consider for them]?
Transformation to AML is negative for multiple reasons. The biggest issue is that this is an elderly group of patients, so if they progress on a HMA, which is the main backbone of treatment, there is really a lack of available options—unless they are younger or fit, which is less likely. [Also,] many of these patients do not necessarily have targetable mutations, although some do acquire those on their transformation to AML.
[It should be noted that] this does not happen with all patients. Overall, 30% to 35% of patients with higher-risk MDS may ultimately progress [to AML]. What is more important than the progression is, again, the lack of options. Optimizing first-line treatment [is crucial]. If it is a major change, it is going to decrease the time to AML. It is not as important what the percentage reduction is. [Regardless of] how high of a response rate we are achieving [or] what the duration of the response is, when patients progress, it is bad. There is just a lack of options [for] elderly [patients with] AML once [they] progress on HMAs; [this is an area of unmet need].