Luspatercept Outperforms ESA in Duration of Anemia Response in MDS
During a live event, Thomas LeBlanc, MD, MA, discussed the outcomes of the COMMANDS trial of luspatercept in myelodysplastic syndromes.
Thomas W. LeBlanc, MD, MA
For patients with low-risk myelodysplastic syndrome (MDS), control of disease-related anemia is the main treatment goal. Reducing the need for red blood cell (RBC) transfusions is a vital quality of life priority, and treatment options beyond erythropoietin-stimulating agents (ESAs) are now being employed in this setting. In a recent in-person Case-Based Roundtable meeting for oncologists in Raleigh, North Carolina, Thomas W. LeBlanc, MD, MA, associate professor of medicine in the Duke University School of Medicine, discussed the trial data supporting the use of luspatercept-aamt (Reblozyl) as first-line therapy with the goal of reducing transfusion dependence.
Targeted OncologyTM: Could you describe the design and goals of the COMMANDS trial (NCT03682536) of luspatercept?
Thomas LeBlanc, MD: This was the phase 3 randomized controlled trial looking at ESA-naive patients with lower-risk MDS who are requiring some transfusions, at least 2 units of blood over an [8-week] period at enrollment. There was a randomization to get either luspatercept or ESA. This is the pivotal trial that proved to us that luspatercept is superior to ESA as a first-line treatment in these kinds of patients. The eligibility criteria [included] adults with low-risk MDS who don't have deletion 5q, who've never had a hypomethylating agent or other active treatment, and who are ESA naive.
They had to have serum erythropoietin [EPO] levels under 500 U/L because they were randomly assigning to ESA or luspatercept and couldn't enroll people with higher EPO levels, because it wouldn't be ethical to randomly assign them to something you know is not going to work. Luspatercept probably does work in people with higher EPO levels too, but ESA doesn't work, so you couldn't do this randomization. That's the reason this has now made it into some guidelines—I think incorrectly—about guiding who should get what therapy.
The primary end point for this trial is RBC transfusion independence for at least a 12-week period, plus an increase in average hemoglobin by 1.5 g/dL or higher. It's a pretty stringent end point.
These are all patients with low-risk MDS. These are people who have had MDS for months, sometimes even longer, and that's typical of lower-risk MDS presentations where they may not need transfusions yet. They may not have symptomatic anemia yet, but if it progresses, they need transfusions, and they get randomly assigned on a study like this. Approximately three-quarters had ring sideroblasts [RS]. About two-thirds had an SF3V1 mutation. Some higher-risk patients were RS negative and don't have the SF3V1 mutation, and there was a [varying degree] of how much [transfused] blood patients were needing prior to randomization. But everybody was anemic, because you had to be to enroll in this trial.1
What were the key outcomes of this trial?
Looking at the topline efficacy results, the reason why the COMMANDS trial led to this frontline indication in the label for luspatercept from the FDA is because…in the overall intention-to-treat population…there was almost a twice as high likelihood of achieving RBC transfusion independence with luspatercept compared with ESA [60% vs 35%, respectively].2 This is why it's the new standard for most people with lower-risk MDS.
If you look at more or less heavily transfusion-dependent patients, EPO levels, SF3V1 mutation, and RS status, these were all important subgroups going into this trial. In the heavily transfusion-dependent patients, ESA performs worse, and so does luspatercept, but there's still a pretty huge difference here [48% with luspatercept vs 21% with ESA]. The benefit appears to persist across a lot of these different key subgroups. With the EPO levels, when you get to more than 200 U/L, ESA is very unlikely to help. Some people at 200 to 500 U/L get that benefit [11%], but more will get it with luspatercept [38%]. There are differences with SF3V1 mutation status, although when they're negative, there's a little bit less of a difference [45% vs 36%, respectively], and for the RS-negative patients, things look about the same with luspatercept vs ESA [47% vs 50%, respectively], although with longer follow-up, we do see some separation.
How did patients respond over a long-term period with luspatercept?
In those maintaining a 1.5-year transfusion-independence duration, there is a nice benefit here in some of these more exceptional responders.3 All in all, it seems like the overwhelming majority of groups and subgroups have a meaningful benefit from luspatercept upfront compared with ESA upfront. This is why luspatercept has that category 1 recommendation now in the NCCN guidelines.4 No matter how you look at it, it's pretty clear that luspatercept works better in more people, and the duration of benefit is superior as well. The average duration of benefit was approximately 2.5 years with luspatercept vs 1.5 years with ESA on the COMMANDS trial.5
Time to RBC need looks better with luspatercept as well [HR, 0.579; 95% CI, 0.446-0.750; P < .0001].5 It's going to be a longer time before the patient starts needing blood again, but everybody ultimately loses their transfusion independence. This is not a disease-modifying therapy. It's a supportive care therapy. That's nice because that means it has a better tolerability profile than a cytotoxic therapy, and it works better than ESA with a very similar adverse event [AE] profile. But it doesn't work forever. It just works longer and better than ESA.
[Looking at] the mean change in hemoglobin levels plotted over time on the COMMANDS trial, ESA [remains] at 1.5 g/dL and the luspatercept at 2 or greater. You get a more meaningful improvement in the hemoglobin level in even the patients who do not achieve transfusion independence. If you look at the proportion of patients who hit 1.5 g/dL improvement or higher with luspatercept, it's approximately 75% of patients. What I usually tell patients in the clinic is, 3 out of 4 people who I give luspatercept will have at least a meaningful improvement in their hemoglobin level but 60% will come off transfusions entirely for at least a 12-week period. With ESA, it's about 50% who will hit that hemoglobin threshold, and only about 30% to 33% who will achieve the RBC transfusion independence. It's easy to say it works about twice as well as ESA.
What was the AE profile seen in this trial?
Looking at the AE profile with 10% or higher of any grade, there are almost no high-grade AEs with this therapy, other than anemia, which is due to the MDS.2 But there is high-grade hypertension with this therapy. We know ESA causes hypertension. It's 4.5% high-grade here on COMMANDS, and it's about 10% high-grade hypertension with luspatercept. You see high-grade hypertension about twice as often with this therapy as you do with the ESAs. The other AEs are the same [rate of] high grade from luspatercept to ESA, but there are some lower grade AEs that we see a little bit more often with this therapy. I usually tell patients they may have some nausea; it's usually going to be mild to moderate. We can typically manage it with good supportive care.
You see a bit more gastrointestinal toxicity with this therapy, and you see this same aches and pains, bone pain, low-grade fevers, and fatigue that we've come to see with ESA with luspatercept as well, with slightly higher fatigue and slightly lower asthenia. When you correct these things for the amount of exposure, most of it washes away.
The difference I found is that when you give someone ESA, you see a response in 6 to 8 weeks if you're going to get one. When you give luspatercept, most people don't have the response that quickly, and most people have to dose escalate to achieve the response. Some of these AEs are the early-on AEs and symptoms that people get before they're getting their hemoglobin improvement, which is going to happen later with this therapy.
DISCLOSURES: LeBlanc previously reported honoraria for consulting/advisory boards from AbbVie, Agilix, Agios/Servier, Apellis, Astellas, AstraZeneca, Beigene, BlueNote, BMS/Celgene, CareVive, Daiichi-Sankyo, Flatiron, Genentech, Geron, Gilead, GSK, Incyte, Lilly, Meter Health, Menarini-Stemline, Novartis, Pfizer, Rigel, Seattle Genetics, Syndax; speaking related honoraria from AbbVie, Agios, Astellas, BMS/Celgene, and Incyte.
