Trials Seek to Assess New Treatments for Lower-Risk MDS

Guillermo Garcia-Manero, MD

Treatment with luspatercept-aamt (Reblozyl) generated a higher rate of sustained transfusion independence (58.5%) vs erythropoiesis stimulating agents (ESAs; 31.2%) in patients with ESA-naïve, lower-risk myelodysplastic syndrome (MDS), meeting the primary end point of the phase 3 COMMANDS study (NCT03682536; P < .0001).

According to Guillermo Garcia-Manero, MD, luspatercept is the first and only therapy to demonstrate superiority against ESAs in a head-to-head study for patients with transfusion-dependent lower-risk MDS. As a result, he expects this to shift the treatment of lower-risk MDS-associated anemia.

“I think that these results of the COMMANDS trial suggest that this will be the standard-of-care for now for our patients,” Garcia-Manero, lead study author and professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston, told Targeted Oncology^TM.

Another trial in progress Garcia-Manero highlighted is a phase 2/3 study (NCT05469737) evaluating the safety and efficacy of oral azacitidine in patients with low- or intermediate-risk MDS.

Previously, oral azacitidine has shown to be well-tolerated in patients and induced hematologic improvement among those with lower-risk MDS. The treatment also significantly improved the rate of red blood cell (RBC) transfusion independence in patients with low-risk MDS with RBC-transfusion-dependent anemia and thrombocytopenia.2 If positive, Garcia-Manero notes the potential of oral hypomethylating agents and their convenience for patients with low-risk MDS.

In the interview with Targeted Oncology^TM, Garcia-Manero discussed 2 studies evaluating therapies for patients with lower-risk MDS.

Targeted Oncology: Can you discuss the rationale behind the COMMANDS study?

Garcia-Manero: The COMMANDS trial focused on patients with lower-risk myelodysplastic syndrome. Myelodysplastic syndrome is a condition where the bone marrow does not have the capacity to fully mature into the elements that confirm the blood, like the white cells, red cells, and platelets. Patients will have what we refer to as cytopenia, meaning a low white count or low hemoglobin or platelets. The most frequent cytopenia is anemia. That is low-hemoglobin, and this is a major problem and burden for our patients.

Patients with MDS are often divided into what we call lower- vs high-risk. Low-risk patients are generally [expressed] by the cytopenias. The treatment of anemia, for instance, is quite important because this is a significant burden for our patients. They may need transfusions, those transfusions have a lot of associated problems beyond requiring the patient to, for a few hours, once a week, or twice a week, or whenever it's needed, get the transfusions. This is a major need. Traditionally, patients with this disease had been treated with a type of drug that we call ESA, or an erythropoietin stimulating agent, but luspatercept was approved in the United States a couple of years ago for second-line patients, so a patient that had already received an ESA. Because of the safety profile activity that we saw in the MEDALIST trial [NCT02631070], the FDA approved the drug, and we decided to perform this frontline trial, randomizing head-to-head loose luspatercept vs an ESA, kind of like the initial therapy for anemia for these patients.

How did the prior FDA approval impact the methods and design used in this study?

Based on the toxicity and the known efficacy, we also designed a study also based on the prior suspected with the ESAs to prove superiority, in this case of the investigational agent, luspatercept. The study was for any type of lower-risk MDS. There was a definition of what transmission dependency is, basically mandated by the FDA. Then, the primary objective was to determine the frequency or the fraction of patients that achieved transmission and dependency that is defined by being transmission independent for at least 12 weeks, with a concomitant increase in hemoglobin of around 1.5 grams. That was the primary end point. [Patients] needed to be transmission independent plus have an increase in hemoglobin.

What were the key safety and efficacy findings reported?

The study showed in the intent-to-treat population, the response rates for this primary objective were double. Now, we're close to 60% for patients treated with luspatercept, so that is important. In addition, the duration of those responses, though not the primary end point but a very important end point as well, were significantly prolonged with luspatercept vs the ESA. Finally, the toxicity profile was not dissimilar. With these drugs, there's not a lot of expectation in terms of severe toxicities, but they were very similar, so there's no bad toxicity profile. Furthermore, the rates of transformation or death, that unfortunately are seen in this disease, were similar between both compounds. So, it looks to be very safe, and significantly more effective than ESA.

What are the next steps for research evaluating luspatercept?

What we're seeing is suddenly, a major emphasis in developing new drugs for this early-stage disease. I think what we're going to see is a number of studies combining different agents that we know are active in this disease. This is already being done. For instance, some groups are studying combination ESA with luspatercept that work through different mechanisms of action. So why couldn't you do that?

There are a number of new drugs that have been also developed for anemia that work through different mechanisms. I think we're going to see quite a bit of this in terms of, can we even improve the results of luspatercept? That would be fantastic if we could. We're saying this response rate is 60%. If we can make it 80% or 100%, they will probably be much better, so that's very exciting. I think that's what's gonna happen. In the interim studies though, they are gonna take time, they're gonna take other randomized trials, etc. In the interim, I think that these results of the COMMANDS trial suggest that this will be the standard-of-care for now for our patients.

Another trial you discussed at ASCO 2023 was a phase 2/3 study of oral azacitadine [Vidaza] in patients with low- or intermediate-risk MDS? What can you tell me about this early clinical trial?

This is a study that is just starting. It started to accrue a few months ago, and it is an important study. The 2 drugs that we use as a standard-of-care in myelodysplastic syndrome, beyond what we just discussed, are a class of drugs known as hypomethylating agents. There are 3 of them. One is called azacitidine, the other is called decitabine, and the third is called oral decitabine. With the standard hypomethylating agents, patients need to get 3-7 days every month of this injection, so it's cumbersome. We've been working for many years on the oral development of these compounds. I had the opportunity to lead those studies over kind of like 15 years, and there are 2 of them. There is the oral decitabine instead of solid that was approved a couple of years ago, and then this other drug called CC-486. That is the oral azacitidine that is currently approved for post-consolidation therapy in acute myelogenous leukemia, but that was originally intended to be for patients with lower-risk myelodysplastic syndrome.

We led a study a number of years ago called the MDS-003 trial [NCT01566695], and what we saw in that study was that there was merit to this drug, and there was quite a bit of activity. But there were also issues with toxicities, early deaths, and it was probably because of the trial design. The dose that we used was 21 days. We thought that the methodological responses, meaning improvements in hemoglobin platelets, were good enough to go back and redesign this trial. Basically, this study is a real attempt to establish oral azacitidine in low-risk in the MDS. It uses a different patient population than in the original clinical trial and in addition, it uses a 14-day schedule vs 21 so this would be less toxic.

The way this was designed was first to have kind of like a running phase, phase 2, to see if this is safe because we had some issues with toxicity with the initial version of this trial. Then if we meet whatever rules, we can go into phase 3. If that happens, then this study could establish a role for a hypomethylating agents for low-risk MDS, which will be exciting for us because in North America, we use these drugs all the time once patients failed other drugs, maybe now like luspatercept, so there may be a role for those.

What are the end points being evaluated in this study?

As opposed to the original, we will be looking more at improvement on blood counts as opposed to survival. That was the original end point of the trial. It's a more logical design than the original, so looking more at responses and duration of those responses than overall survival. That is a more realistic and probably meaningful end point in patients with lower-risk myelodysplastic syndrome.

If positive, how do you hope that these findings will impact the future of the space?

This will be great because we are moving into oral hypomethylating agents or chemotherapies. But if you can give them orally, then it will be much better for our patients. I think we're moving into a space of these oral drugs that are effective in this disease, and I think this could be transformative for our patients. Soon, we are showing the first results of a total oral therapy with oral decitabine and venetoclax [Venclexta], with incredible response rates in patients with high-risk disease. I think the field is moving into oral compounds. For this group of patients, that will be a major breakthrough in terms of not having to come here, etc. If you think about the prior conversation with luspatercept, we render these patients' transmission independent. Maybe we'll start helping our patients a little bit, and they will not have to spend so much time here with us in the hospital.

REFERENCES:

1. Garcia-Manero G, Platzbecker U, Santini V, et al. Efficacy and safety results from the COMMANDS trial: A phase 3 study evaluating luspatercept vs epoetin alfa in erythropoiesis-stimulating agent (ESA)‑naive transfusion-dependent (TD) patients (pts) with lower‑risk myelodysplastic syndromes (LR-MDS). J Clin Oncol. 2023;41(suppl 16):7003. doi:10.1200/JCO.2023.41.16_suppl.7003

2. Garcia-Manero G, Santini V, Fenaux P, et al. A phase 2/3 trial of oral azacitidine (Oral-AZA) in patients (pts) with low- or intermediate-risk myelodysplastic syndromes (MDS). J Clin Oncol. 2023;41(suppl 16):TPS7083. doi:10.1200/JCO.2023.41.16_suppl.TPS7083