Doublet Combinations Could Shift Frontline Treatment Paradigm in High-Risk MDS

Monotherapy with azacitidine (Vidaza) or decitabine has been the established standard of care in the up-front setting for patients with high-risk myelodysplastic syndromes (MDS). However, combination therapies featuring venetoclax (Venclexta), magrolimab, or sabatolimab (MBG453) could shift the frontline paradigm in the near future, according to Guillermo Garcia-Manero, MD.

“We have 2 major needs [in high-risk MDS],” he said. “The first is we need better therapies to replace the results of single-agent azacitidine or decitabine in the up-front [setting]. We also need new therapies for patients that relapsed after this kind of therapy in the frontline setting.”

In an interview with OncLive^®, Garcia-Manero discussed the exploration of these doublet therapies and what they could mean for the high-risk MDS treatment landscape, the difficulties in making strides for patients with relapsed/refractory disease, and the top highlights in MDS from the 2022 ASH Annual Meeting. Garcia-Manero is the fellowship program director in the Department of Leukemia, Division of Cancer Medicine; the chief of the Section of MDS, Department of Leukemia, Division of Cancer Medicine; the deputy chair of Translational Research, in the Department of Leukemia, Division of Cancer Medicine; and a chair in the Faculty Senate, at The University of Texas MD Anderson Cancer Center.

OncLive^®: What efforts are being made to improve upon the outcomes of first-line azacitidine or decitabine monotherapy for patients with high-risk MDS?

Garcia-Manero: This is currently being addressed in the frontline setting by combination studies. [These studies are] adding a second drug to azacitidine or decitabine. Examples include the phase 3 VERONA trial [NCT04401748] with venetoclax [plus azacitidine], the phase 3 ENHANCE trial [NCT04313881] with magrolimab [plus azacitidine], and the phase 3 STIMULUS-MDS2 trial [NCT04266301] adding sabatolimab [to azacitidine]. Those are 3 examples of combinations that are currently being studied in phase 3 trials, and there may be others [in the future].

If those trials generate positive data, how could these combinations potentially shift the treatment paradigm for high-risk MDS in the frontline setting?

If they're positive in the phase 3 setting, this likely means that the [regulatory agencies] will approve them. Then we'll have a new standard with a doublet, either with a BCL2 inhibitor [with venetoclax], magrolimab, or the immune checkpoint inhibitor sabatolimab. Those studies are going read out at some point next year, so this could be a very interesting 12 months.

What data have investigators recorded thus far with these combinations in high-risk MDS?

What we have seen from these doublets is that they increase the rate of complete remission, so the responses are greater. The studies are designed to improve the overall survival of our patients, so if we see an improvement in overall survival, that is what we want, as opposed to what we have now with single-agent azacitidine.

In particular with [magrolimab], it has been extensively tested in patients with a p53-mutated disease, which is a major unmet need. We need better therapies for this group of patients that constitutes approximately one-third of the patient population at The University of Texas MD Anderson Cancer Center, and maybe a bit lower at community centers. This is a major subgroup of patients. We are looking for survival improvements, not only [improvement in] responses. The group of patients with p53-mutated disease right has a poor prognosis, [and seeing improved outcomes would be] major.

How are investigators addressing the unmet need for new therapies for patients with relapsed MDS?

Here, we are in bad shape, because there are no major efforts right now. At the 2022 ASH Annual Meeting, there were [not much data] in this context. We're struggling here, and there are no major clinical trials addressing this question. The way to think about this is by looking into detail of the molecular classic characteristics of these patients.

We have published recent data with IDH2-mutated patients having great benefit from enasidenib [Idhifa]. There are similar data from France and the United States with IDH1 inhibitors. There may be some patients that are candidates for more intensive therapies, such as cladribine- [Mavenclad] or CPX-351–based therapies, but this still is a very tough group of patients [to find new therapies for] where there is no major progress. It is difficult that there are no major studies right now looking at this in a phase 2/3 situation.

These patients are resistant to therapy. We have tried multiple clinical trials. Patients are enriched for p53 mutations or complex karyotyping, and they constitute a difficult group of patients to treat.

Was there anything in particular at the 2022 ASH Annual Meeting that you would like to highlight?

In summary, this probably was a transition year because we're expecting data in 2023 from trials such as the phase 3 COMMANDS trial [NCT03682536] of luspatercept-aamt [Reblozyl]. We expect data from other phase 3 trials, including the study of Imetelstat (GRN163L) in a [phase 2/3 trial (NCT02598661)] in second-line, low-risk disease. We expect the VERONA results with venetoclax and ENHANCE with magrolimab. This could be a very important year where we get some positive studies that could lead to more approvals for our patients.

In the meeting, we saw a lot of data in molecular classification, such as the International Prognostic Scoring System–molecular classification [IPSS-M], and a lot on how we use molecular information to prognosticate patients, and more detail in terms of DDX41 and p53 [mutations] in myeloid neoplasms.

In terms of therapies, we didn't see much. Perhaps the one of the most exciting things I could highlight was that we saw interesting data with oral decitabine in p53-mutated disease. This is a subset analysis from the [phase 3] ASCERTAIN trial [NCT03306264] with better-than-expected outcomes. However, this was a not controlled trial, so we don't [fully understand] what it means, but the data look much better than anything that we have seen.

We saw results from the [phase 2] STIMULUS-MDS1 trial [NCT03946670], the randomized study of sabatolimab [plus a hypomethylating agent (HMA) vs an HMA plus placebo]. Unfortunately, the phase 2 trial was negative so far. We have to wait for the STIMULUS-MDS2 trial data, so that was a little disappointing. We saw the final report from the [phase 3] SINTRA-REV trial [NCT01243476]. This is the study of low-dose lenalidomide [Revlimid] for 5q deletion MDS, and this is highly positive data. This is very exciting to see in an early intervention type of approach in these patients.

We saw a couple of very important clinical trials that are starting. We saw data with a low-dosage schedule of oral decitabine for low-risk MDS, and we saw an interesting trial with canakinumab [Ilaris] in patients with low-risk disease. The investigators showed data with a sequential single-cell analysis that has never been done. We saw data with IPSS-M applied to this situation. We saw some reports of early therapeutics, [including] initial reports from major phase 2 trials.

However, half of the meeting was about molecular classification and how to think about how we classify these patients. Next year, I hope we see a bit more in terms of therapeutics from important trials. This will start quickly, because I think we'll hear more about the COMMANDS trial early on [in 2023].

Are there any novel agents that that you're particularly excited to see more data on?

We are excited about expanding canakinumab. We are excited to see venetoclax [and magrolimab] incorporated in our treatment.

There are now emerging protocols with MCL-1 inhibitors for MDS. This could be a good intervention for HMA or BCL-2 failure in patients with MDS. There is a [phase 1] trial [NCT05209152] of AMG 176 [plus azacitidine] starting. Those are some very exciting compounds. There are a number of IRAK-4 inhibitors being tested both in MDS and acute myeloid leukemia.

We are moving along well in terms of therapies. There are some gaps, such as for p53 mutations and for HMA failure, where we are lacking studies.

How would you describe the current state of treatment and research in MDS?

There still is supportive care for low-risk disease and HMAs for those that are not candidates for transplant. However, we're getting there. A couple of years ago, we got the luspatercept approval in the second line. We got oral decitabine approved. There is no doubt that there is effort.

[In 2023], if we got luspatercept approved in the up-front setting for low-risk MDS and doublets in high-risk disease, that will be major. We still must address p53-mutated disease and those with relapsed/refractory [disease], but maybe there will be less and less of those patients if we continue to develop more effective therapies up-front.