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Naval G. Daver, MD, discusses the rationale for the ongoing ENHANCE trial and explained magrolimab’s unique role as a macrophage immune checkpoint blocker. He also outlines unmet needs throughout the entire high-risk myelodysplastic syndrome population, and how novel approaches, such as magrolimab combinations, may fulfill these needs.
Magrolimab plus azacitidine (Onureg), a combination currently being investigated in the phase 3 ENHANCE trial (NCT04313881), could vastly improve the treatment landscape for patients with high-risk myelodysplastic syndrome (MDS), according to Naval G. Daver, MD. If approved, this combination would signal the first new development in decades for this population.
Investigators in ENHANCE trial are evaluating magrolimab plus azacitidine vs azacitidine plus placebo in untreated patients with MDS. Magrolimab is a first-in-class monoclonal antibody that blocks CD47 on tumor cells. Azacitidine, a hypomethylating agent that enhances the “eat me” signal on tumor cells. The FDA approved the agent in May 2004 for all MDS types, based on findings from the phase 3 Cancer and Leukemia Group B 9221 trial, in which azacitine elicited a 16.2% response rate vs no response with placebo.1
“It’s critical for us to get at least 1 or 2 drugs approved in frontline MDS. Two decades have passed by, [and although] azacitidine and decitabine [Dacogen] were good additions, response rates are still below 30% to 35%,” Daver said. “We’re not close to 80% to 90% like we are in most lymphomas, myeloma, [acute lymphoblastic leukemia (ALL)], and [acute myeloid leukemia (AML)]. There’s much room for improvement.”
In an interview with OncLive®, Daver, an associate professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center, discussed the rationale for the ongoing ENHANCE trial and explained magrolimab’s unique role as a macrophage immune checkpoint blocker. He also outlined unmet needs throughout the entire high-risk MDS population, and how novel approaches, such as magrolimab combinations, may fulfill these needs.
Daver: For patients with newly diagnosed high-risk MDS, the current approved treatment per FDA and European regulations is hypomethylating agents, also called DNA methyltransferase inhibitors, such as azacitidine and decitabine. These drugs show a response rate of about 20% to 30%, [with slightly lower] true complete response [CR] rates of 15% to 20%. These agents have been shown to be well tolerated and have been associated with improved overall survival compared with the other therapies that were available when these studies were done about 20 years ago. [These findings] led to the approval of both azacitidine and decitabine in the front line for patients with high-risk MDS.
We also sometimes consider the use of intensive chemotherapy in certain subsets of high-risk MDS, usually in patients who have AML-defining mutations, even though their blast percentage may be less than 20%, which does not meet the historically established cutoff of 20% blasts for MDS vs AML. This includes patients with isolated NPM1 or FLT3 mutations. Recently, the World Health Organization and intraclass correlation classifications [of AML] have included the MECOM rearrangement inversion 3q, as well as the core binding factor inversion 16, translocation 8;21, and APL. [In general,] any patients who have any of these aberrations, regardless of the blasts, are often treated as if they had AML.
Stem cell transplant is usually the goal of therapy for most patients with MDS who are high risk, because that is the only known curative option with long-term survival. Hypomethylating agents [can prolong survival by decades], but this is not common. Often, we will see transformation, progression, or relapse of the disease. We usually get our stem cell transplant team involved early and consider early onset allogeneic stem cell transplant once the patients are in a morphological remission.
Nowadays, we have a number of donor options including sibling transplant, matched unrelated donors, haploidentical donors, and cord donors, so we’re able to find a donor for [more than] 95% of our patients. This is now the goal of therapy in high-risk MDS, especially in those with high blast percentages or established adverse cytogenetic or molecular features.
The entire population of high-risk MDS is an unmet need. The median survival for these patients is in the range of 1 and a half to 2 and a half years, especially in patients who have a very high-risk molecular mutation such as TP53, or RUNX1 or those who have adverse cytogenetics, [such as] deletion 7 or deletion 5, with other abnormalities, [such as] 17p abnormalities or chromosome 3q abnormalities.
In general, survival is less than 1 year for all these ultra-high-risk molecular cytogenetic subsets. [Patients with] TP53 mutations and other adverse cytogenetics have the most unmet need because even if we’re able to get them into a remission—which, in most cases, is usually transient and rarely lasts more than 6 to 8 months—and get them to transplant, they are still relapsing quite early post-transplant, within 8 to 12 months.
This group with TP53 mutations, 3q inversions, 7q deletions, and complex abnormalities like 17p abnormalities, still has a major unmet need with no therapies currently established. Even the standard therapies, when a response is achieved, are giving us a limited duration of response. There’s a huge effort for these populations, especially, to develop novel therapeutic approaches, moving away from the traditional targeted, cytotoxic, or apoptosis-inducing therapies, because we have tried all those for the past decade with limited to no improvements in outcomes for these particular mutational subsets.
Now, we’re moving heavily toward immunotherapy approaches, such as antibody-based adaptive T-cell engagers, innate immune system macrophage activation, or even potential cellular therapies such as T cells and natural killer cells that will hopefully be coming along in the near future.
Magrolimab is an IgG antibody [that blocks] CD47. The CD47 pathway itself, in at least the clinical setting, is quite new. We’ve just started trials using this pathway and these drugs in the past 3 to 4 years. PD-1 and PD-L1 inhibition, which works to unleash T cells by blocking the adaptive immune checkpoints, has been extremely successful, with more than 20 drug approvals across over 8 malignancies in the past 15 years.
Unfortunately, in AML and MDS, we found in many trials that were led by us at MD Anderson, that these traditional T-cell engaging immune checkpoints did not work as well, especially in patients with active bone marrow disease. When we went back to the lab and looked at these T cells, the reason they didn’t work was because the T cells themselves often either carried the mutation or were significantly dysfunctional because of the effects of prior purine analogues, transplants, or high-dose chemotherapy that abrogated their function.
We started looking for other immune-activating agents. One agent that the group at Stanford Medicine, with Ravindra Majeti, MD, PhD, and Irving Weissman, MD, has shown to be active is magrolimab, which works on a macrophage immune checkpoint.
Just like T cells, macrophages also have immune checkpoints. They are mediated through CD47 sirpα interaction, an inhibitory interaction that results in dampening or shutting down macrophage activity. By blocking this inhibitory interaction, we release the macrophages from the inhibitory signals, and they can then continue with their function of phagocytosis in attacking tumor or leukemia cells.
This signal is called the “don’t eat me signal” and by blocking it, you allow the macrophages to go ahead with their “eat me” function. In addition, usually macrophages require a second signal called the “eat me” signal. This [signal is comprised of several] pro-phagocytic markers that are expressed on the surface of leukemia tumor cells and that can be enhanced by hypomethylating agents, traditional chemotherapy, and radiation therapy.
We are now working to find ways to combine these CD47 antibodies with other agents that will enhance the “eat me” signal, which has led to various combinations of magrolimab with azacitidine, intensive chemotherapy with azacitidine and venetoclax [Venclexta], and others.
One reason why we combined these agents is that we knew, preclinically and biologically, that CD47 inhibition alone, which would block the “don’t eat me” signal, would not be sufficient to generate antitumor response. We needed to have a second signal, the “eat me” signal, [which would act as] a homing signal so the macrophages could recognize and attack the tumor cells.
These “eat me” signals include various pro-phagocytic molecules that are expressed on the surface of cells, such as calreticulin and SLAMF7. We found that drugs like azacitidine, as well as decitabine, significantly increase these pro-phagocytic signals on the surface of the leukemia cells, resulting in bringing that second component, the “eat me” signal. This is 1 of the reasons we felt that magrolimab would be best in combination.
Other agents besides hypomethylating agents can also increase the “eat me” signal. It can also be achieved with intensive chemotherapy, apoptosis-inducing drugs like venetoclax, and radiation therapy. A number of these combinations are also starting.
The second reason was that azacitidine is approved in AML and MDS. It’s a more practical and logistically clear path to combine magrolimab with an agent that is already approved. [Instead of] doing a novel-novel [comparison], we’re investigating an established agent plus a new agent.
The third reason was that we already did a phase 1 study [NCT03248479] with single-agent magrolimab in the relapsed/refractory AML setting. This study, led by Paresh Vyas, MRCP, FRCP, FRCPath, of the University of Oxford, was presented [at the 2022 ASCO Annual Meeting] and will hopefully be published in the near future. We saw limited activity, as only [6 of 72] patients had a marrow remission, and most patients progressed.
For these 3 reasons, we knew we had to [investigate] a combination, and we wanted to do it with an established agent so there was a regulatory path, as well as a clear biological rationale for this combination. This has led to the combination of azacitidine and magrolimab in frontline MDS.
In MDS, the ENHANCE study in AML is the main study, but we are also looking at a triplet of azacitidine plus venetoclax, which is now the established backbone in AML, plus magrolimab. This is an ongoing study at MD Anderson that was presented at [the 2021 ASH Annual Meeting and Exposition] showing encouraging responses, especially true CR rates of greater than 55%, which are better than what we have seen historically with azacitidine plus venetoclax, a combination which gives a true CR rate of about 35% to 40%. [These findings have] led to the phase 3 ENHANCE-3 study [NCT05079230] of azacitidine, venetoclax, and magrolimab vs azacitidine, venetoclax, and placebo.
Other studies are combining magrolimab with the intensive chemotherapy mitoxantrone, etoposide, and cytarabine, also known as MEC chemotherapy, in relapsed/refractory patients with AML and MDS. There are also efforts looking at magrolimab in combination with other immune-activating drugs, such as sabatolimab [MBG453], which is a TIM-3 T-cell activating agent, as well as with other TP53-directed therapies like APR-246.
A number of these trials are expected to open or are ongoing, but the main study right now is the ENHANCE study of azacitidine plus magrolimab vs azacitidine plus placebo in frontline, high-risk MDS.
Hopefully, the ENHANCE study will lead to higher response rates, more durability, and a greater ability to get patients safely to allogeneic stem cell transplant, eventually improving both survival and quality of life. Early responses and high response rates are usually associated with transfusion independence, less time in the transfusion chair, fewer hospital visits, and fewer labs. These factors almost always go hand-in-hand.
That said, there are other drugs we’re also excited about. Venetoclax in combination with azacitidine in frontline MDS also has shown good data. We’re hoping that combination also [shows] positive [data], because then we can move to the next step as we have in AML, to look at either sequencing or combining azacitidine, venetoclax, and magrolimab, which might then move the incremental survival up further than either doublet [alone].
It’s critical in the next year for 1 or 2 of these agents, which are in phase 3 development in MDS, including sabatolimab, which is still in MDS development, [to be approved]. Then, we need to find optimal ways to sequence them, find the right patient population to use them in, and potentially combine them in some patients. This will hopefully start improving the survival dramatically.
This is a great time in clinical research across the world in general, and this progress is not happening in silos. As we’re seeing dramatic progress happening in lymphomas, myeloma, AML, and ALL, it’s only a matter of time before this progress comes through to MDS. I expect that in the next 5 years, we will hopefully see breakthroughs in MDS therapies, with magrolimab, venetoclax, and sabatolimab, as well as with other agents also in the pipeline.
In the next 8 to 10 years, we have a great opportunity to hopefully change the face of these myeloid diseases, and we’re excited for that to happen. One of the things we need is clinical trial enrollment. I would encourage all the physicians, patients, and regulatory groups to strongly encourage clinical trial enrollment, so that we can quickly move the bar further in the next few years.