The combination of CD47-targeting magrolimab plus azacitidine did not improve survival compared with physician’s choice of treatment in patients with TP53-mutated acute myeloid leukemia (AML), according to the results of the interim analysis of the ENHANCE-2 study published in Blood.
“Currently, there is no standard of care (SOC) for patients with TP53-mutated AML, as conventional intensive and nonintensive treatments do not improve outcomes in TP53-mutated AML; that is the challenge and was the impetus for this study design,” said study researcher Joshua Zeidner, MD, of the University of North Carolina School of Medicine. “Unfortunately, azacitidine/magrolimab didn’t show any improvement compared with the current treatment regimens. We have to continue to try to find better therapies for patients with TP53-mutated AML.”
In older, unfit patients with AML, a combination of azacitidine/venetoclax is the standard for all newly diagnosed patients, according to Dr. Zeidner. However, in patients whose AML has TP53 mutations, this combination improves response rates compared with azacitidine alone but does not improve survival outcomes.
“Median survival is five to six months for TP53-mutated AML, regardless of what frontline treatment is chosen,” Dr. Zeidner said.
Magrolimab is a monoclonal antibody that blocks CD47 and is thought to promote immunogenic cancer cell death. Earlier studies of magrolimab/azacitidine showed increased AML cell phagocytosis compared with azacitidine alone.
Dr. Zeidner explained that three phase III studies of magrolimab/azacitidine were launched, starting with ENHANCE, which looked at the combination in myelodysplastic syndromes (MDS). ENHANCE-2 enrolled patients with untreated TP53-mutated AML. Those deemed inappropriate for intensive therapy were randomly assigned to magrolimab/azacitidine or venetoclax/azacitidine; those appropriate for intensive therapy were randomly assigned to magrolimab/azacitidine or 7+3 induction chemotherapy. ENHANCE-3 looked at magrolimab/azacitidine/venetoclax versus marolimab/azacitidine/placebo in newly diagnosed AML.
“When ENHANCE was reviewed and the primary endpoint was not met, the other two studies had their own interim futility analysis,” Dr. Zeidner said.
Two hundred fifty-seven out of 346 planned patients were randomized and included (nonintensive arm, n=205; intensive arm, n=52). The majority of patients had AML with biallelic TP53 alterations. At the final analysis of ENHANCE-2, median overall survival was 4.4 months with magrolimab/azacitidine compared with 6.6 months with venetoclax/azacitidine, and 7.3 months for magrolimab/azacitidine compared with 11.1 months in the 7+3 group. Rates of grade 3 or worse adverse events were similar between study arms.
There are important lessons to be learned from this negative study though, Dr. Zeidner said. First, the researchers were able to successfully conduct a large, international, randomized phase III study in a specific subset of patients with AML.
“With the current treatment armamentarium for AML being so individualized, it is critical to have biomarker-based trials to inform whether different treatment combinations work better in different patient populations,” Dr. Zeidner said.
Second, the data reinforce that there is no SOC treatment for patients with TP53-mutated AML.
“We designed this study with physician’s choice control arm for intensive chemotherapy or azacitidine/venetoclax, and both subgroups had poor outcomes, as expected,” Dr. Zeidner said.
One of the potential reasons that ENHANCE-2 was not as successful as the earlier phase Ib trial of magrolimab/azacitidine was that patients may not have been on the study drugs long enough to achieve response, Dr. Zeidner said. The median duration of exposure to magrolimab was 8.6 weeks.
“Most patients did not complete even 12 weeks of treatment,” he said. “We know that with the mechanisms of action of magrolimab/azacitidine it takes several months to see clinical activity, unlike azacitidine/venetoclax, which has a quicker onset. That may be one of the reasons the study was negative.”
Only 33 of 101 patients in the nonintensive arm received 12 or more weeks of therapy. In this group, the rate of composite complete remission was 36.4% with an overall response rate of 57.6%, results that were more consistent with those in the phase Ib trial.
Dr. Zeidner suggested that had patients stayed on study longer, they may have been able to develop a response over time.
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Zeidner JF, Sallman DA, Recher C, et al. Magrolimab plus azacitidine vs physician’s choice for untreated TP53-mutated acute myeloid leukemia: the ENHANCE-2 study [published online ahead of print, 2025 Feb. 26]. Blood. doi: 10.1182/blood.2024027408.
