The investigational anti-CD47 monoclonal antibody magrolimab combined with azacitidine showed promising efficacy and was well tolerated in patients with untreated higher-risk myelodysplastic syndromes (MDS), according to a phase Ib trial.
In a cohort of 95 patients treated with the combination, 32.6% achieved complete remission (CR), with objective responses observed in 74.7% overall, reported Naval Daver, MD, of the University of Texas MD Anderson Cancer Center in Houston, at the Society of Hematologic Oncology annual meeting.
Median duration of complete remission was 11.1 months, and median duration of response was 9.8 months, he said.
For 25 patients with TP53-mutated disease and 61 with TP53-wild type disease, CR was achieved in 31.1% and 40.0%, with objective responses in 78.7% and 68.0%. Median durations of complete remission were 12.9 months and 7.6 months, and median durations of response were 9.8 months and 9.2 months.
In addition, with a median follow-up of 17.1 months, median overall survival (OS) was not reached in the total study population, and was 16.3 months in patients with hard-to-treat TP53-mutated disease, “which looks encouraging,” Daver said. “But, of course, we have seen encouraging survivals in the past, and in randomized studies we have to wait for confirmation. The good news is that the randomized study in MDS [ENHANCE] has just completed accrual, so we hopefully will have data in the very near future.”
“CR rates are what we should focus on,” he added. “These are reasonably encouraging numbers.”
Of note, stem cell transplant outcomes were also promising in patients treated with the combination.
“Allogeneic stem cell transplant is the standard of care for fit patients under the age of 75, but getting more patients there is an important secondary endpoint,” said co-author David A. Sallman, MD, of the Moffitt Cancer Center in Tampa, in a video accompanying a poster presentation of the study.
He pointed out that 35 of the 95 patients were taken to transplant, and these patients had 1- and 2-year OS rates of 91.4% and 73%, respectively.
“Taking these patients to transplant … that should be the goal of the therapy, and it looks like that could be achieved with this doublet,” Daver said.
As for safety and tolerability, the most common treatment-emergent adverse events occurring in more than 50% of patients were constipation, thrombocytopenia, and anemia, while grade 3 or higher adverse events occurred in 90.5% of patients.
“It is difficult to tease out if it is just azacitidine-related versus the combination, but the side effect profile is quite reminiscent of single-agent azacitidine,” Sallman noted.
Serious adverse events occurred in 63% of patients, and eight patients had events leading to death, none of which were magrolimab-related.
Daver said a key takeaway from the safety data was the incidence of anemia. On-target anemia is a pharmacodynamic effect of treatment and could be mitigated with an initial magrolimab priming dose and with transfusions.
“In this study, and I think this is partly because of the centers in the study being large academic centers … often patients were getting daily labs, close monitoring,” he explained. “So, we did not see any anemia-related mortality or severe events.”
However, he noted hemoglobin drops that could be particularly serious for a small percentage of patients, especially when you’re dealing with older patients with MDS, in the first 7 to 10 days after treatment.
“I think monitoring, transfusion, and especially for the first 7 to 10 days, either doing daily labs, or considering admission if you have a 70- to 75-year-old patient, is very reasonable,” he added.
“There is clearly a very high unmet need with no change in standard of care for higher-risk myelodysplastic syndrome since 2006,” Sallman said. Magrolimab is a monoclonal antibody that blocks CD47 — a “don’t eat me” signal overexpressed on cancer cells — which results in rapid induction of phagocytosis. In preclinical models, magrolimab was synergistic with azacitidine, he noted.
For the current study, patients with previously untreated intermediate- to very-high-risk MDS, per the International Prognostic Scoring System, received magrolimab as a priming dose (1 mg/kg) followed by ramp-up to a 30 mg/kg weekly, or every two weeks, maintenance dose. Azacitidine 75 mg/m2 was administered intravenously or subcutaneously on days 1-7 of each 28-day cycle.
The median age of the entire cohort was 69 years. Half of patients had high-risk MDS, while 27.4% and 21.1% had intermediate- and very-high-risk disease, respectively.
Daver noted that 26% of patients had TP53 mutations, and 62% were in the poor cytogenetic risk category — more than is usually seen in patients with MDS. “And that is fine, because these are populations where we need therapies,” he said. “And hopefully, if the data are positive, that will eventually lead to benefit for difficult-to-treat patients.”
The study was sponsored by Gilead Sciences.
Daver and Sallman listed no disclosures.