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Magrolimab-azacitidine shows promise in untreated high-risk MDS

The investigational anti-CD47 monoclonal antibody magrolimab combined with azacitidine showed promising efficacy and was well tolerated in untreated patients with high-risk myelodysplastic syndromes (MDS), according to phase Ib trial.

In a cohort of 95 patients treated with the combination, 32.6% achieved complete remission (CR), with objective responses seen in 74.7% overall, reported Naval Daver, MD, of MD Anderson Cancer Center in the University of Texas at Houston, at the Society of Hematologic Oncology annual meeting.

The median duration of complete remission was 11.1 months and the 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%. The median duration of complete remission was 12.9 months and 7.6 months, and the median duration of response was 9.8 months and 9.2 months.

Furthermore, with a median follow-up of 17.1 months, the median overall survival (OS) was not reached in the entire study population and was 16.3 months in patients with difficult-to-treat disease. TP53-mutated disease, “which looks encouraging,” Daver said. “But of course we have seen encouraging survivals in the past, and in randomized trials we have to wait for confirmation. The good news is that the randomized trial in MDS [ENHANCE] just completed the build, so we hope to have data in the very near future.”

“CR rates are what we should be focusing on,” he added. “These are reasonably encouraging numbers.”

Of note, the results of stem cell transplantation were also promising in patients treated with the combination.

“Allogeneic stem cell transplantation is the standard of care for fit patients younger than 75, but getting more patients there is an important secondary endpoint,” said co-author David A. Sallman, MD, of Moffitt Cancer Center. in Tampa, in a video that accompanies a poster presenting the study.

He noted that 35 of the 95 patients underwent transplantation, and these patients had 1-year and 2-year OS rates of 91.4% and 73%, respectively.

“Getting these patients to transplant … that should be the goal of therapy, and it looks like it could be done with this double,” Daver said.

In terms of 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% from the patients.

“It’s hard to tell if it’s related to azacitidine alone versus the combination, but the side effect profile is very 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 related to magrolimab.

Daver said that a key takeaway from the safety data was the incidence of anemia. Anemia in the target is a pharmacodynamic effect of treatment and could be mitigated with an initial dose of magrolimab preparation and with transfusions.

“In this study, and I think this is in part because the study centers are large academic centers … patients often had daily labs, close follow-up,” he explained. “So, we didn’t see any anemia-related mortality or serious events.”

However, he noted drops in hemoglobin that could be particularly severe for a small percentage of patients, especially older MDS patients, 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.

Study justification

“Clearly there is a very high unmet need with no change in the standard of care for high-risk myelodysplastic syndrome since 2006,” Sallman said. Magrolimab is a monoclonal antibody that blocks CD47, a “don’t eat me” signal that is overexpressed on cancer cells, resulting in rapid induction of phagocytosis. In preclinical models, magrolimab was synergistic with azacitidine, he noted.

For the current study, treatment-naïve patients with intermediate-to-very-high-risk MDS, based on the International Prognostic Scoring System, received magrolimab as a starting dose (1 mg/kg) followed by a gradual increase to 30 mg/kg weekly. . , or every two weeks, maintenance dose. Azacitidine 75 mg/mtwo it 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 the 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 low cytogenetic risk category, higher than is typically seen in patients with MDS. “And that’s fine, because these are populations where we need therapies,” she said. “And hopefully, if the data is positive, that will eventually lead to a benefit for hard-to-treat patients.”

  • Author['full_name']

    Mike Bassett is a staff writer specializing in oncology and hematology. He is based out of Massachusetts.

Disclosures

The study was sponsored by Gilead Sciences.

Daver and Sallman did not list disclosures.

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