Oral Azacitidine Shows Preliminary Safety, Efficacy in Lower-Risk MDS

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Dosing oral azacitidine (Oral-AZA; Onureg) with a decreased dosing schedule did not impact the previously known safety profile of the agent in patients with lower-/intermediate-risk myelodysplastic syndrome (MDS), based on a report from the phase 2/3 ASTREON trial (NCT05469737) presented at the 2024 ASCO Annual Meeting.¹

“We showed that the safety profile of oral azacitidine in both 200 or 300 milligrams is identical or similar to our prior experience in other trials, such as the AZA-MDS-003 trial,” study author Guillermo Garcia-Manero, MD, Department of Leukemia, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, Houston, said during a presentation of the data.

The primary end points in the trial were adverse events (AEs) and complete remission (CR) within 6 cycles per International Working Group (IWG) 2006 criteria.

Regarding AEs, patients in both treatment arms experienced similar rates. Twenty-three patients (96%) in the 200-mg arm and 20 patients (87%) in the 300-mg arm reported having at least 1 treatment-related treatment-emergent AE (TEAE).

The most common treatment-related AEs patients experienced in either group were hematologic- and gastrointestinal-related.

“The most common [treatment-related toxicities] were neutropenia followed by constipation, nausea, thrombocytopenia. Basically, prototypical hematological and GI toxicity profile that we saw with this agent in the past,” Garcia-Manero explained.

Serious TRAEs occurred in 1 patient from the 200-mg arm and 3 patients from the 300-milligram arm, researchers noted. There were 2 deaths that occurred in the 300-mg arm, which were treatment-related and treatment-emergent, respectively. No patients from the 200-mg arm experienced grade 5 AEs.

Of note, the rates of TRAEs of all grades leading to treatment discontinuation or dose reduction was higher in the 300-mg arm. Four patients (17%) in the 200-mg arm, Garcia-Manero said, discontinued treatment due to disease progression. Three patients (13%) in the 300-mg arm discontinued treatment due to TRAEs.

Regarding the co-primary end point, Garcia-Manero noted that none of the patients achieved a CR in either arm.

Secondary end points were achievement of overall response (OR)–which included complete response (CR), partial remission, marrow CR, hematologic improvement-erythroid response (HI-E), HI-platelet (HI-P) response, and HI-neutrophil (HI-N) response per IWG 2006 criteria–as well as best OR and OR duration.

There were 6 patients from both dose arms that achieved HI-E; zero patients in the 200-mg arm and 1 patient in the 300-mg arm achieved HI-P; and 1 patient in each dose group achieved HI-N.

Of note, HI rates within 6 cycles were calculated by investigator assessment per IWG 2006 criteria. This was calculated for patients who received at least 75% of the dose from cycle 1 and had at least 1 post-baseline efficacy assessment, which was the modified intent-to-treat (mITT) population.

In the mITT population, 8 of 22 patients in the 200-mg arm achieved any HI and 7 of 21 patients in the 300-mg arm achieved any HI.

About the Phase 2/3 Trial

In the trial, 47 patients with lower-/intermediate-risk MDS were randomly assigned 1:1. The study evaluated safety and efficacy of Oral-AZA with best supportive care (BSC) in this patient population. Patients were assigned to 2 arms to receive at least 1 Oral-AZA dose of either 200 mg (n=24) or 300 milligrams (n=23) for 14 days per a 28-day cycle plus BSC. Eligible patients were at least 18 years old and at least 1 cytopenia.

The phase 2 portion of the trial was an open-label, dose optimization trial to help determine the recommended dose of Oral-AZA for phase 3. Most patients (89.4%) had previously received treatment for MDS, which included, but was not limited to, erythropoiesis-stimulating agents, luspatercept (Reblozyl), lenalidomide (Revlimid), and imetelstat. 

REFERENCE:

1. Garcia-Manero G, Yee K, Hernandez F, et al. Preliminary safety and efficacy of oral azacitidine (Oral-AZA) in patients (pts) with low-/Intermediate (Int)-risk myelodysplastic syndromes (MDS): Phase 2 results from the ASTREON trial. J Clin Oncol. 2024;42(suppl 16):6509. doi:10.1200/JCO.2024.42.16_suppl.6509