Ceralasertib Shows Promise in MDS and CMML With Reduced Toxicity on an Adjusted Schedule

A novel oral ataxia telangiectasia and Rad3-related (ATR) kinase inhibitor, ceralasertib, demonstrated comparable efficacy but improved safety with an alternative 7 days on/7 days off (7 on/7 off) schedule in participants with relapsed or refractory myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) after hypomethylating agent (HMA) therapy. The findings highlight the potential for dose schedule optimization to enhance the tolerability of ceralasertib while maintaining therapeutic benefits.

Patients with MDS and CMML often present with poor outcomes after HMA treatment failure. These patients frequently harbor mutations in genes that regulate pre-mRNA splicing, resulting in increased R-loops, which are reverted via ATR kinase. Therefore, targeting ATR, particularly in splicing factor–mutant MDS, may present an emerging therapeutic approach.

Andrew M. Brunner, MD, Massachusetts General Hospital, Boston, and colleagues presented results from their phase 1 trial (NCT03770429), which evaluated the efficacy and safety of the oral ATR inhibitor ceralasertib.¹ Participants with splicing factor-mutant MDS or CMML, relapsed or refractory after HMA treatment failure, were enrolled in the trial to receive 160 mg of ceralasertib twice daily on the standard monotherapy schedule of 14 days on and 14 days off (14 on/14 off, n=30) or an alternative 7 on/7 off (n=14) schedule.

The overall response rate (ORR) was similar between the two schedules, with an OR of 29% in the 7 on/7 off group and 27% in the 14 on/14 off group. Responses in the alternative schedule included marrow complete remission, red blood cell transfusion independence, and hematologic improvement in erythroid and neutrophil lineages for one participant each. Despite comparable efficacy, the 7 on/7 off regimen significantly reduced severe thrombocytopenia (1 of 14 participants) compared with the 14 on/14 off schedule (11 of 30 participants; P=.038). Participants on the 7 on/7 off schedule were also less likely to require platelet transfusions during treatment. Survival outcomes were similar between schedules, with a median overall survival of 12 months for the 14 on/14 off schedule and 13 months for the 7 on/7 off schedule (P=.44). Progression-free survival was 5.9 months across both cohorts. Serial gene panel sequencing revealed that at the time of progression, RUNX1 mutations were enriched.

No dose-limiting toxicities were observed in the 7 on/7 off group, and grade 3 or higher adverse events, such as febrile neutropenia and pneumonia, were manageable. The 7 on/7 off dosing schedule reduced the rate of severe grade 4 thrombocytopenia (1 of 14) compared with the 14 on/14 off schedule (11 of 30).

Overall, the 160-mg twice-daily dosage schedule of 7 on/7 off showed similar response rates, overall survival, and progression-free survival compared with the 14 on/14off schedule, but with a lower incidence of severe thrombocytopenia. This schedule warrants further investigation and illustrates the potential of ceralasertib as a targeted therapy for patients with post-HMA MDS and CMML.

REFERENCE

Brunner AM, Liu Y, Garcia JS, et al. Clinical activity and safety of the oral ATR inhibitor ceralasertib (AZD6738) in patients with MDS or CMML after prior HMA therapy. Abstract #1833. Presented at the ASH Annual Meeting; December 7-10, 2024; San Diego, California.