Updated Preliminary Results from a Phase II Study Combining Azacitidine and Pembrolizumab in Patients with Higher-Risk Myelodysplastic Syndrome

Background: Hypomethylating agents (HMAs) are the standard of care in patients with higher-risk myelodysplastic syndrome (MDS), but the survival of patients after failure of HMA therapy is poor at approximately 4 to 6 months. Expression of PD-1 and PD-L1 was increased in CD34 positive cells from patients with MDS with further upregulation following HMA therapy and HMA failure (Yang H, Leukemia 2014). Pembrolizumab is a humanized monoclonal antibody targeting PD-1, thus blocking its interaction with ligands PD-L1 and PD-L2. A phase Ib, multicohort study of pembrolizumab in advanced hematologic malignancies showed a small number of patients with long-term survival and no immune-mediated adverse events in the higher-risk MDS cohort (Garcia-Manero G, Blood 2016). We report updated results from an ongoing phase II clinical trial evaluating the safety and clinical activity of azacitidine and pembrolizumab in patients with higher-risk MDS. Methods: Adult patients with intermediate-1- or higher-risk disease by the International Prognostic Scoring System (IPSS) with adequate renal and hepatic function and no prior stem cell transplantation, active autoimmune disease, or immunodeficiencies were eligible for the study. Patients were divided into two cohorts: those who were treatment-naïve and those who had not responded to, progressed on, or relapsed after HMA therapy. Patients received azacitidine 75 mg/m2 intravenously (IV) or subcutaneously daily for 7 days every 28-day cycle and pembrolizumab 200 mg IV starting on cycle 1 day 1 and every 21 days thereafter independent of the azacitidine dosing schedule. The endpoints were overall response rate, survival, and safety. The criteria for early trial termination included an overall response rate (ORR) < 20%, incidence of grade 3-4 adverse events (AEs) > 30%, poor adherence to protocol and regulatory requirements, severe and adverse drug reactions, and plans to modify or discontinue development of the study drug. Clinical trial information: NCT03094637. Results: At data cut-off (July 2019), 35 patients have been enrolled and 30 patients treated with combination azacitidine and pembrolizumab with a median follow-up time of 10.7 months and 10 patients continuing on treatment in cycles 1-16. Twenty patients were enrolled in the HMA failure cohort and 10 patients in the treatment-naïve MDS cohort. Overall responses rates were 30% in the HMA failure cohort and 70% in the HMA therapy-naïve cohort. In the HMA failure cohort, 2