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

Background: Hypomethylating agents (HMAs) are the standard of care in patients with higher-risk myelodysplastic syndrome (MDS). However, the expression of PD-1 and PD-L1 was found to be increased in CD34 positive cells from patients with MDS (Yang H, Leukemia 2014). Pembrolizumab is a humanized monoclonal antibody targeting PD-1, thus blocking its interaction with its ligands PD-L1 and PD-L2. A phase 1b, multicohort study of pembrolizumab in advanced hematologic malignancies revealed that a small number of patients with higher-risk MDS had long-term survival and no immune-mediated adverse events (Garcia-Manero G, Blood 2016). We report updated results from a phase II clinical trial evaluating the safety and clinical activity of the combination of azacitidine and pembrolizumab in previously-untreated patients with higher-risk MDS.

Methods: Adult patients with untreated 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 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 2020), 17 therapy-naïve patients have been enrolled and treated with frontline combination azacitidine and pembrolizumab with a median follow-up time of 13.8 months and 5 patients continuing on treatment in cycles 4-28. The median age of patients treated is 71 years (range 36-82), and additional patient characteristics are depicted in Figure A. The overall response rate is 80%, with 3 patients reaching complete remission (CR), 4 patients attaining marrow CR (mCR), 4 patients exhibiting mCR with either hematologic improvement of platelets (HI-P) or erythrocytes (HI-E), and 1 patient demonstrating HI-E. Out of the 12 responders, 7 patients have normal cytogenetics, 1 has del(7q), 1 has del(5q), and 1 has complex karyotype. The most frequently observed mutations in these individuals are TET2 in 5 patients, ASXL1 and SRSF2 in 4 patients each, and RUNX1 and TP53 in 3 patients each. Overall survival was not reached in the frontline HMA + immunotherapy cohort (Figure B).

Treatment was overall well-tolerated. The most common treatment-related adverse events (all grades) observed were arthralgias (40%), pneumonia (33%), nausea (27%), and skin rash (27%). One patient died in the first 60 days while receiving treatment from the unrelated cause of ventricular fibrillation.

Conclusions: In this phase II trial, preliminary data suggest that combining azacitidine and pembrolizumab was relatively safe and well-tolerated in patients who had never received prior therapy. Though overall survival was not yet reached with the current follow-up time, combination therapy may have antitumor activity in these patients.