Pembrolizumab, a PD-1 Inhibitor, in Patients with Myelodysplastic Syndrome (MDS) after Failure of Hypomethylating Agent Treatment

Background: Upregulation of the immune checkpoint receptor PD-1 and its ligands, PD-L1 and PD-L2, has been demonstrated in peripheral blood mononuclear cells from patients with MDS (Yang H et al. Leukemia2014;28:1280-1288). This upregulation is enhanced by epigenetic modifiers, such as 5-azacitidine, and has been associated with poor survival. The PD-1 pathway thus represents an attractive target in patients with MDS that has failed first-line treatment with a hypomethylating agent. Pembrolizumab is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands and can restore antitumor immune activity in solid tumors and hematologic malignancies. KEYNOTE-013 (NCT01953692) is a multicenter, multicohort phase 1b study of pembrolizumab in patients with hematologic malignancies. Results from the MDS cohort of KEYNOTE-013 are presented.

Methods: Key eligibility criteria for this cohort included age ≥18 years, primary or secondary MDS with IPSS score of intermediate 1, intermediate 2, or high; and failure (defined as worsening of cytopenias, increase in percentage of bone marrow blasts, or progression to more advanced MDS FAB subtype than at pretreatment) to respond to at least 4 cycles of prior treatment with a hypomethylating agent (azacitidine or decitabine). Pembrolizumab was administered intravenously at a dose of 10 mg/kg every 2 weeks for up to 2 years or until confirmed progression or unacceptable toxicity. Response was assessed by investigator every 6 weeks using IWG 2006 criteria (Cheson BD et al. Blood2006;108:419-425). The primary end points were safety and objective response rate; secondary objectives included overall survival, bone marrow response, and hematologic improvement. Bone marrow samples were collected at predefined time points during the study for analysis of gene expression profiles with the NanoString platform.

Results: Among the 28 patients enrolled in the MDS cohort, median age was 73 years (range, 38-84 years), 64% were male, and IPSS scores were intermediate 1 in 10 patients (36%), intermediate 2 in 9 patients (32%), and high in 7 patients (25%). 54% of patients had a FAB classification of refractory anemia with excess blasts. At the time of data cutoff on May 27, 2016, the median follow-up duration was 5.6 months (range, 1-29 months). 10 patients (36%) experienced treatment-related adverse events (AEs); the most frequent were hypothyroidism in 4 patients (14%) and fatigue in 3 patients (11%). Grade 3/4 treatment-related AEs occurred in 2 patients (7%), including grade 3 gastroenteritis and grade 4 tumor lysis syndrome in 1 patient each. 2 patients discontinued because of treatment-related AEs, including grade 4 tumor lysis syndrome in 1 patient, and grade 2 arthralgia, grade 1 musculoskeletal stiffness, and grade 1 peripheral edema in 1 patient. There were no treatment-related deaths. Of the 27 patients evaluated for efficacy, there were no complete remissions (CRs), and 1 patient achieved a partial remission, for an overall response rate of 4% (90% CI, 0.2%-16%). Among the remaining patients, best overall response was marrow CR in 3 patients (11%), stable disease in 14 patients (52%), and progressive disease in 9 patients (33%). Hematologic improvement was seen in 3 patients (11%). The overall survival rate at 24 weeks was 49% across the cohort, including 89% in patients with intermediate 1 IPSS score, 22% in patients with intermediate 2 IPSS score, and 29% in patients with high IPSS score. For patients with intermediate 1 score, the 1-year overall survival rate was 89%; the 2-year overall survival rate was 57%. Biomarker data will be presented.

Conclusion: PD-1 blockade with pembrolizumab was associated with a manageable safety profile and potential clinical activity in patients with MDS after failure of first-line treatment with a hypomethylating agent. Future studies in combination with azacitidine are planned.