Updated Results from a Phase II Study Combining Azacitidine and Pembrolizumab in Previously-Untreated Patients with Higher-Risk Myelodysplastic Syndrome
Authors: Chien Kelly S. , Borthakur Gautam , Naqvi Kiran , Daver Naval , Montalban Bravo Guillermo , Cortes Jorge E. , DiNardo Courtney D. , Jabbour Elias , Alvarado Yesid , Andreeff Michael , Bose Prithviraj , Jain Nitin , Sheppard Kimberly , Klingner-Winton Cheri , Pierce Sherry A. , Dong Xiao Qin , Soltysiak Kelly A. , Kantarjian Hagop M. , Garcia-Manero Guillermo 
Published: November 2020

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) &lt; 20%, incidence of grade 3-4 adverse events (AEs) &gt; 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.
Figure 1

Disclosures
Borthakur: Abbvie: Research Funding; Jannsen: Research Funding; Novartis: Research Funding; Incyte: Research Funding; PTC Therapeutics: Research Funding; Treadwell Therapeutics: Consultancy; Cyclacel: Research Funding; Curio Science LLC: Consultancy; Xbiotech USA: Research Funding; Oncoceutics: Research Funding; BioLine Rx: Research Funding; Polaris: Research Funding; BMS: Research Funding; AstraZeneca: Research Funding; BioLine Rx: Consultancy; PTC Therapeutics: Consultancy; Argenx: Consultancy; FTC Therapeutics: Consultancy; BioTherix: Consultancy; Nkarta Therapeutics: Consultancy; GSK: Research Funding. Daver:Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees. Cortes:Arog: Research Funding; Amphivena Therapeutics: Research Funding; Astellas: Research Funding; Telios: Research Funding; BioPath Holdings: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sun Pharma: Research Funding; Takeda: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; BiolineRx: Consultancy, Research Funding; Merus: Research Funding; Immunogen: Research Funding. DiNardo:MedImmune: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Jazz: Honoraria; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Novartis: Consultancy; Notable Labs: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Calithera: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; ImmuneOnc: Honoraria; Syros: Honoraria; Agios: Consultancy, Honoraria, Research Funding. Jabbour:Pfizer: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding. Alvarado:BerGenBio ASA: Research Funding; Tolero Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Research Funding; Daiichi-Sankyo: Research Funding; MEI Pharma: Research Funding; Astex Pharmaceuticals: Research Funding; FibroGen: Research Funding; Sun Pharma: Research Funding. Andreeff:Daiichi-Sankyo; Breast Cancer Research Foundation; CPRIT; NIH/NCI; Amgen; AstraZeneca: Research Funding; Centre for Drug Research & Development; Cancer UK; NCI-CTEP; German Research Council; Leukemia Lymphoma Foundation (LLS); NCI-RDCRN (Rare Disease Clin Network); CLL Founcdation; BioLineRx; SentiBio; Aptose Biosciences, Inc: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo; Jazz Pharmaceuticals; Celgene; Amgen; AstraZeneca; 6 Dimensions Capital: Consultancy; Amgen: Research Funding. Bose:Incyte Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene Corporation: Honoraria, Research Funding; Promedior, Inc.: Research Funding; CTI BioPharma: Honoraria, Research Funding; Constellation Pharmaceuticals: Research Funding; Kartos Therapeutics: Honoraria, Research Funding; Astellas Pharmaceuticals: Research Funding; NS Pharma: Research Funding; Pfizer, Inc.: Research Funding; Blueprint Medicines Corporation: Honoraria, Research Funding. Jain:Pfizer: Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fate Therapeutics: Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Bioscienes: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; BMS: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Aprea Therapeutics: Research Funding; Incyte: Research Funding; ADC Therapeutics: Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kantarjian:Pfizer: Honoraria, Research Funding; Sanofi: Research Funding; Ascentage: Research Funding; Amgen: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive biotechnologies: Honoraria; Aptitute Health: Honoraria; BioAscend: Honoraria; Delta Fly: Honoraria; Immunogen: Research Funding; Janssen: Honoraria; Oxford Biomedical: Honoraria; Abbvie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Jazz: Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; BMS: Research Funding. Garcia-Manero:Amphivena Therapeutics: Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Merck: Research Funding; Jazz Pharmaceuticals: Consultancy; Acceleron Pharmaceuticals: Consultancy, Honoraria; H3 Biomedicine: Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Onconova: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding.