Updated Preliminary Results from a Phase II Study Combining Azacitidine and Pembrolizumab in Patients with Higher-Risk Myelodysplastic Syndrome
Authors: Chien Kelly S. , Borthakur Gautam M. , Naqvi Kiran , Daver Naval G. , Cortes Jorge E. , DiNardo Courtney D. , Jabbour Elias , Andreeff Michael , Alvarado Yesid , Bose Prithviraj , Jain Nitin , Sheppard Kimberly , Klingner-Winton Cheri , Pierce Sherry A. , Dong Xiao Qin , Soltysiak Kelly , Kantarjian Hagop M. , Garcia-Manero Guillermo 
Published: November 2019

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 patients achieved complete remission (CR), 2 patients attained marrow CR (mCR), and 2 patients showed hematological improvement of platelets (HI-P). In the previously untreated MDS cohort, 2 patients reached CR, 2 patients had mCR, 2 patients exhibited mCR with HI-P, and 1 patient demonstrated HI-P. The most frequently observed mutations in the 13 responding patients were ASXL1 and TET2 in 4 patients each and DNMT3A and TP53 in 3 patients each. Six of the responders had normal cytogenetics, 1 had del(20q), and 2 had complex karyotype. Overall survival was 5.9 months in the HMA failure cohort and 12.9 months in the HMA naïve cohort.
Treatment was overall well-tolerated. The most common treatment-related adverse events (all grades) were neutropenia (37%), myalgias/arthralgias (20%), constipation (17%), and elevated alanine aminotransferase levels and injection site reactions (13%). Three patients died in the first 60 days while receiving treatment from the unrelated causes of cardiac arrest from ventricular fibrillation, septic shock and multiorgan failure, and fungal pneumonia.
Conclusions: In this ongoing phase II trial, preliminary data suggest that azacitidine and pembrolizumab was relatively safe and well-tolerated. Combination therapy may have antitumor activity in patients who failed HMA, though no significant improvement in overall survival was observed.

Disclosures
Borthakur: FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; AbbVie: Research Funding; Merck: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Eisai: Research Funding; Xbiotech USA: Research Funding; Strategia Therapeutics: Research Funding; AstraZeneca: Research Funding; Novartis: Research Funding; Bayer Healthcare AG: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Research Funding; Cyclacel: Research Funding; Oncoceutics, Inc.: Research Funding; BMS: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Cantargia AB: Research Funding; PTC Therapeutics: Consultancy; NKarta: Consultancy; Agensys: Research Funding; Oncoceutics: Research Funding; Arvinas: Research Funding; Polaris: Research Funding; Eli Lilly and Co.: Research Funding; Tetralogic Pharmaceuticals: Research Funding. Daver:Astellas: Consultancy; Immunogen: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Agios: Consultancy; Agios: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Servier: Research Funding; Servier: Research Funding; Karyopharm: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; NOHLA: Research Funding; NOHLA: Research Funding; Glycomimetics: Research Funding; Glycomimetics: Research Funding; Otsuka: Consultancy; Otsuka: Consultancy; Celgene: Consultancy; Celgene: Consultancy; Hanmi Pharm Co., Ltd.: Research Funding; Hanmi Pharm Co., Ltd.: Research Funding; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Forty-Seven: Consultancy; Astellas: Consultancy; Immunogen: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Forty-Seven: Consultancy; Jazz: Consultancy; Novartis: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Jazz: Consultancy; Daiichi Sankyo: Consultancy, Research Funding. Cortes:Immunogen: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; BiolineRx: Consultancy; Biopath Holdings: Consultancy, Honoraria; Sun Pharma: Research Funding. DiNardo:agios: Consultancy, Honoraria; syros: Honoraria; medimmune: Honoraria; jazz: Honoraria; daiichi sankyo: Honoraria; celgene: Consultancy, Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; abbvie: Consultancy, Honoraria. Jabbour:AbbVie: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding. Andreeff:Daiichi Sankyo, Inc.: Consultancy, Patents & Royalties: Patents licensed, royalty bearing, Research Funding; Celgene: Consultancy; Jazz Pharmaceuticals: Consultancy; Amgen: Consultancy; AstaZeneca: Consultancy; 6 Dimensions Capital: Consultancy; Reata: Equity Ownership; Aptose: Equity Ownership; Eutropics: Equity Ownership; Senti Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Oncoceutics: Equity Ownership; Oncolyze: Equity Ownership; Breast Cancer Research Foundation: Research Funding; CPRIT: Research Funding; NIH/NCI: Research Funding; Center for Drug Research & Development: Membership on an entity's Board of Directors or advisory committees; Cancer UK: Membership on an entity's Board of Directors or advisory committees; NCI-CTEP: Membership on an entity's Board of Directors or advisory committees; German Research Council: Membership on an entity's Board of Directors or advisory committees; Leukemia Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; NCI-RDCRN (Rare Disease Cliln Network): Membership on an entity's Board of Directors or advisory committees; CLL Foundation: Membership on an entity's Board of Directors or advisory committees; BiolineRx: Membership on an entity's Board of Directors or advisory committees. Alvarado:Jazz Pharmaceuticals: Research Funding; Abbott: Honoraria. Bose:Constellation: Research Funding; CTI BioPharma: Research Funding; Celgene Corporation: Consultancy, Research Funding; Blueprint Medicine Corporation: Consultancy, Research Funding; Kartos: Consultancy, Research Funding; Incyte Corporation: Consultancy, Research Funding, Speakers Bureau; Pfizer: Research Funding; Astellas: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding. Jain:AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kantarjian:Jazz Pharma: Research Funding; Ariad: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Takeda: Honoraria; Astex: Research Funding; Cyclacel: Research Funding; Novartis: Research Funding; BMS: Research Funding; Immunogen: Research Funding; Daiichi-Sankyo: Research Funding. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding.