A randomized, open-label, phase II study of azacitidine (AZA) in combination with durvalumab in patients (pts) with previously untreated higher-risk myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) ineligible for hematopoietic stem cell transplantation (HSCT).

Abstract

TPS7074 Background: Hypomethylating agents (HMAs) induce hematologic response in ~ 50% of higher-risk MDS pts; however, there are few treatment options for nonresponding pts at increased risk of AML progression and death. While older AML pts ineligible for HSCT have similar overall survival (OS) with AZA and chemotherapy (13.3 vs 12.2 months) (Döhner et al. Haematologica 2015;100:P566), there is an opportunity to further improve responses and OS in these pts. Blockade of the programmed cell death-1 (PD-1)/PD-ligand 1 (PD-L1) pathway with immune checkpoint inhibitors is an emerging paradigm in anticancer therapy. PD-L1 is expressed on cells from AML and MDS pts; expression is upregulated on myeloblasts following HMA therapy (Yang et al. Leukemia 2014;28:1280) and during MDS transformation to AML (Ogata et al. Leuk Res 2012;36:1229). Durvalumab (MEDI-4736), a human anti-PD-L1 monoclonal antibody, is well tolerated and induces durable responses in pts with solid tumors (Lutzky et al. JCO 2014;32:3001). This randomized, open-label, phase 2 study evaluates efficacy and safety of subcutaneous (SC) AZA ± durvalumab in pts with higher-risk MDS and older pts with AML. Methods: Eligible MDS pts ( < 20% blasts) aged ≥ 18 years, with IPSS intermediate- or high-risk MDS, and AML pts (≥ 20% blasts) aged ≥ 65 years, are randomized 1:1 to receive either AZA 75 mg/m2 SC for 7/28 days or AZA 75 mg/m2 SC for 7/28 days plus durvalumab 1500 mg IV on day 1 of 28-day cycles. Pts are stratified by cytogenetic risk: intermediate- vs poor-risk AML, and intermediate- vs poor-/very-poor-risk MDS. Primary endpoint is overall response rate per IWG 2006 criteria in MDS pts, and proportion of pts achieving complete response (CR) or CR with incomplete blood count recovery (CRi) per modified IWG 2003 criteria in AML pts. Other endpoints include safety, time to response, overall survival and PD-1/PD-L1 activity. Pts will be followed every 3 months until discontinuation. Target enrollment is 182 pts: 72 MDS pts and 110 AML pts. Enrollment began in June 2016 (ClinicalTrials.gov NCT02775903).