Lirilumab plus Azacitidine in Heavily Pretreated, Relapsed AML
Based on the hypothesis that inhibition of KIR-receptor blockade with lirilumab, a specific monoclonal antibody targeting KIR2DL1/2/3, may improve response rates to hypomethylating agents, a phase 1b/2 study evaluated this combination in patients with relapsed acute myeloid leukemia (AML); results of this ongoing study are reported here.
Eligible patients had AML and failed prior therapy including a hypomethylating agent, and had adequate performance status (Eastern Cooperative Oncology Group ≤2) and organ function. Patients were treated with azacitidine (AZA) 75 mg/m2 on days 1 through 7 plus lirilumab 1 and 3 mg/kg on day 8 in 2 consecutive cohorts (n = 6 each), repeated every 4 to 5 weeks. Responses were evaluated at the end of 3 courses of therapy.
No dose-limiting toxicities were observed, and lirilumab 3 mg/kg was established as the recommended phase 2 dose with AZA, with 9 additional patients treated at that dose. A total of 35 patients were enrolled in the study; 21 (60%) patients were aged ≥60 years, 52% had adverse cytogenetics, and 12 patients had secondary AML. The patient population was heavily pretreated and had received a median of 3 prior therapies (range, 1-8) including prior allogeneic stem-cell transplantation in 7 (20%) patients. Based on baseline next-generation sequencing (n = 32), the most commonly mutated genes were ASXL1, TP53, NRAS, and RUNX1.
Grade 3/4 nonhematologic toxicities were consistent with AZA-based salvage therapies, and included mucositis (3%), pneumonitis (3%), urinary tract infection (3%), abdominal pain (3%), colitis (3%), skin infection (9%), pneumonia (17%), and bloodstream infection (43%). Of note, grade 2 to grade 4 immune-related adverse events (AEs) occurred in 4 patients, who responded rapidly to steroids. No treatment discontinuation due to AEs occurred with AZA or lirilumab treatment.
Preliminary efficacy results indicate that the median duration of complete remission (CR)/CR with partial hematologic response/CR with incomplete hematologic response and hematologic improvement was 3.0 months (range, 1.1-9.7+ months). With a median follow-up of 3.6 months, the median overall survival (OS) in the total population was 4.2 months (range, 0.4-15.1 months), with responders showing a significant OS benefit compared with nonresponders (P = .001). The 4-week and 8-week mortality was estimated to be 7% and 15%, respectively.
The investigators concluded that the combination of AZA plus lirilumab was well-tolerated in heavily pretreated patients with relapsed AML with poor-risk disease features.
Daver N, et al. 2017 ASH. Abstract 2634.