Lirilumab/Azacytidine Combo Safe, Active in AML

Naval Daver, MD

The combination of the killer-cell immunoglobulin-like receptors inhibitor lirilumab with the hypomethylating agent azacytidine was well tolerated and showed early signals of activity in heavily pretreated patients with acute myeloid leukemia (AML), according to phase Ib/II findings presented at the 2016 ASH Annual Meeting.

The responses included 1 complete remission (CR), 1 CR with insufficient count recovery, and 3 patients with hematologic improvement >6 months. The median duration of response was 2 months.

“The efficacy data is early for this combination…at this time the response rate is about 20%. We anticipate additional data by the middle of next year,” Naval Daver, MD, assistant professor, Department of Leukemia, MD Anderson Cancer Center, said in an interview with OncLive.

The single-institution, single-arm phase Ib/II trial enrolled patients with relapsed/refractory AML with an ECOG performance status ≤2. Twenty-five patients have been treated and are evaluable for response.

Patients received azacytidine at 75mg/m² on days 1 through 7. In the dose-finding phase, lirilumab was administered on day 8 at either 1 or 3 mg/kg in 2 consecutive 6 patient-cohorts. The treatment courses were repeated approximately every 4 to 6 weeks.

The researchers did not observe any dose-limiting toxicities, and lirilumab at 3 mg/kg was established as the recommended phase II dose. Thirteen additional patients have been treated at this dose.

The primary outcome measure for the trial was response at 3 months. Secondary endpoints included overall survival (OS), progression-free survival (PFS), and the identification and management of immune-mediated toxicities.

The median patient age was 64 years (range, 30-89), with 14 patients aged >60 years. The median number of prior therapies was 3 (range, 1-8). Prior therapies included HMA-based (56%), HiDAC-based (64%), intermediate-dose AraC-based (36%), and molecular (36%). Twenty-eight percent of patients had prior stem cell transplant.

Patients had baseline next-generation sequencing for 28-genes. Frequently identified mutations included TP53 (n = 7), TET2 (n = 4), ASXL1 (n = 9), RUNX1 (n = 3), EZH2 (n = 3), DNMT3A (n = 1), CEBPA (n = 1), RAS (n = 4), and IDH2 (n = 1).

The median number of treatment cycles before response was 3 (range, 1-11). At a median follow-up of 5.1 months, the median PFS and OS were 3.3 months and 4.4 months, respectively.

Among responders and nonresponders, the median OS was 12.9 and 3.5 months, respectively. The median OS was 5.2 and 4.4 months among patients who were on their first or second salvage regimen, respectively.

The most frequently occurring grade 3/4 toxicities included neutropenic infection (60%), pneumonia (24%), abdominal pain (8%), and skin infection, UTI, and mucositis (1 patient each).

Ongoing studies are also evaluating lirilumab as a maintenance therapy in patients with high-risk AML and in the frontline and salvage settings for patients with MDS.

Daver N, Garcia-Manero G, Basu S, et al. Phase IB/II study of lirilumab in combination with azacytidine (AZA) in patients (pts) with relapsed acute myeloid leukemia (AML). 58th ASH Annual Meeting and Exposition; San Diego, California; December 2-6, 2016.

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