Phase IB/II Study of Lirilumab with Azacytidine (AZA) in Relapsed AML

Background: Lack of inhibitory killer-cell immunoglobulin receptor (KIR) interaction with HLA class I has been associated with NK-mediated antitumor efficacy in AML patients (pts) in remission upon KIR-mismatched haploidentical stem cell transplantation (SCT) (Ruggeri L et al., Science 2002). Blockade of KIR2DL1, 2, and 3 receptors induced augmented NK-cell mediated lysis of tumor cells (Romagne F et al., Blood 2009). Hypomethylating agents such as AZA possess anti-leukemia activity, and increase MHC II expression, cancer antigen exposure in solid and hematologic malignancies, and interferon-gamma signature. KIR-receptor blockade by lirilumab (KIR2DL1/2/3-specific monoclonal antibody) may improve response rates to hypomethylating agents

Patients and Methods: Pts with AML who have failed prior therapy (including prior therapy with hypomethylating agent), have adequate performance status (ECOG ≤ 2) and organ function are eligible (NCT02399917). AZA 75mg/m² Days 1-7 was given with lirilumab on Day 8 at the dosage of 1 and 3 mg/kg in 2 consecutive cohorts of 6 patients each. Courses were repeated every 4-5 weeks. Lirilumab 3mg/kg established as recommended phase 2-dose (RP2D) with AZA. 23 additional pts treated at the recommended RP2D. Responses were evaluated at the end of 3 courses of therapy.

Results: To date, 35 pts (23 de novo, 12 secondary AML) have been enrolled. Pt and disease characteristics are outlined in table 1. Among them, 21 (60%) were above 60 years of age at enrollment, 52% had adverse cytogenetics; median prior therapies received were 3 (range, 1-8) including prior allogeneic SCT in 7 (20%) patients. Thirty-two pts had baseline next generation sequencing for 28 myeloid-associated genes with most commonly mutated genes shown in Table 1. Four (11%) pts achieved CR/CRp/CRi and 1 (3%) achieved hematologic improvement for an overall response rate of 14%; additionally 3 (9%) patients had a ≥50% reduction in blast count. The median number of cycles to response was 2 (range, 1-11). The median duration of CR/CRp/CRi and HI responses were 3.0 months (range 1.1 - 9.7+ months). The 4-week and 8-week mortality were 7% and 15%, respectively. With a median follow up of 3.6 months (range, 1.1-15.1 months), the median overall survival among all patients was 4.2 months (range, 0.4-15.1) (figure 1A). As anticipated, the median survival was superior in responders as compared to non-responders (Figure 1B; p = 0.001)

Grade 3/4 toxicities were similar to those expected with AZA-based salvage therapies (Table 2). Immune mediated Grade 2-4 toxicities were observed in 4 (16%) pts (1, pneumonitis Grade 3; 2, colitis Grade 3; 1, colitis Grade 2). The immune mediated toxicities responded rapidly to steroids and 3 of the pts could be rechallenged safely with lirilumab. Additional immune mediated toxicities included Grade 1 skin rash in 2 patients and grade 1 infusion associated chills in 1 patient. Seven pts were post allogeneic SCT at enrollment and no Grade 3/4 GVHD flares were noted. AZA or lirilumab have not been discontinued in any patients due to toxicities.

Conclusion: Full doses of AZA and lirilumab were well tolerated in heavily pretreated pts with relapsed AML with poor risk disease features. The efficacy data are preliminary and the study is ongoing. AZA with lirilimumab is also undergoing investigation in frontline and salvage settings in myelodysplastic syndrome (NCT02599649).

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