Natural Killer (NK) cells are regulated by interactions between Killer-Immunoglobulin-Like Receptors (KIRs) and their corresponding Human Leukocyte Antigen (HLA) ligands. KIRs can be grouped into either inhibitory (KIR A) or activating and inhibitory receptors (KIR B). KIR A negatively regulate NK cell-mediated killing of HLA class I-expressing tumors. Lack of KIR–HLA class I interactions has been associated with antitumor efficacy and increased survival in patients with AML in CR after haploidentical stem cell transplantation from KIR-mismatched donors. Lirilumab is an anti-KIR monoclonal antibody, which is designed to activate NK cells thereby aiding their activation by blocking their inhibitory receptors.
Norbert Vey from the Paoli-Calmettes Institute, Marseille, France, presented at the 59th American Society of Hematology (ASH) Annual meeting, Atlanta, GA, results from the phase II EFFIKIR randomized study (NCT01687387), which is assessing lirilumab monotherapy as maintenance therapy for elderly patients with AML in first Complete Remission (CR1). The main objectives of this study are to evaluate whether lirilumab could improve Leukemia Free Survival (LFS) and to assess two dose schedules including continuous (CONT) or intermittent (INT) full KIR occupancy.
Overall, 152 AML patients aged 60–80 years in CR1 following standard induction were randomized to receive placebo (n = 51, median age = 69 years) or lirilumab (0.1 mg/kg q for 12 weeks [INT, n = 50, median age = 70 years] or 1 mg/kg q for 4 weeks [CONT, n = 51, median age = 70 years]). The primary endpoint of the study was Leukemia Free Survival (LFS) by Independent Review Committee (IRC).
- Median follow-up: 37 months
- Median LFS
- INT vs placebo arm respectively; 17.6 vs 13.9 months, HR = 0.98, P = 0.929
- CONT vs placebo arm respectively; 6.7 vs 13.9 months, HR = 1.42, P = 0.144
- Study discontinuation occurred in patients (n = 41) in the CONT arm due to excess early relapse (n = 37), adverse events (n = 3) and other reasons (n = 1)
- Study discontinuation occurred in patients (n = 38) in the INT arm, due to relapse (n = 27), adverse events (n = 8) and other reasons (n = 3)
- Study discontinuation occurred in patients (n = 38) in the placebo arm, due to relapse (n = 32), adverse events (n = 5) and other reasons (n = 1)
- Transient full KIR occupancy lasting 7–28 Days was observed for the majority of patients in the INT arm and permanent full occupancy was observed in patients in the CONT arm
- Lirilumab did not induce major modifications in peripheral blood NK and T cell subsets
In an interview with the AML Global Portal (AGP), Norbert Vey, noted that single agent “lirilumab administered for up to 24 cycles was well tolerated”. However, the findings of the phase II EFFIKIR trial were “negative” as lirilumab did not result in a statistically significant “improvement of LFS in the challenging setting of maintenance in AML in elderly patients” in CR1.
Furthermore, there were no significant difference observed between the lirilumab arms and plaebo but reverse trends suggesting a clinical impact of intermittent (favorable trend) versus continuous (detrimental trend) KIR blockade.