γ9δ2 T-cell (γ9δ2TC) activation with ICT01 and azacitidine-venetoclax (Aza-Ven) induces high rates of remission and overall survival in patients with newly diagnosed (ND) acute myeloid leukemia (AML): Results from the phase 1/2 study eviction

Abstract Background: AML impairs immunosurveillance and cytotoxic T-cell responses. γ9δ2TCs are known to drive anti-leukemia benefit in the post-transplant setting and intra-tumor presence of γ9δ2TCs is prognostic. ICT01 is a first-in-class anti-butyrophilin 3A mAb which induces γ9δ2TC activation for direct anti-leukemic cytotoxicity and a bystander effect of NK/CD8 T cell activation mediated through IFNγ/TNFα release. ICT01 with Aza-Ven has shown synergistic efficacy in vivo in a mouse model with adoptive γδTC transfer. From the dose-optimization phase 1/2 study investigating 10 mg (ICT01LOW) and 75 mg ICT01 (ICT01HIGH) with Aza-Ven and based on the emerging benefit-risk profile assessed at an interim analysis, ICT01LOW was chosen as the recommended phase 2 dose (Maiti et al. Cancer Res. 2025;85[suppl. 2]:CT024) and the dose-level cohort was expanded to 41 patients. Here, we report updated safety and efficacy results, including a preliminary analysis for overall survival from the fully enrolled cohort from EVICTION (NCT04243499).Methods: ND-AML patients ≥ 75 years or unfit for intensive chemotherapy were randomized 1:1 to standard dosing of Aza-Ven plus ICT01 at either 10 mg (ICT01LOW) or 75 mg ICT01 (ICT01HIGH) on day 1 of each cycle. The primary objective was anti-leukemic efficacy measured as CR and CRc (CR/CRi) by ELN 2022; we further assessed safety per NCI-CTCAE 5.0, and ICT01 pharmacodynamics (PD) in peripheral blood (PB) and bone marrow (BM).Results: Of 57 patients, 54 were evaluable for efficacy; 38 had ICT01LOW and 16 had ICT01HIGH. Median age was 75 yrs (range 51‒87). Median baseline BM blasts percentage was 40% (range 7‒98%). Per refined ELN 2024 risk classification (rELN24), 30%, 28% and 42% of the enrolled patients had favorable, intermediate and adverse risk disease. Median days (IQR) of venetoclax dosing in cycles 1, 2, 3, and 4 were 22 (20, 27), 20 (13, 21), 13 (6, 16), 12 (6, 20), respectively, with a numerical trend for shorter dosing with the ICT01LOW regimen. Median duration (IQR) of cycles 1, 2, and 3 was 29 (28, 36), 31 (28, 47), and 29 (28, 44) days, with similar duration for both ICT01 dose levels. Patients who had ICT01LOW achieved 68% CR (95% CI, 51–82%) and 84% CRc (69–94%) vs 44% CR (95% CI, 20–70%) and 69% CRc (41–89%) in patients who had ICT01HIGH (p=0.0006 and p=0.02 for CR and CRc respectively; χ2 test). For patients with favorable, intermediate and adverse-risk AML (per rELN24) who had ICT01LOW, CRc rates were 100%, 82% and 67% and CR rates were 80%, 64% and 58%, with a time to first CRc response of 0.9 months (range, 0.7–2.9). After a median follow-up time of 8.5 months (95% CI, 7.1–10.3), 9-months OS was 74% (59‒91%) in the ICT01LOW cohort and 56% (36‒87%) in the ICT01HIGH cohort (HR 0.4 [0.2–0.8] for OS [p=0.03; log rank]). Patients achieving CRc or MLFS as compared with those who had NR or PR, had significantly higher baseline γ9δ2TC counts (p=0.001) and a greater increase in serum IFNγ 4h post first ICT01 dose (p=0.0001 vs. p=0.38; Wilcoxon test), suggesting direct contribution of on-target effector cells to the anti-leukemic efficacy of ICT01-Aza-Ven. Higher trough PB γ9δ2TC levels with ICT01LOW in subsequent cycles were associated with higher efficacy. In contrast, lower trough PBγ9δ2TC levels with ICT01HIGH, possibly associated with activation-induced cell death, abolished ICT01-mediated effects of increased serum IFNy and downstream activation of immune effector cells. No DLT was reported, all patients had at least one adverse event, and 30-day mortality was 4%. No new safety signal was detected for ICT01. Grade 3/4 febrile neutropenia was seen in 29 patients (51%) overall. No ICT01-related deaths or treatment discontinuations were reported.Conclusions: ICT01 was safe, well tolerated and generated very high CR and CRc rates in older/unfit patients with ND-AML. Both the high response rate and the promising early OS signal which compare favorably to recently published studies warrant further clinical investigation. Consistent PD effects suggest an individual contribution of ICT01 to the efficacy of the novel triplet regimen ICT01-Aza-Ven.