γ9δ2 T-cell activation (γδTCA) with ICT01 combined with azacitidine-venetoclax (AV) for older/unfit adults with newly diagnosed (ND) AML: Preliminary efficacy and dose selection in phase 1/2 study EVICTION.

6507 Background: AML impairs immunosurveillance bypassing target recognition and subsequent cytotoxic T cell responses. Immunomodulatory and cytotoxic effects of AV and γδTCA with ICT01 have shown synergistic efficacy in an in-vivo AML model with adoptive γδTC transfer. ICT01 is a first-in-class humanized, Fc-disabled anti-butyrophilin 3A mAb selectively inducing γδTCA for direct anti-leukemic cytotoxicity and IFNγ/TNFα release. γδTC are known to drive anti-leukemic efficacy in the post-transplant setting and intratumor presence of γδTCs is prognostic. γδTCA by ICT01 was dose dependent, safe, and tolerable. Here, ICT01-mediated γδTCA added to AV has been investigated in a dose-optimization Phase 1/2 study. Methods: ND-AML pts ≥ 75 years old or unfit to receive intensive chemotherapy were randomized 1:1 to AV plus either 10 mg (ICT01 LOW ) or 75 mg ICT01 (ICT01 HIGH ) Q4W. We assessed cytogenetics, NGS, pharmacodynamics (PD) in peripheral blood (PB) and bone marrow (BM), safety, and anti-tumor efficacy. Results: Of 45 pts randomized, 33 had conclusive disease assessments as of 20-Jan-2025, median age was 75 yrs (range 51‒87), the minority (30%) had favorable risk (ELN 2024) and 55% had abnormalities of uncertain risk, some of which are suggestive of a poor response to AV. Median number of BM blasts at diagnosis was 38% (range 5‒98%). No DLT was reported, and all pts had at least one adverse event; 30-day mortality was 3%. Grade 3/4 febrile neutropenia was seen in 19 (42%) and neutropenia in 32 pts (71%). ICT01 reproducibly induced rapid γδTCA in PB and BM, followed by increased serum IFNγ/TNFα reflective of downstream immune-cell effects. γδTC counts rapidly dropped in both PB and BM upon first ICT01 dosing and returned to near baseline values during ICT01 LOW dosing but became almost undetectable during continued ICT01 HIGH dosing. ICT01 LOW exhibited a favorable benefit–risk profile with 90% CR/CRi (71% CR, 19% CRi) and lower rates of neutropenia/febrile neutropenia than both ICT01 HIGH and published data, while PD effects seen with ICT01 HIGH suggestive of activation-induced γδTC death upon repeated dosing were associated with less efficacy (75% CR/CRi [42% CR, 33% CRi]). Notably, response rates were high (particularly with ICT01 LOW ) both in pts with adverse (CR 40% / CR/CRi 60% for TP53/CK ; N=10), intermediate/uncertain (CR 47% / CR/CRi 95% for MECOMr, NRAS, ASXL1 , JAK2 , DNMT3A , SF3B1 , U2AF1 , SRSF2 , RUNX1 , STAG2 ; N=19) and favorable (CR 80% / CR/CRi 90% for NPM1 , IDH1/2 ; N=10) risk mutations per ELN 2024. Conclusions: For AV combination, the recommended Phase 2 dose is 10 mg ICT01 Q4W. Both ICT01 regimens were safe and very well tolerated and generated very high CR and CR/CRi rates in older/unfit ND-AML pts. The high response rates seen in adverse risk pts warrant further clinical investigation. Clinical trial information: NCT04243499 .