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Background γ9δ2 T-cell tumor infiltration confers favorable prognosis, qualifying these cells as promising targets for cancer immunotherapy. Nonclinical studies showed that ICT01 (first-in-class anti-BTN3A and selectively γ9δ2 T-cell-activating mAb) upregulates PD-1 on γ9δ2 T cells and PD-L1 on tumor cells. Addition of pembrolizumab to ICT01 dose-dependently enhances IFNγ release, potentiates tumor cell killing, and induces immune cell-mediated tumor-microenvironment remodeling. Here, we present final results for the combination of ICT01 and pembrolizumab treatment of 2L melanoma patients with CPI-refractory disease per SITC criteria from the Phase 1/2 study EVICTION ( NCT04243499).Methods We evaluated ICT01 (20μg to 200mg, Q3W) plus pembrolizumab (200mg, Q3W) in patients with advanced/metastatic melanoma. Tumor imaging Q8W was evaluated per (i)RECIST 1.1; DCR comprised rates of CR/PR and SD ≥24 weeks). Schedule of assessments included TRAE, irAE, and ICT01 pharmacodynamics.Results As of 15-July-2025, 27 patients with non-uveal 2L cutaneous (n=16), mucosal (n=5) or other/unknown (n=6) melanoma were evaluable for efficacy of ICT01-pembrolizumab; of these, 26 had primary CPI resistance. Median DoT was 3.4 months (95%CI, 2.2-6.1). Grade ≥3 TRAEs and Grade ≥2 irAEs were overall rare and without excess toxicity over that expected for pembrolizumab, confirming prior reports of clinically very well manageable toxicity of ICT01. CRS was a mild, largely first-dose effect and clinically manageable with antipyretics. Only temporary (no permanent) drug-related treatment modifications occurred in 5 (19%) patients. ICT01 low (dose ≤7 mg Q3W) revealed a more favorable benefit-risk profile versus ICT01high (≥20 mg Q3W) with both less CRS and infectious TRAEs or irAEs. ORR was 15% (4/27) with DCR attained by 8 patients (30%, 1 CR, 3 PR, 4 SD ≥24 weeks) with median DoR of 9.5 (95%CI, 5-NR) months. The patient with CR had remission of brain and liver metastases and is ongoing for >4 years. Median PFS was 3.5 months (95%CI, 1.9-5.5), and the 6-month PFS rate was 26% (%CI, 14-49). DCR was strongly associated with sustained elevation of ICT01-mediated IFNγ levels and cyclic reappearance of ≥20,000 peripheral γ9δ2 T cells/mL·d post-dose, as prerequisite of cyclic ICT01-mediated re-activation, both resulting in NK/CD8 bystander activation and tumor-microenvironment remodeling, effects seen predominantly with ICT01low, while ICT01high revealed signs of (over)activation-induced cells death.Conclusions ICT01 in combination with pembrolizumab generated clinically meaningful anti-tumor efficacy in 2L CPI-refractory melanoma patients, indicating the potential to overcome resistance to checkpoint inhibitors and chemotherapy. The modeled dose of 10 mg ICT01 Q3W is proposed for future studies investigating the clinical potential of ICT01-pembrolizumab.Trial Registration ClinicalTrials.gov ID: NCT04243499 EudraCT Number: 2019-003847-31Ethics Approval All patients gave informed consent before taking part in the study. The study obtained ethics approval from all institutions involved including Vall hebron (Spain), N°412 Universite Dresden (Germany) AMG MONO-EK-5012020, Institut Jules Bordet (Belgium): CE3083, IRAS ID 282711 (UK), CPP Sud mediterrannée V N°2019-003847-31 et N° CNRIPH 19.10.30.51143 (France) and all IRBs of US institutions involved.