Document resource
Background Casitas B-lineage lymphoma proto-oncogene B (CBL-B) is an E3 ubiquitin ligase that functions as a cytoplasmic immune checkpoint, constraining immune cell activation. NX-1607 is a first-in-class, orally bioavailable, small-molecule inhibitor of CBL-B with the potential to enhance antitumor immunity. In preclinical models, NX-1607 effectively inhibits tumor growth by reshaping the intratumoral innate and adaptive immune response. 1 2 NX-1607-101, a Phase 1 first-in-human study, demonstrated that NX-1607 exhibits a tolerable safety profile and is associated with radiographic and biomarker signals of tumor regression in patients, including tumor volume and prostate-specific antigen (PSA) reductions.Methods As of 25 Feb 2025, 75 heavily pretreated patients with advanced solid tumors (including 19 with metastatic castration-resistant- prostate cancer [mCRPC]) were enrolled in the Phase 1 study. NX-1607 was administered at doses ranging from 5 mg once daily to 40 mg twice daily. Translational analysis of pharmacodynamics (PD) included assessment of the proximal biomarker phospho-HS1 (pHS1) in CD8 + T cells, circulating chemokines and cytokines, and transcriptomic profiling of paired (baseline vs on-treatment) peripheral blood mononuclear cells (PBMCs) from pan-tumor and prostate cancer patients specifically, and its relationship with pharmacokinetics (PK).Results NX-1607 exhibited dose-dependent PK with an increase in pHS1/CD8 + T cells. Post-treatment upregulation of circulating CXCL10 and CCL4 was observed, consistent with reported anti-PD-1 response profiles.3 4 RNA-seq on PBMCs from pan-tumor patient samples showed approximately 2 log2 enrichment of immune modulation-related pathways, including IFN-γ signaling and antigen presentation. In the mCRPC patient subset, specific PBMC transcriptomic profiling revealed upregulation of innate immune responses and lymphocyte proliferation, including higher granulocyte gene expression, complement activation, cell proliferation, and cell cycle regulation. PSA reductions of ≥30% were observed in 6 out of 14 evaluable mCRPC patients. At higher doses of NX-1607, a greater reduction in PSA was associated with a trend toward increased activation of pHS1.Conclusions NX-1607 demonstrates dose-dependent increases in PK with corresponding peripheral immune activation and preliminary antitumor signals observed in advanced solid tumors. PD data are consistent with the peripheral upregulation of both innate and adaptive immune activation pathways after NX-1607 treatment. These findings suggest that NX-1607 has the potential to modulate the tumor microenvironment and elicit antitumor immune responses in heavily pretreated patients with solid tumors. Exploratory biomarker analyses are ongoing to further evaluate PD and to inform on mechanisms of action and resistance to NX-1607.Trial Registration NCT05107674References Gallotta M, et al. NX-1607, a small molecule inhibitor of CBL-B, enhances anti-PD-1-mediated tumor growth inhibition by reshaping intratumoral innate and adaptive immune responses. Presented at Society for Immunotherapy of Cancer (SITC) Annual Meeting. San Diego, CA, USA. 2023Gallotta M, et al. NX-1607, a small molecule inhibitor of the CBL-B E3 ubiquitin ligase, promotes T and NK cell activation and enhances NK-mediated ADCC in a mouse lymphoma tumor model. Presented at Society for Immunotherapy of Cancer (SITC) Annual Meeting. Boston, MA, USA. 2022.Mitsuhashi A, Kondoh K, Horikawa K, et al. Programmed death-1/PD-L1 blockade mediates anti-angiogenic effects by tumour-derived CXCL10/11 as a potential predictive biomarker. Cancer Sci. 2021;112:4853–4866.Naing A, Infante J, Goel S, et al. Anti-PD-1 monoclonal antibody MEDI0680 in a phase I study of pts with advanced solid malignancies. J Immunother Cancer. 2019;7:225.