Abstract CT172: Pharmacodynamic and gene expression profiling of patients treated with BLZ945 + spartalizumab demonstrates on-target peripheral and tumor immune microenvironment modulation
Authors: Jincheng Wu, Chia-Chi Lin, Marta Gil-Martin, Aung Naing, Liqiong Fan, Fang Yang, David Quinn, Pei-Jung Tu, Cornelia Quadt, Jennifer Mataraza
Journal: Cancer Research (2020)

Abstract Background: The colony stimulating factor 1 receptor (CSF-1R) signaling pathway promotes tumor progression via the recruitment, differentiation, and survival of immuno-suppressive tumor-associated macrophages (TAMs). Blocking CSF-1R signaling may lead to the depletion of TAMs and increased T-cell activation. BLZ945 is an oral, highly selective and potent kinase inhibitor of CSF-1R, which can cross the blood-brain barrier. By reducing TAMs and promoting a pro-inflammatory microenvironment, BLZ945 may stimulate T-cell responses, thereby sensitizing solid tumors to anti–PD-1 therapy. Methods: BLZ945X2101 is an ongoing Ph I/II study investigating the use of BLZ945 as single agent and in combination with spartalizumab (anti–PD-1) in advanced solid tumors. Eligible pts (aged ≥18 years, ECOG 0–1) with advanced/metastatic solid tumors received BLZ945 (300 mg–1600 mg QD and 600 mg BID) Q1W, 7d on/7d off (150 mg–300 mg QD), or 4d on/10d off (300 mg–1200 mg QD and 600 mg BID); or BLZ945 (150 mg–1400 mg QD, 600 mg–800 mg BID) Q1W or 4d on/10d off (300 mg–1200 mg) plus spartalizumab at a fixed dose of 400 mg IV, Q4W. Baseline and on-treatment tumor samples were collected. Here we report flow cytometric, soluble ligand and gene expression profiling analyses as evidence of on-target pharmacodynamic effects of BLZ945 + spartalizumab in treated patients. Results: In total, paired samples for 61 pts for flow cytometry, samples from 30 pts for CSF-1 plasma and paired samples from 35 pts for RNAseq analysis were analyzed. BLZ945 (+/-spartalizumab) induced increases in plasma CSF-1 and decreased peripheral intermediate and nonclassical monocytes, at all doses and schedules tested. Gene expression profiling by RNAseq in paired biopsies showed downregulation of macrophage associated genes in patients treated with both single-agent BLZ945 and BLZ945 + spartalizumab. In patients treated with the BLZ945 + spartalizumab combination, upregulation of cytokine, chemokine, and HLA genes was observed. Signs of antitumor activity were observed in several tumor types including glioblastoma and head and neck cancer. Conclusions: Flow cytometric, soluble ligand and gene expression profiling demonstrated BLZ945-mediated CSF-1R blockade in the periphery and tumor microenvironment in patients with advanced cancers. Ongoing analyses include identification of transcriptomic signatures associated with response. These data support further clinical development of BLZ945 ± spartalizumab in advanced cancers (NCT02829723). Citation Format: Jincheng Wu, Chia-Chi Lin, Marta Gil-Martin, Aung Naing, Liqiong Fan, Fang Yang, David Quinn, Pei-Jung Tu, Cornelia Quadt, Jennifer Mataraza. Pharmacodynamic and gene expression profiling of patients treated with BLZ945 + spartalizumab demonstrates on-target peripheral and tumor immune microenvironment modulation [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT172.