Abstract LB061: On-target peripheral and tumor immune microenvironment modulation in patients treated with lacnotuzumab (anti-CSF1, MCS110) + spartalizumab

Background: The CSF-1/CSF-1R (colony-stimulating factor-1) pathway plays a significant role in the tumor microenvironment via regulation of tumor-associated macrophages (TAMs). Lacnotuzumab (MCS110) is a humanized monoclonal antibody against CSF-1. Lacnotuzumab may counteract the tumor suppressive microenvironment induced by CSF-1, potentially enhancing the efficacy of PD-1 inhibition. Methods: MCS110Z2102 is a phase 1b/2 study in cancer patients with advanced malignancies treated by lacnotuzumab combined with the PD-1 inhibitor spartalizumab. Eligible patients with previously treated advanced/metastatic solid tumors received 1, 3, 5, 7.5 and 10 mg/kg intravenous doses of lacnotuzumab in dose escalation combined with 100 mg or 300 mg of spartalizumab administered every 3 weeks. Then, the selected recommended phase 2 dose (RP2D, 7.5 mg/kg lacnotuzumab in combination with 300 mg spartalizumab every 3 weeks) was explored in 4 expansion groups of pancreatic cancer, triple-negative breast cancer (TNBC), endometrial cancer (EC) and malignant melanoma. Here, we report flow cytometric, circulating total CSF1 in plasma and gene expression profiling analyses as evidence of on-target pharmacodynamic effects of lacnotuzumab + spartalizumab in treated patients. Results: The combination of lacnotuzumab and spartalizumab increased the levels of circulating total CSF-1 in plasma, thereby suggesting target engagement and selectively decreased peripheral CSF-1R-expressing intermediate and nonclassical monocytes, at all doses tested. Gene expression profiling by RNA-sequencing in paired biopsies showed down-regulation of macrophage associated genes in patients treated with lacnotuzumab + spartalizumab. In addition, the upregulation of cytotoxic T cell gene signatures was observed. A limited antitumor activity was observed: 2 pancreatic cancer, 1 TNBC and 2 EC patients had a confirmed partial response over 141 patients treated. Conclusions: Flow cytometric, circulating total CSF1 in plasma and gene expression profiling results demonstrated that targeting CSF-1 with lacnotuzumab in the periphery and tumor microenvironment leads to decrease in monocytes and reduced expression of macrophage associated genes in patients with advanced cancers. Unfortunately, in the heavily pretreated patient populations studied in this trial, only a limited clinical efficacy was demonstrated. Citation Format: Jincheng Wu, Shuqi Chen, Guillaume Baneyx, Anne-Laure Marchal, David S. Quinn, Miguel Martin, Andres Cervantes, Janna Sand-Dejmek, Jennifer Marie Mataraza. On-target peripheral and tumor immune microenvironment modulation in patients treated with lacnotuzumab (anti-CSF1, MCS110) + spartalizumab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB061.