Phase Ib study of xentuzumab and abemaciclib in patients with advanced solid tumors and in combination with endocrine therapy in patients with advanced breast cancer

Abstract

Background: This phase Ib trial assessed the insulin-like growth factor 1/2 neutralizing antibody, xentuzumab, plus abemaciclib +/- endocrine therapy (ET) in patients with advanced/metastatic solid tumors, including hormone receptor (HR)-positive breast cancer. Patients and methods: In part 1, patients with advanced solid tumors received escalating doses of xentuzumab + abemaciclib (cohort A). In part 2, dose-finding cohorts B-D had advanced/metastatic HR-positive, human epidermal growth factor receptor 2-negative breast cancer and received xentuzumab + abemaciclib plus letrozole, anastrozole, or fulvestrant. Part 3 included expansion cohorts assessing xentuzumab + abemaciclib plus fulvestrant in patients with HR-positive, human epidermal growth factor receptor 2-negative breast cancer with visceral (cohort D1) or non-visceral disease (cohort D2) who had progressed following ET, or non-visceral disease who had progressed following ET and a cyclin-dependent kinase inhibitor (cohort F). Primary endpoints were maximum tolerated dose (cohorts A-D), 18-month progression-free survival (cohort D1/D2) and disease control (cohort F). Comprehensive biomarker analyses were undertaken. Results: A total of 133 patients were treated. The maximum tolerated dose was xentuzumab 1000 mg once weekly plus abemaciclib 150 mg twice daily (cohorts A-D). The most common grade >= 3 adverse event was decreased neutrophil count. Cohorts B-D demonstrated response rates of >= 25%. The 18-month progression-free survival rate in cohorts D1/D2 was 41.4%/78.5%. The disease control rate in cohort F was 40.0%. Biomarker analysis indicated target engagement. Prognostic biomarkers included total serum insulin-like growth factor 1 concentrations, expression of CCND1, and MCL-1 mutations. Conclusions: Xentuzumab + abemaciclib + ETs demonstrated manageable tolerability and promising efficacy, especially in patients with breast cancer and non-visceral metastases.