Results of a Phase Ib Study Investigating Durvalumab in Combination with Eribulin in Patients with HER2-negative Metastatic Breast Cancer and Recurrent Ovarian Cancer

Introduction: The release of tumor-associated antigens with cytotoxic chemotherapy treatment may enhance the response to immune checkpoint blockade. Eribulin is a microtubule inhibitor with proven overall survival (OS) benefit in metastatic breast cancer (MBC), which may also enhance intratumoral vascular remodeling. Durvalumab, a humanized monoclonal antibody, targets the programmed cell death ligand-1 (PD-L1) receptor. This study sought to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of eribulin in combination with durvalumab, as well as the safety and preliminary antitumor activity of the combination in patients with previously treated HER2-negative (HER2-) MBC and recurrent ovarian cancer (ROC). Methods: Cohorts of 3-6 patients with HER2- MBC and ROC were treated in a modified 3+3 design. Eligible patients received escalating doses of eribulin (1.1mg/m2 or 1.4 mg/m2 IV on day 1 and day 8) with durvalumab (1.12g IV on day 1) in 21-day cycles until dose-limiting toxicity (DLT), intolerable adverse events (AEs), disease progression, or other reasons for withdrawal. Primary endpoint: the rate of dose limiting toxicities (DLTs) during cycle 1 and 2 of therapy. Secondary endpoints: AE rate, Objective Response Rate (ORR), progression-free survival (PFS), and OS. Results: Nine patients with a median of 4 prior therapies for advanced disease were treated: 5 patients with HER2- MBC (1 with triple negative disease and 4 with hormone positive disease) and 4 patients with ROC. The RP2D of eribulin was 1.4mg/m2 in combination with durvalumab. There were no DLTs experienced during the first two cycles of therapy. The most common treatment-related AEs (>50%) were fatigue, neutropenia, decreased white blood cell count, anemia, AST and alkaline phosphatase elevation, hyperglycemia, and nausea; most were grade 1 or 2. There was one immune-related AE of grade 3 (hepatitis) after 5 cycles of treatment, for which patient came off study. Two other patients discontinued study drug related to toxicity [neutropenia (n=1), hepatic toxicity (n=1)]. ORR was 55% and 4 additional patients experienced 3 stable disease. All MBC patients exhibited a response to therapy. Median PFS was 6.2 months. Median OS was 15.0 months. Conclusion: The combination of eribulin at a dose of 1.4 mg/m2 with standard dose durvalumab had a favorable AE profile in patients with previously treated HER2- MBC and ROC. The early anti-tumor activity observed in all MBC patients enrolled in the study suggests that further investigation of this combination is warranted.