Background: Inflammatory breast cancer (IBC) is unresectable at presentation, thus neoadjuvant systemic therapy (NAS) is the primary treatment for this aggressive disease. Eribulin (E) (Eisai Co., Ltd) is a synthetic analog of Halichondroin B that suppresses microtubule growth. Its properties of inducing a mesenchymal-to-epithelial transition and normalizing the vasculature of mammary tumors are particularly relevant to IBC. Pre-clinical data revealed changes in dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) parameters after exposure to E, thought to reflect tumor vasculature remodeling. We sought to examine the efficacy of E-containing NAS specifically for patients (pts) with HER2- IBC. We also characterized changes in breast DCE-MRI and diffusion weighted MRI (DWI) between baseline and 1 week (wk) after NAS. Methods: Pts with newly diagnosed HER2- IBC received 4 cycles of E 1.4 mg/m2 day (D)1, D8 every 21 D followed by 4 cycles of dose-dense (dd) doxorubicin (A) 60 mg/m2 + cyclophosphamide (C) 600mg/m2 every 2 wk followed by modified radical mastectomy (MRM) + postmastectomy radiation (PMRT) on a phase II prospective study (Cohort A). Primary endpoint was pathologic complete response (pCR) defined as no invasive disease in breast + axillary lymph nodes. Based on a Simon 2-stage design, if ≥ 2 of 16 pts had pCR then enrollment would continue to 25, with the regimen worthy of study if pCR ≥ 0.30 and not if pCR ≤ 0.10 (α=0.10, β=0.10). A second cohort was opened, changing the NAS sequence to ddAC followed by E (Cohort B). All pts had 2 research breast biopsies (rbx) for genomic analysis at baseline and 1 wk after first dose of NAS. An imaging study evaluated breast DCE-MRI and DWI at baseline and 1 wk after first dose of NAS. Tofts 2-compartment pharmacokinetic (PK) model calculated Ktrans, Ve, Kep, and iAUC from DCE. ADC was calculated from DWI. The change in Ktrans, Ve, Kep, iAUC, and ADC between baseline and wk 1 was evaluated using a signed-rank test. The magnitude of these changes was compared between Cohort A and Cohort B using a Wilcoxon rank-sum test. All testing was two-tailed and exact p-values were used; p-value < 0.05 were considered statistically significant. Results: 22 pts were enrolled, 16 pts in Cohort A and 6 pts in Cohort B before the study was closed due to slow accrual. Median age was 58 years, 3 pts (13.6%) had triple negative disease. 13 pts (59%) were postmenopausal. All but 1 had stage III disease. All 22 pts completed NAS followed by MRM + PMRT. 19 pts completed full course of NAS, 1 pt received E followed by 3 cycles of AC and 2 pts received 3 cycles of E in addition to 4 cycles of AC. In Cohort A, 1/16 pts had pCR (6.3%; 80% CI 0,22.2%). At a median follow up of 51 months, 3 pts had distant disease recurrence with 1 death; no local-regional recurrence. 7 pts experienced grade (gd) 3 or 4 adverse event (AE); most common were neutropenia and aminotransferase increase. 10 pts participated in the DCE-MRI and DWI substudy: 5 from Cohort A, 5 from Cohort B. Decrease in value from baseline to wk 1 was detected in Ktrans (median -49), Ve (-128), and iAUC (-57). The magnitude of changes was not different when comparing Cohort A to Cohort B. There was no significant change in Kep or ADC. Given the small size of each group, a lack of statistical significance should not be interpreted as suggestive of no effect. Evaluation of changes in angiogenesis- and EMT-related gene expression in rbx + residual disease is ongoing.Conclusion: A regimen of E + ddAC is tolerable NAS for HER2- IBC. All pts underwent curative surgery despite low pCR rate, commonly observed in ER+ IBC. There were changes in some DCE-MRI parameters after exposure to chemotherapy but may not be specific to E. Studies specifically designed for IBC are needed to enhance the understanding of this disease. Clinical trial: NCT02623972 Citation Format: Filipa Lynce, Eren D. Yeh, Meredith M. Regan, Lei Qin, Camden P. Bay, Ian Krop, Beth T Harrison, Faina Nakhlis, Jennifer Bellon, Beth Overmoyer. A phase 2 study of neoadjuvant systemic therapy with eribulin followed by doxorubicin and cyclophosphamide for HER2-negative inflammatory breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-12-18.