Clinical and translational analysis of a phase Ib/II combination of atezolizumab, cobimetinib, and eribulin (ACE) to demonstrate inflammatory and metabolic programs define divergent response states.

1138 Background: Inflammatory breast cancer (IBC) is a rare, aggressive subtype with poor outcomes and limited immunotherapy data. Preclinical studies suggest MAPK inhibition enhances antitumor immunity and synergizes with checkpoint blockade. We report results from a phase Ib/II trial of atezolizumab (A), cobimetinib (C), and eribulin (E) in metastatic IBC with integrated molecular profiling. Methods: Patients (pts) with metastatic/recurrent IBC received ACE (cohort 1, n=17). Following cobimetinib supply discontinuation, an exploratory cohort received AE (cohort 2, n=10). Primary endpoint: objective response rate (ORR) per RECIST v1.1. Secondary endpoints: safety, progression-free survival (PFS), overall survival (OS), and correlative genomic, transcriptomic, spatial immune, and circulating tumor DNA (ctDNA) analyses. Results: ACE achieved ORR 50% (7/14; 3 patients were unevaluable for response), disease control rate (DCR) 71% (10/14), median PFS 3.7 months (mo), and median OS 10.6 mo, with 2 exceptional responders achieving >5-year survival. AE showed limited activity (ORR 10%, median OS 7.8 mo). No grade 4/5 toxicities occurred. Molecular profiling revealed distinct response states: responders demonstrated immune-activated, epithelial-like transcriptional programs with CD8+ T-cell infiltration; non-responders exhibited metabolically hyperactive, immune-excluded phenotypes with KRAS pathway activation, T-reg enrichment, CD8+ T-cell exclusion, VEGFA/GSDMB upregulation, and elevated ctDNA. Conclusions: ACE demonstrated encouraging activity in metastatic IBC with durable benefit in two pts. Resistance was associated with metabolic reprogramming and stromal immune exclusion, supporting rational development of metabolism-targeting, stroma-modifying, or T-reg/macrophage-directed combinations in this high-risk population. Clinical trial information: NCT03202316 .