Abstract Background: Chemotherapy and HER2-targeted antibodies are standard-of-care (SOC) treatments (tx) for HER2+ breast cancer (BC) in several settings. Atezolizumab (atezo) + chemotherapy improves progression-free survival (PFS) and overall survival (OS) in PD-L1+ advanced triple-negative BC. Due to the potential for effective tumor cell death and anti-tumor immunity, this study investigated the safety and clinical activity of novel atezo-based combination therapy in HER2+ and HER2-negative BC. In addition, the study evaluated changes in the tumor microenvironment with the combination of immune checkpoint inhibition (atezo) with antibody-dependent cellular cytotoxicity (ADCC) agents (trastuzumab [T] + pertuzumab [P]) or with antibody drug conjugates (ADCs; trastuzumab emtansine [T-DM1]). Methods: GO29831 (NCT02605915) is a multi-cohort Phase Ib study evaluating the safety of atezo-containing tx combinations in patients (pts) with BC. Evaluation of clinical activity and biomarkers were exploratory objectives. PD-L1 status by VENTANA SP142 IHC assay, CD8 IHC and RNA-based gene expression signatures were assessed in pre-tx and on-tx biopsies. See table for patient populations and interventions. Results: At clinical data cutoff (Dec 17, 2018), 76 pts were safety evaluable across 8 tx cohorts. Patient demographics in this completely enrolled study were heterogeneous between cohorts (e.g., hormone receptor status, no. of prior therapies in metastatic setting). No new safety signals were observed beyond the established safety profiles of the individual drugs. Two up-front cycles of atezo combination therapy with anti-HER2 therapy had no detrimental effect on the pathologic complete response (pCR) rates expected with SOC regimens. Increases in PD-L1-expressing tumor-infiltrating immune cells were observed in both HER2+ early BC (eBC) and metastatic BC (mBC) with the combination of atezo + T-DM1 or atezo + T + P. Consistent increases in CD8+ T cells in the tumor area were observed only in eBC. Increases in RNA gene signatures associated with antigen presentation, cytolytic activity and immune checkpoints were observed with both atezo + T-DM1 and atezo + T + P in eBC, whereas statistically significant increases in B-cell (P = 0.0322) and T-cell gene signatures (P = 0.0049) were observed only with atezo + T + P. Conclusions: These tx combinations were tolerable, and safety signals were in line with the known safety profiles of the individual drugs. Biomarker analyses showed that combining atezo with ADCC or ADC agents promoted the activation of the adaptive immune system in the tumor microenvironment. TableCohortPatient PopulationInterventionNo. of Pts1APts with HER2+ mBC or LABCAtezo 1200 mg, T 6 mg/kg, P 420 mg q3w61BPts with HER2+ mBC or LABCAtezo 1200 mg, T-DM1 3.6 mg/kg q3w61EPts with HER2-negative mBC or LABCAtezo 840 mg, doxorubicin 60 mg/m2, cyclophosphamide 600 mg/m2 and pegfilgrastim or G-CSF q2w for 4 cycles, followed by atezo 1200 mg q3w31FPts with HER2+ mBCAtezo 1200 mg, T 8-mg/kg loading dose (maintenance: 6 mg/kg), P 840-mg loading dose (maintenance: 420 mg) and docetaxel 75 mg/m2 q3w62APts with HER2+ operable LABC or inflammatory eBC (tumor > 2 cm)Neoadjuvant atezo 1200 mg + T 8 mg/kg (c2: 6 mg/kg) + P 840 mg (c2: 420 mg) for 2 cycles, followed by 6 cycles of docetaxel 75 mg/m2, carboplatin AUC 6 mg/mL x min, T 6 mg/kg, P 420 mg q3w prior to breast surgery202BPts with HER2+ operable LABC or inflammatory eBC (tumor > 2 cm)Neoadjuvant atezo 1200 mg + T-DM1 3.6 mg/kg q3w for 2 cycles, followed by 6 cycles of docetaxel 75 mg/m2, carboplatin AUC 6 mg/mL x min, T 6 mg/kg, P 420 mg q3w prior to breast surgery202CPts with HER2+ mBC or LABC with PD on mBC tx or ≤ 6 mo of adjuvant txAtezo 1200 mg, T-DM1 3.6 mg/kg q3w142DPts with HER2+ mBC or LABC with PD on T- and P-containing regimen ≤ 12 wkAtezo 1200 mg, T 8-mg/kg loading dose (maintenance: 6 mg/kg), P 840-mg loading dose (maintenance: 420 mg) q3w1AUC, area under the curve; c2, cycle 2; G-CSF, granulocyte colony-stimulating factor; LABC, locally advanced breast cancer; PD, progressive disease; pt, patient; q2w, every 2 weeks; q3w, every 3 weeks. NCT02605915 Citation Format: Erika Paige Hamilton, Virginia Kaklamani, Carla Falkson, Gregory A Vidal, Patrick J Ward, Monika Patre, Stephen Y Chui, Jacob Rotmensch, Kushagra Gupta, Luciana Molinero, Yijin Li, Leisha A Emens. Atezolizumab in combination with trastuzumab emtansine or with trastuzumab and pertuzumab in patients with HER2-positive breast cancer and atezolizumab with doxorubicin and cyclophosphamide in HER2-negative breast cancer: Safety and biomarker outcomes from a multi-cohort Phase Ib study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD1-05.