Impact of Anti-HER2 Treatments Combined With Atezolizumab on the Tumor Immune Microenvironment in Early or Metastatic Breast Cancer: Results From a Phase Ib Study

Atezolizumab (anti-programmed death-ligand 1) plus targeted therapies may enhance antitumor activity in early-stage and metastatic HER2+ breast cancer. This phase Ib study evaluated the safety of atezolizumab plus HER2-targeted antibodies or antibody-drug conjugate agents. Safety profiles were tolerable. T-cell signatures were enhanced more in early-stage versus metastatic tumors. Biomarkers of antitumor immunity were different in early-stage versus metastatic tumors. Background: Despite advances, there continues to be unmet need in breast cancer. Combining anti-programmed death-ligand 1 (PD-L1) cancer immunotherapy atezolizumab with other targeted therapies may enhance T-celldependent cytolytic antitumor activity. Methods: This open-label, phase Ib study evaluated the safety of atezolizumabbased combinations with antibody-dependent cellular cytotoxicity or antibody-drug conjugate (ADC) agents. Patients with unresectable human epidermal growth factor receptor 2-positive (HER2(+)) locally advanced or metastatic breast cancer (mBC) received atezolizumab with trastuzumab/pertuzumab, atezolizumab with the ADC ado-trastuzumab emtansine (T-DM1), or atezolizumab with trastuzumab/pertuzumab and docetaxel. In an early-breast cancer (eBC) window of opportunity study, patients with operable HER2(+) locally advanced or inflammatory eBC received neoadjuvant atezolizumab with trastuzumab/pertuzumab or atezolizumab/T-DM1, followed by docetaxel, carboplatin, and trastuzumab/pertuzumab. Exploratory outcomes included tumor response and biomarkers. Results: By March 15, 2019, 73 patients were enrolled. Safety findings were consistent with the treatment components' individual profiles. Objective responses were observed in 2 of 6 and 5 of 14 patients in 2 mBC cohorts receiving atezolizumab/T-DM1 and in 6 of 6 patients with mBC receiving atezolizumab, trastuzumab/pertuzumab, and docetaxel. PD-L1 in immune cells was the only biomarker that increased with atezolizumab/T-DM1. In the window of opportunity cohorts, PD-L1 levels and CD8(+) T-cell infiltration increased from baseline in HER2(+) eBC tumors receiving atezolizumab with trastuzumab/pertuzumab or TDM1, irrespective of response. Despite increases in T-cell and B-cell gene signatures with trastuzumab/pertuzumab, but not T-DM1, neither combination promoted T-cell receptor clonal expansion. Conclusion: Atezolizumab with antibodydependent cellular cytotoxicity or ADC agents appears safe and may activate the adaptive immune system of patients with HER2(+) eBC tumors more than those with mBC tumors. (C) 2021 Elsevier Inc. All rights reserved.

Automated summary

The combination of atezolizumab with targeted therapies may enhance antitumor activity in early-stage and metastatic HER2+ breast cancer, with manageable safety profiles. T-cell signatures and biomarkers of antitumor immunity differ between early-stage and metastatic tumors.