Mechanisms of action and acquired resistance to atezolizumab plus nab-paclitaxel in metastatic triple-negative breast cancer (mTNBC).
Authors: Molinero Luciana , Emens Leisha A. , Goldstein Leonard D. , Abbas Alexander R. , Koeppen Hartmut , Rugo Hope S. , Adams Sylvia , Chui Stephen Y. , Schmid Peter , Loi Sherene 
Published: June 2022

1078 Background: In the IMpassion130 study (NCT02425891) first-line atezolizumab plus nab-paclitaxel (A+nP) provided clinical benefit compared with placebo plus nP (P+nP) in patients with mTNBC whose tumors were PD-L1+ (Schmid NEJM 2018). However, in many patients, disease that was initially controlled eventually progressed. The mechanism of action of A+nP and nP in the mTNBC tumor microenvironment (TME) and the biological changes associated with tumor progression with these therapies remain largely unknown. The goal of the current study was to evaluate biological changes in the TME induced by atezolizumab and nP early on treatment (OT) and at the time of progressive disease (PD) in IMpassion130. Methods: Paired tumor biopsies from IMpassion130 collected pre-treatment at baseline (BL), after 4 weeks OT, and at clinical PD were evaluated histologically for PD-L1 expression, CD8 content, stromal tumor infiltrating lymphocytes and immune phenotypes. RNA sequencing was also used to evaluate TNBC molecular subtypes and gene expression (hallmark gene sets, and immune cell and stromal gene signatures). Matched tumor pair samples from BL and PD were further analyzed by next-generation sequencing for genomic changes using the FoundationOne gene panel. Wilcoxon, Fisher, and McNemar’s tests were used for statistical analysis. Results: OT A+nP (n = 24 pairs), but not P+nP (n = 18 pairs) increased PD-L1 in both tumor-infiltrating immune cells and tumor cells, and increased frequency of immune-inflamed tumors. RNA-based signatures for A+nP showed an increase in lymphocytes (T-, B-, and NK cell), as well as IFN-α and IFN-γ responses, driven mainly by responders. While P+nP increased RNA-based stromal signatures (cancer-associated fibroblasts, pericytes, and angiogenesis) and epithelial mesenchymal transition, these changes were not observed with A+nP. OT A+nP and P+nP both reduced cell proliferation but only A+nP reduced metabolic pathways. At PD there was a significant reduction of RNA-based immune and stromal signatures in both A+nP (n = 59) and P+nP (n = 55) arms. Cell proliferation and DNA repair signatures were increased with A+nP but not P+nP. Evaluation of genomic changes suggested that both A+nP and P+nP increased tumor mutational burden (TMB), but only A+nP increased genomic scarring. At PD, the tumor immune phenotypes changed at PD with no directionality, while TNBC subtypes remained stable. Conclusions: A+nP boosted tumor immune inflammation and decreased tumor cell proliferation and metabolism in mTNBC patients, particularly in responders. Addition of atezolizumab prevented early stromal recruitment induced by nP. While decreased immune and stromal components and increased TMB were observed with both nP and A+nP, A+nP tumor escape was characterized by increased cell proliferation and DNA scarring. Clinical trial information: NCT02425891.