Atezolizumab and nab-Paclitaxel in Advanced Triple-Negative Breast Cancer

Biomarker Evaluation of the IMpassion130 Study

Leisha A. Emens, MD, PhD; Luciana Molinero, PhD; Sherene Loi, MD, PhD; Hope S. Rugo, MD; Andreas Schneeweiss, MD; Véronique Diéras, MD; Hiroji Iwata, MD, PhD; Carlos H. Barrios, MD; Marina Nechaeva, MD; Anh Nguyen-Duc, PhD; Stephen Y. Chui, MD; Amreen Husain, MD; Eric P. Winer, MD; Sylvia Adams, MD; Peter Schmid, MD, PhD

Disclosures

J Natl Cancer Inst. 2021;113(8):1005-1016. 

In This Article

Abstract and Introduction

Abstract

Background: Understanding the impact of the tumor immune microenvironment and BRCA1/2-related DNA repair deficiencies on the clinical activity of immune checkpoint inhibitors may help optimize both patient and treatment selection in metastatic triple-negative breast cancer. In this substudy from the phase 3 IMpassion130 trial, immune biomarkers and BRCA1/2 alterations were evaluated for association with clinical benefit with atezolizumab and nab-paclitaxel (A+nP) vs placebo and nP in unresectable (P+nP) locally advanced or metastatic triple-negative breast cancer.

Methods: Patients were randomly assigned 1:1 to nab-paclitaxel 100 mg/m2 (days 1, 8, and 15 of a 28-day cycle) and atezolizumab 840 mg every 2 weeks or placebo until progression or toxicity. Progression-free survival and overall survival were evaluated based on programmed death-ligand 1 (PD-L1) expression on immune cells (IC) and tumor cells, intratumoral CD8, stromal tumor-infiltrating lymphocytes, and BRCA1/2 mutations.

Results: PD-L1 IC+ in either primary or metastatic tumor tissue was linked to progression-free survival and overall survival benefit with A+nP. PD-L1 IC+ low (26.9%; 243 of 902 patients) and high (13.9%; 125 of 902 patients) populations had improved outcomes that were comparable. Intratumoral CD8 and stromal tumor-infiltrating lymphocytes positivity (sTIL+) were associated with PD-L1 IC+ status; improved outcomes were observed with A+nP vs P+nP only in CD8+ and sTIL+ patients who were also PD-L1 IC+. BRCA1/2 mutations (occurring in 14.5% [89 of 612 patients]) were not associated with PD-L1 IC status, and PD-L1 IC+ patients benefited from A+nP regardless of BRCA1/2 mutation status.

Conclusions: Although A+nP was more efficacious in patients with richer tumor immune microenvironment, clinical benefit was only observed in patients whose tumors were PD-L1 IC+.

Introduction

Patients with metastatic triple-negative breast cancer (mTNBC) have a median overall survival (OS) of less than 18 months with standard chemotherapy.[1–4] Targeted drugs, including bevacizumab plus chemotherapy[5] or poly(ADP-ribose) polymerase (PARP) inhibitors for BRCA1/2-mutant, HER2-negative metastatic breast cancer,[6,7] are associated with progression-free survival (PFS) benefit. The randomized phase 3 study IMpassion130, evaluating atezolizumab and nab-paclitaxel (A+nP) vs placebo and nab-paclitaxel as first-line treatment for mTNBC, met its co-primary PFS endpoint in the intention-to-treat (ITT) population and in patients whose tumors had 1% or higher programmed death-ligand 1 (PD-L1)–expressing tumor-infiltrating immune cells (IC+). Improved activity with A+nP was only observed in PD-L1 IC+ patients.[8,9] Although not testable for statistical significance because of the hierarchical study design, PD-L1 IC+ patients also had clinically meaningful OS improvement (hazard ratio = 0.71, 95% confidence interval [CI] = 0.54 to 0.93) with A+nP.[9]

CD8+ T cells,[10,11] stromal tumor-infiltrating lymphocytes (sTILs),[12–15] and PD-L1 expression on tumor cells (TC)[16] are other biomarkers associated with improved clinical outcomes with PD-L1/PD-1 inhibition, and patients with mTNBC who have BRCA1/2 gene mutations derive clinical benefit with PARP inhibitors.[6,7] It has been hypothesized that BRCA1/2-deficient tumors may be more responsive to immune checkpoint inhibitors because of DNA damage accumulation, but whether this occurs in breast cancer is not established. This exploratory analysis aimed to evaluate whether PD-L1 TC+, CD8+ T cells, sTILs, or BRCA1/2 mutation status, in addition to PD-L1 IC+, are suitable biomarkers for selecting patients likely to benefit from A+nP.

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