Neoadjuvant atezolizumab in combination with dual HER2 blockade plus epirubicin in women with early HER2-positive breast cancer: the randomized phase 2 ABCSG-52/ATHENE trial

Abstract

The role of anthracyclines in the treatment of early breast cancer (EBC) is increasingly being challenged, especially in de-escalation strategies. However, owing to their immunogenic effects, anthracyclines are promising combination partners with immunotherapies. In the randomized phase 2 trial ABCSG-52 (EudraCT no. 2019-002364-27), we investigated epirubicin plus immunotherapy in women with human epidermal growth factor receptor 2 (HER2)-positive EBC. A total of 58 patients were randomized 1:1 to two cycles of a chemotherapy-free induction phase (part 1) of dual HER2 blockade with trastuzumab and pertuzumab (TP) plus the anti-programmed death ligand 1 antibody atezolizumab (TP-A) or TP alone. Thereafter, all patients received four cycles of TP-A in combination with epirubicin (part 2). The primary endpoint, pathological complete response (pCR), was met in 35 patients (60.3%; 95% confidence interval (CI) 47.5% to 71.9%), 19 patients (65.5%) in the TP-A group and 16 patients (55.2%) in the TP group. The residual cancer burden 0/I rate and objective response rate (secondary endpoints) in all patients with evaluable data were 80.0% (n = 44/55; 95% CI 67.6% to 88.4%) and 89.3% (n = 50/56; 95% CI 78.5% to 95.0%), respectively. Grade ≥3 adverse events were reported in 17 patients (29.3%). Based on our findings, we conclude that a neoadjuvant chemotherapy de-escalation immunotherapy regimen with trastuzumab, pertuzumab, atezolizumab and epirubicin is effective and safe in patients with HER2-positive EBC.

Fig. 1. Study design.

Stratification criteria: baseline TILs (<5% versus ≥5%), HR status (positive versus negative) and prognostic stage (≤IIA versus ≥IIB (American Joint Committee on Cancer staging manual version 8.0)). ASCO, American Society of Clinical Oncology; CAP, College of American Pathologists; ECOG, Eastern Cooperative Oncology Group; LVEF, left ventricular ejection fraction; R, randomization; TP-A + E, TP-A plus epirubicin.

Fig. 2. CONSORT diagram.

IC, informed consent.

Fig. 3. Covariate association with pCR.

The prognostic stage is given according to the American Joint Committee on Cancer staging manual version 8.0. The column ‘alternative cat.’ refers to the alternative category, and ‘reference cat.’ refers to the reference category of the covariate. An OR of >1 indicates a higher pCR rate of the alternative category (left category in the ‘category’ column) or with higher age and BMI. Events: patients achieving pCR; sample size: 58. P values are from two-sided Wald tests with no adjustment for multiple testing. Covariate effects are presented as ORs including 95% CIs. NST, invasive carcinoma of no special type.