Neoadjuvant Atezolizumab Combo Yields High pCR Rates in HER2+ Breast Cancer

"In summary, our data provide evidence that the addition of anti–PD-L1 inhibitors to abbreviated monotherapy with an anthracycline leads to high pCR rates in HER2-positive breast cancer," according to the study authors.

Adding atezolizumab (Tecentriq) to trastuzumab (Herceptin) and pertuzumab (Perjeta) followed by epirubicin (Ellence) produced high pathological complete response (pCR) rates among patients with HER2-positive early breast cancer, according to data from the phase 2 ABCSG-52/ATHENE trial (2019-002364-27) published in Nature Cancer.¹

The pCR rate was 60.3% (n = 35/58; 95% CI, 47.5%-71.9%) across the intent-to-treat population, which included rates of 65.5% (n = 19/29; 95% CI, 47.3%-80.1%) in patients who received atezolizumab plus trastuzumab/pertuzumab and 55.2% (n = 16/29; 95% CI, 37.5%-71.6%) in those who received trastuzumab/pertuzumab alone. Among those with available residual cancer burden (RCB) status, the complete or near-complete remission rate was 80.0% (n = 44/55; 95% CI, 67.6%-88.4%), 85.7% (n = 24/28; 95% CI, 68.5%-94.3%), and 74.1% (n = 20/27; 95% CI, 55.3%-86.6%) in each respective group.

Of note, numerically lower pCR rates occurred in patients who were peri/premenopausal vs postmenopausal based on univariate analysis (odds ratio [OR], 0.48; 95% CI, 0.16-1.40; 2-sided P = .18). Additionally, patients with a higher body mass index were more likely to achieve pCR (OR per 10-unit increase, 1.97; 95% CI, 0.62-6.22; 2-sided P = .25). None of these associations reached statistical significance.

The overall response rate (ORR) was 89.3% (95% CI, 78.5%-95.0%). Data showed a radiological complete response (CR) rate of 37.5% (n = 21), a radiological partial response (PR) rate of 51.8% (n = 29), and a radiological stable disease rate of 10.7% (n = 6).

The pCR rate was 69.2% (n = 18/26; 95% CI, 50.0%-83.5%) among patients with PD-L1–negative disease vs 55.2% (n = 16/29; 95% CI, 37.5%-71.6%) in those with PD-L1–positive disease. Additionally, the highest pCR rates were reported in patients with PD-L1–negative disease receiving the atezolizumab combination (73.3%; 95% CI, 48.0%-89.1%), and the lowest rates occurred in patients with PD-L1–positive disease who received trastuzumab/pertuzumab alone (52.9%; 95% CI, 31.0%-73.8%).

“In summary, our data provide evidence that the addition of anti–PD-L1 inhibitors to abbreviated monotherapy with an anthracycline leads to high pCR rates in HER2-positive breast cancer,” Gabriel Rinnerthaler, a professor in the Division of Oncology in the Department of Internal Medicine at Medical University of Graz, Graz, Austria, wrote with coauthors.¹ “Our study also raises interesting questions about the sequencing of chemotherapy and immunotherapy in a combined approach and regarding the biological meaning of PD-L1 expression and its therapeutic inhibition in relation to the sensitivity of tumor cells against HER2 blockade.”

In this phase 2 study, 58 patients in the ITT population were randomly assigned to receive neoadjuvant atezolizumab plus trastuzumab/pertuzumab (n = 29) or trastuzumab/pertuzumab alone (n = 29) in part 1 followed by the trastuzumab combination plus epirubicin in part 2. Study treatment in part 1 consisted of pertuzumab at 840 mg intravenously for one 3-week cycle followed by 420 mg intravenously thereafter plus trastuzumab at 600 mg subcutaneously or 8 mg/kg intravenously on cycle 1 followed by 600 mg subcutaneously or 6 mg/kg intravenously thereafter with or without atezolizumab at 1200 mg intravenously. In part 2, patients received four 3-weekly cycles of atezolizumab at 1200 mg intravenously, pertuzumab at 420 mg intravenously, trastuzumab at 600 mg subcutaneously or 6 mg/kg intravenously, and epirubicin at 90 mg/m² per cycle.

The trial’s primary end point was pCR. Secondary end points included RCB and ORR assessed at the time of surgery.

Patients 18 years and older with histologically confirmed invasive unilateral adenocarcinoma of the breast and histologically confirmed HER2-positive status were eligible for enrollment in the trial.² Other requirements for study entry included having an ECOG performance status of 0 or 1, adequate left ventricular ejection fraction at baseline, and the ability to understand and fill out patient-reported outcome questionnaires.

The median age was 57 years (range, 33-82), and most patients were postmenopausal at baseline (59%). Additionally, most of the study population had hormone receptor–positive disease (72.4%) and stage IIA disease or lower (77.6%).

Grade 3 or higher treatment-emergent adverse effects (TEAEs) occurred in 29.3% (n = 17) of the overall population, 31.0% (n = 9) in the atezolizumab arm, and 27.6% (n = 8) in the trastuzumab/pertuzumab arm. The most common AEs in the trastuzumab triplet and trastuzumab/pertuzumab alone arms, respectively, included nausea (69% vs 69%), diarrhea (59% vs 62%), fatigue (48% vs 59%), and alopecia (41% vs 28%). Investigators observed no grade 3 or higher AEs of special interest.

References

1. Rinnerthaler G, Egle D, Bartsch R, et al. 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. Nat Cancer. 2025;6:41–50. doi:10.1038/s43018-024-00890-2
2. 2019-002364-27. EU Clinical Trials Register. Accessed February 21, 2025. https://tinyurl.com/mr3p6cwx