Atezolizumab Added to SOC in HER2-Positive Breast Cancer Does Not Increase Responses

Pertuzumab plus trastuzumab and chemotherapy remains the standard of care for HER2-positive breast cancer, after the addition of atezolizumab did not benefit responses in the Impassion050 study.

Atezolizumab (Tecentriq) added to neoadjuvant dose-dense doxorubicin and cyclophosphamide–paclitaxel with standard of care pertuzumab (Perjeta) and trastuzumab (Herceptin; PH) did not increase pathologic complete response (pCR) in high-risk patients with HER2-positive early breast cancer when compared with placebo, according to data published in the Journal of Clinical Oncology.1

Results from the double-blind, randomized, placebo-controlled phase 3 IMpassion050 trial (NCT03726879) showed that while PH and chemotherapy remain the standard of care for this patient population the addition of atezolizumab did not benefit responses. In the intent-to-treat population 62.7% of patients in the placebo arm had a pathologic complete response (pCR) compared with 62.4% of patients on atezolizumab for a difference of 0.33% (95% CI, –9.23 to 8.57, P = .9551).

Of the 109 patients with PD-L1 positive disease, patients on placebo had a higher rate of pCR at 72.5% compared with 64.2% in the atezolizumab arm. However, patients on atezolizumab who had negative PD-L1 tumors had a higher pCR rate than those in the placebo arm at 60.7% vs 53.8%, respectively (difference 6.90%; 95% CI, –5.69 to 19.49).

“Consistent with reports suggesting a prognostic role for PD-L1 expression in breast cancer patients with PD-L1–positive tumors in IMpassion050 demonstrated higher pCR rates than those with PD-L1–negative tumors,” the researchers said in their published discussion. “Conversely, no pCR benefit of adding atezolizumab to PH and chemotherapy was observed in patients with PD-L1–positive tumors.”

The researchers also wrote that these results were surprising as previous findings in other studies, like the KATE2 (NCT02924883) trial, showed promise when adding atezolizumab to trastuzumab emtansine (Kadcyla) for patients with HER2 positive breast cancer. However, they also noted that there has been growing evidence that in neoadjuvant trials of patients with early triple-negative breast cancer (TNBC) PD-L1 checkpoint inhibition has not been as important, impacting the role of chemoimmunotherapy.

As a result, pCR not favoring the addition of atezolizumab was consistent throughout patient subgroups in both the ITT population and patients with PD-L1 positive disease. For example, White patients, who made up most patients in the study with 291 patients, at a pCR rate of 69% in the placebo arm compared with 65.8% in the atezolizumab arm (difference -3.24; 95% CI, -14.01%-7.52%).

Moreover, pCR rates favored placebo vs atezolizumab in patients with stage T2 disease (63.6% vs 60%), patients with stage N2 regional lymph nodes (65.2% vs 55.3%), and patients with an ER-positive tumor (54.7% vs 50.9%). However, ER-negative patients favored the addition of atezolizumab at 74.5% compared with 71.2% in the placebo arm (difference 3.37; 95% CI, -8.34%-15.09%). Other subgroups that favored the use of atezolizumab vs placebo included patients with T3-T4 staging (67.1% vs 61%) and patients with a mutated central PIK3CA status (59.7% vs 55.7%).

Patients included in the trial had to be 18 years or older with a primary tumor that was larger than 2 cm and had a histologically confirmed, positive lymph node status of either T2-4, N1-3, or M0, an ECGOG performance score of 0/1, and a left ventricular ejection fraction of 55% or more. Patients were excluded from the trial had either a history of invasive breast cancer, stage IV breast cancer, prior systemic therapy for BC, or prior anthracyclines or taxane therapies for any malignancy.

Eligible patients had their HER2 positivity, PD-L1 status, hormone receptor status, and PIK3CA mutation status assessed centrally. They were then randomized 1:1 to either receive intravenous atezolizumab or placebo, with neoadjuvant dose-dense doxorubicin and cyclophosphamide, followed by paclitaxel and PH. The patients’ assignment was stratified by tumor stage at their diagnosis (T2 vs T3-4), hormone receptor status, and PD-L1 status.

In the neoadjuvant phase of treatment, patients were given 4 cycles of 840 mg of IV atezolizumab or placebo plus60 mg/m2 of IV doxorubicin and 600 mg/m2 of cyclophosphamide, along with myeloid growth factor support according to local clinical guidelines. An additional 4 cycles of 1,200 mg of atezolizumab/placebo were given once every 3 weeks, then 80 mg/m2 paclitaxel once weekly, an 8 mg/kg IV loading dose of trastuzumab followed by 6 mg/kg given once every 3 weeks, and an 840 mg IV loading dose of pertuzumab followed up with 420 mg once every 3 weeks.

In the adjuvant phase of the study, patients continued either atezolizumab or placebo with PH to complete 1 year of HER2 targeted therapy. By this phase, 208 patients in the atezolizumab had at least one dose of adjuvant therapy and 206 patients in the placebo arm had at least one dose of PH in the adjuvant setting. At a median duration of follow-up at 15.9 months in the placebo arm and 15.7 months in the atezolizumab arm, 102 patients remained on treatment in the placebo arm compared with 100 patients in the atezolizumab arm.

During the neoadjuvant phase of the trial, 131 patients withdrew from the placebo arm with 35 patients withdrawing due to adverse events (AEs) and 137 patients withdrew from the atezolizumab arm with 41 withdrawing due to AEs. Safety was observed at this point of the study with researchers seeing the overall incidence of treatment-related serious AEs, grade 3-4 AEs, and AEs of special interest increased in the atezolizumab arm vs the placebo group at 15% vs 10.7%, 47.3% vs 42.4%, and 72.6% vs 61.3%, respectively.

AEs which lead to the withdrawal of treatment were deemed similar between the treaqtment arms. Moreover, Grade 5 AEs were seen in 4 patients in the atezolizumab arm compared with none in the placebo group. Two of these AEs were fatal, alveolitis and septic shock, and attributed to the addition of atezolizumab.

Reference

Huober J, Barrios CH, Niikura N, et al; IMpassion050 Trial Investigators. Atezolizumab with neoadjuvant anti-human epidermal growth factor receptor 2 therapy and chemotherapy in human epidermal growth factor receptor 2-positive early breast cancer: Primary results of the randomized phase III IMpassion050 trial. J Clin Oncol. 2022 Sep 1;40(25):2946-2956. doi: 10.1200/JCO.21.02772