Neoadjuvant Atezolizumab/Trastuzumab/Pertuzumab Is Effective and Safe in HER2+ Early Breast Cancer

The addition of neoadjuvant atezolizumab (Tecentriq), trastuzumab (Herceptin), pertuzumab (Pertuzumab) to abbreviated epirubicin monotherapy generated pathologic complete responses (pCRs) in patients with early HER2-positive breast cancer, meeting the primary end point of the phase 2 ABCSG-52/ATHENE trial (EudraCT: 2019-002364-27), which were published in Nature Cancer.1

In the ITT population (n = 58), the pCR rate was 60.3% (95% CI, 47.5%-71.9%). The pCR rate was 65.5% (95% CI, 57.3%-80.1%) among patients who received trastuzumab plus pertuzumab and atezolizumab and 55.2% (95% CI, 37.5%-71.6%) among those who received trastuzumab plus pertuzumab alone.

The role of neoadjuvant dual HER2 blockade in HER2-positive breast cancer has been well established in the literature, and studies have shown the potential benefits of combining anthracyclines with immune checkpoint inhibitors (ICIs) in this population. Furthermore, chemotherapy de-escalation has become a research focus for research in recent years. Notably, the phase 3 Impassion 050 trial (NCT03726879) showed that ICIs had no additive effect when combined with standard HER2-directed therapy and polychemotherapy in patients with HER2-positive early breast cancer. The pCR rate was 62.4% among patients who received atezolizumab plus dose-dense doxorubicin/cyclophosphamide followed by paclitaxel, trastuzumab, and pertuzumab (n = 226); vs 62.7% among those who received placebo instead of atezolizumab (n = 228; difference, –0.33%; 95% CI, –9.2 to 8.6; P = .9551).2

“Therefore, we hypothesized that the addition of [immune checkpoint blockade] to dual HER2 blockade may add activity in regimens with a de-escalated chemotherapy backbone,” lead study author, Gabriel Rinnerthaler, MD, and coauthors, wrote in the paper.1 “The optimal cytotoxic drug in such an approach remains to be determined, and the particular role of epirubicin monochemotherapy has not been previously investigated. Therefore, in ABCSG-52/ATHENE, we investigated an anthracycline-based chemotherapy de-escalation immunotherapy regimen in patients with HER2-positive early breast cancer.”

Rinnerthaler is program director in the Division of Oncology in the Department of Internal Medicine at the Medical University of Graz; a senior physician in the Department of Internal Medicine III Division of Hematology, Medical Oncology, Hemostaseology, Rheumatology, Infectiology and Oncologic Center at Paracelsus Medical University in Salzburg; and a member of the Salzburg Cancer Research Institute at the Center for Clinical Cancer and Immunology Trials, Cancer Cluster Salzburg in Austria.

Between June 2020 and December 2021, in part 1 of the trial, 58 patients were enrolled. Patients needed to have previously untreated, histologically confirmed HER2-positive early breast cancer per ASCO/CAP guidelines with a clinical prognostic stage of cT1c to CT3a-d, N0-3 and M0; an ECOG performance status of 0 or 1; and adequate cardiac (LVEF ≥ 55%), renal, liver, and bone marrow function.

Patients were excluded if they had a history of malignancies other than nonmelanoma skin cancer and in situ carcinomas, a history of autoimmune disease, bilateral breast cancer, or other concomitant serious medical conditions.

In part 1, patients were randomly assigned 1:1 to receive 2 cycles of a chemotherapy-free induction regimen consisting of dual HER2 blockade with trastuzumab and pertuzumab alone (n = 29) or combined with the PD-L1 inhibitor atezolizumab (n = 29). Trastuzumab was administered at a starting dose of 600 mg subcutaneously or 6 mg/kg–1 IV on cycle 1 followed by 600 mg subcutaneously or 6 mg/kg–1 intravenously (IV) on subsequent cycles. IV pertuzumab was administered at a starting dose of 840 mg on cycle 1 followed by 420 mg on subsequent cycles. IV atezolizumab was administered in 2 3-weekly cycles at 1200 mg per cycle.

Thereafter, in part 2, all patients received 4 3-weekly cycles of trastuzumab at 600 mg subcutaneously or mg/kg–1 IV per cycle plus pertuzumab at 420 mg IV per cycle and atezolizumab at 1200 mg IV per cycle combined with epirubicin at 90 mg/m–2 per cycle, then proceeded to surgery.

Notably, adjuvant treatment was not part of this trial. Patients who did not achieve a pCR were recommended to receive taxane-based adjuvant chemotherapy. Patients who had completed standard adjuvant HER2-directed therapy and/or had HR-positive disease were recommended to receive standard endocrine therapy.

The primary end point was pCR assessed at the time of surgery. Secondary end points included RCB and ORR, which were both assessed at the time of surgery.

In the ITT population, patients had a median age of 57 years (range, 33-82), all patients were women, and 59% of patients were postmenopausal at baseline. Among all patients, 72.4% had HR-positive tumors. Furthermore, 77.6% of patients had stage IIA or lower disease, and 22.4% of patients had stage IIB or higher disease.

Among patients in the ITT population with an available residual cancer burden assessment (n = 55), the rate of complete or near-complete remission was 80.0% (95% CI, 67.6%-88.4%); this rate was 85.7% (95% CI, 68.5%-94.3%) in the trastuzumab/pertuzumab/atezolizumab arm and 74.1% (95% CI, 55.3%-86.6%) in the trastuzumab/pertuzumab alone arm. A univariable logistic regression model showed numerically lower pCR rates in peri-/premenopausal patients vs postmenopausal patients (odds ratio [OR], 0.48; 95% CI, 0.16-1.40; 2-sided P = .18), as well as in patients with histological subtypes other than “no special type” (OR, 0.37; 95% CI, 0.01-1.48; 2-sided P = .16). Additionally, higher pCR rates were seen in patients with increased body mass index (OR per 10-unit increase, 1.97; 95% CI, 0.62-6.22; 2-sided P = .25). However, the authors noted that none of the covariates were significantly associated with pCR.

The rates of radiological CR, radiological PR, and radiological SD were 37.5%, 51.8%, and 10.7%, respectively. No patients had radiological PD. Among ORR-evaluable patients in the overall population (n = 56), the ORR was 89.3% (95% CI,78.5%-95.0%).

A post hoc exploratory analysis showed that the mean proportions of stromal tumor-infiltrating lymphocytes (TILs) in the ITT population, trastuzumab/pertuzumab/atezolizumab arm, and trastuzumab/pertuzumab arm were 23.9%, 25.0%, and 22.8%, respectively. Lymphocytic-predominant phenotypes were observed in 17.2% and 10.3% of patients in the trastuzumab/pertuzumab/atezolizumab, and trastuzumab/pertuzumab arms, respectively. An association between baseline TIL proportion and pCR was not detected (OR for a 10% increase, 1.02; 95% CI, 0.78-1.34). However, investigators did observe a moderate positive correlation between the numeric values of TILs and PD-L1 (Spearman r = 0.57; 2-sided P < .0001).

In a post hoc exploratory analysis that stratified patients by PD-L1 status, the pCR rates were 69.2% (95% CI, 50.0%-83.5%) and 55.2% (95% CI, 37.5%-71.6%) in patients with PD-L1–negative (n = 18) and -positive disease (n = 16), respectively. The highest pCR rate was seen in patients with PD-L1–negative disease in the trastuzumab/pertuzumab/atezolizumab arm (73.3%; 95% CI, 48.0%-89.1%), and the lowest pCR rates were seen in those with PD-L1–positive disease in the trastuzumab/pertuzumab arm (52.9%; 95% CI, 31.0%-73.8%).

Grade 3 or higher TEAEs were reported in 29.3% of patients in the ITT population, including 31.0% of those in the trastuzumab/pertuzumab/atezolizumab arm and 27.6% of those in the trastuzumab/pertuzumab arm. In the trastuzumab/pertuzumab/atezolizumab arm, the most common any-grade TEAEs were nausea (69.0%; grade ≥ 3, 3.4%), diarrhea (58.6%; grade ≥ 3, 3.4%), fatigue (48.3%), alopecia (41.4%; grade ≥ 3, 3.4%), chills (24.1%), headache (24.1%), decreased appetite (20.7%), neutropenia (20.7%; grade ≥ 3, 20.7%), arthralgia (17.2%), constipation (17.2%), infusion-related reactions (IRR; 17.2%), mucosal inflammation (17.2%), pyrexia (17.2%), dry skin (13.8%), dyspepsia (6.9%), and nasopharyngitis (3.4%).

In the trastuzumab/pertuzumab arm, the most common any-grade TEAEs were nausea (69.0%), diarrhea (62.1%), fatigue (58.6%), alopecia (27.6%; grade ≥ 3, 3.4%), chills (24.1%), headache (27.6%), decreased appetite (13.8%), neutropenia (13.8%; grade ≥ 3, 3.4%), arthralgia (6.9%), constipation (27.6%), IRR (20.7%; grade ≥ 3.4%), mucosal inflammation (17.2%), pyrexia (24.1%), dry skin (17.2%), dyspepsia (17.2%), and nasopharyngitis (17.2%).

The authors noted that limitations of this study included its small sample size, lack of an arm that did not receive ICIs over the entire treatment course, and a lack of long-term outcomes as of the study’s publication.

“Our study…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,” the authors concluded.

References

• 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(1):41-50. doi:10.1038/s43018-024-00890-2
• Huober J, Barrios CH, Niikura N, et al. 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;40(25):2946-2956. doi:10.1200/JCO.21.02772.