Atezolizumab Plus Trastuzumab/Vinorelbine Elicits Responses in HER2+ Advanced Breast Cancer

Eva Ciruelos Gil, MD, PhD

Atezolizumab (Tecentriq) in combination with trastuzumab (Herceptin) and vinorelbine (Navelbine) generated responses and a tolerable safety profile in patients with HER2-positive, estrogen receptor (ER)­–negative or ER-positive/PAM50 non-luminal advanced breast cancer, according to data from a prespecified interim analysis of the phase 2 ATREZZO trial (EudraCT 2020-000245-13; NCT04759248) presented at the 2023 ESMO Breast Cancer Annual Congress.¹

Findings showed that evaluable patients (n = 19) experienced an overall response rate (ORR) of 31.6% (95% CI, 12.6%-56.6%), meeting the prespecified end point for the first stage of the trial. All responders achieved a partial response. Additionally, the stable disease rate was 15.18% (95% CI, 3.4%-39.6%), and the progressive disease rate was 52.6% (95% CI, 28.8%-75.5%).

“Our data further support previous pre-clinical evidence, suggesting that patients with HER2-positive, ER-negative or PAM50 non-luminal tumors might benefit from immunotherapy in combination with chemotherapy,” lead study author Eva Ciruelos Gil, MD, PhD, of Hospital 12 de Octubre, in Madrid, Spain, and colleagues, wrote in a poster presentation of the data.

Although antibody-drug conjugates (ADCs) such as fam-trastuzumab deruxtecan-nxki (Enhertu) have shifted the treatment landscape for patients with metastatic HER2-positive breast cancer, effective treatment options are still need for patients who progress on trastuzumab, pertuzumab (Perjeta), ado-trastuzumab emtansine (T-DM1; Kadcyla), trastuzumab deruxtecan, and/or other therapies. HER2-positive advanced breast cancer that is either ER-negative or PAM50 non-luminal disease is considered more immunogenic and linked with higher tumor-infiltrating lymphocytes and higher expression of immune-related genes.

Stage 1 of ATREZZO enrolled 19 patients, and stage 2 is expected to include 36 patients for a total enrollment of 55. The study includes female patients with advanced or metastatic HER2-positive breast cancer. Patients also need to have hormone receptor (HR)–negative or HR-positive/PAM50 non-luminal disease. PD-L1 status is measured through immunohistochemistry (IHC). Prior treatment with trastuzumab and other anti-HER2 ADCs—not limited to T-DM1—is required.²

In both parts of the single-arm trial with a Simon 2-stage design, patients are receiving 1200 mg of atezolizumab in combination with trastuzumab at 600 mg subcutaneously or 6mg/kg intravenously and vinorelbine at 25 mg/m² intravenously or 60 mg/m2 orally every 3 weeks.

The primary end point of the trial is ORR per RECIST v1.1 criteria. Secondary end points include ORR in the PD-L1–positive cohort, clinical benefit measured with clinical benefit rate at 6 months, progression-free survival (PFS), duration of response (DOR), time to response, and overall survival (OS), clinical benefit in patients with brain metastases, and safety/tolerability. PAM50 and 360 panel genes, DNA mutations, and circulating tumor DNA are serving as biomarkers of response.

In stage 1, patients had a median age of 58 years (range, 33-73). The majority of patients had an ECOG performance status of 1 (63.2%) and had HR-negative disease (68.4%). Patients had a HER2 status of IHC 2+ (amplified; (26.3%) or IHC 3+ (73.7%), and 31.6% of patients had advanced disease at first diagnosis. The mean time from advanced disease diagnosis to start of treatment data was 3.3 years (standard deviation, 2.8).

Furthermore, 21.1% of patients had a history of central nervous system (CNS) metastases, and 15.8% of patients underwent previous local treatment or procedures for their CNS, including stereotactic radiosurgery/stereotactic radiotherapy (5.3%) and whole brain radiotherapy (10.5%). Ninety percent of patients did not have visceral disease.

Notably, 63.2% of patients underwent previous treatment for early breast cancer, including antineoplastic agents (63.2%) and endocrine therapy (31.6%). Patients received a median of 3 (range, 1-4) prior lines of therapy for advanced disease.

Regarding safety, 31.6% of patients experienced grade 3 or higher treatment-emergent adverse effects (TRAEs), including 26.3% of patients with grade 3 TEAEs and 10.5% with grade 4 TEAEs.

The most common grade 3 or higher TEAEs included neutropenia (21.1%), fatigue (5.3%), and acute kidney injury (5.3%).

References

1. Ciruelos E, Tolosa P, Salvador Bofill FJ, et al. Atrezzo trial (SOLTI-1907) a phase II trial targeting estrogen receptor negative or PAM50 non-luminal disease with atezolizumab in combination with trastuzumab and vinorelbine in HER2-positive (HER2+) advanced breast cancer (ABC): interim analysis. Presented at: 2023 ESMO Breast Cancer Annual Congress; May 11-13, 2023; Berlin, Germany. Abstract 197P.
2. Study with atezolizumab in combination with trastuzumab and vinorelbine in HER2-positive advanced/metastatic breast cancer (ATREZZO). ClinicalTrials.gov. Updated April 14, 2023. Accessed May 30, 2023. https://clinicaltrials.gov/ct2/show/NCT04759248