Patients diagnosed with hormone receptor-positive (HR+)/HER2-negative breast cancer frequently experience disease response to neoadjuvant therapy. However, following standard chemotherapy or endocrine therapy, even in combination with CDK4/6 inhibitors, less than than 10% of patients achieve a pathologic complete response (pCR), which refers to the lack of all signs of cancer in tissue samples removed during surgery or biopsy after treatment with radiation or chemotherapy. Hence, finding more effective therapies for the treatment of patients diagnosed with HR+/HER2-negative breast cancer remains an unmet medical need.
A new treatment option may change all of this. In a clinical study, patients diagnosed with localized, HR+/HER2-low breast cancer, defined as HER2 being expressed at a low level (IHC 1+ or 2+)a, were treated with trastuzumab deruxtecan (T-DXd; Enhertu®; Daiichi Sankyo and AstraZeneca) in the neoadjuvant setting. The results showed an overall response rate of 75% in the absence of the aromatase inhibitor anastrozole (Arimidex®; AstraZeneca) and 63% in combination with anastrozole.
This conclusion is based on the results from the phase 2 TRIO-US B-12 TALENT trial (NCT04553770) presented at the 2022 San Antonio Breast Cancer Symposium (SABCS), held December 6-10, 2022 in San Antonio, Tx. 
The primary objective of Phase 2 TALENT trials was designed to evaluate the clinical activity and safety of neoadjuvant trastuzumab deruxtecan alone or in combination with endocrine therapy in patients with HR+/HER2-low early breast cancer.
Both men and women with previously untreated, operable invasive early stage, non-recurrent, HR+, HER2-low (IHC 1+ or 2+/ISH- by local or central review) breast cancer (measuring > 2 cm) were eligible to participate in the study.
In stage 1 of the study, 58 patients were enrolled and treated (29 Arm A, 29 Arm B). These patients were randomized 1:1 to receive trastuzumab deruxtecan (5.4 mg/kg IV q21 days) alone (Arm A), or trastuzumab deruxtecan in combination with the anastrozole (1 mg PO QD) (Arm B).
In the original trials design, 6 cycles were given but in February 2022 an amendment increased the number of treatment cycles from 6 to 8 for newly enrolled patients, or those who had not yet had surgery.
Men and pre/peri-menopausal women randomized to Arm B also received a GnRH
agonist. Stratification factors were HER2 expression (1+ vs. 2+) and menopausal status (men as postmenopausal). Tumor tissue collected at baseline, cycle 1 day 17-21, and at surgery. Breast imaging was performed at baseline, cycle 2 and pre-surgery/EOT.
“This is the first report of neoadjuvant trastuzumab deruxtecan for patients with hormone receptor-positive, HER2-low, localized breast cancer,” said Aditya Bardia, MD, MPH, an attending physician at Mass General Cancer Center and director of breast cancer research and an associate professor at Harvard Medical School.
“It could provide the groundwork for future studies with antibody-drug conjugates, including trastuzumab deruxtecan, for patients with early-stage breast cancer.”
“Patients with localized, high-risk breast cancer are often given chemotherapy before undergoing surgery. However, when such tumors express the estrogen receptor and/or the progesterone receptor, the pathological complete response rate to neoadjuvant chemotherapy is less than 5%t, necessitating new treatment options,” Bardia added.
Trastuzumab deruxtecan is an antibody-drug conjugate or ADC that is internalized into cancer cells upon binding to HER2. Once inside it releases a cytotoxic payload that causes DNA damage and kills the cancer cell. It is currently approved by the U.S. Food and Drug Administration (FDA) to treat several types of tumors that overexpress HER2, and it was recently approved to treat metastatic breast cancer with low HER2 expression.
“While trastuzumab deruxtecan demonstrated impressive efficacy in metastatic HER2-low breast cancer, to date, no trial has evaluated trastuzumab deruxtecan in localized, early-stage, potentially curable HER2-low breast cancer, which led us to design this neoadjuvant clinical trial,” explained Sara Hurvitz, MD, medical director of the Clinical Research Unit at Jonsson Comprehensive Cancer Center, a professor of medicine in the Division of Hematology/Oncology at the University of California, Los Angeles, and co-author of the study.
Bardia, Hurvitz, and colleagues conducted the phase II TRIO-US B-12 TALENT clinical trial to assess the safety and efficacy of trastuzumab deruxtecan when used as a neoadjuvant treatment, either alone or in combination with the aromatase inhibitor anastrozole. At the time of first data cutoff (October 5, 2022), 17 patients had completed the planned eight cycles of trastuzumab deruxtecan, and 16 patients had completed the planned six cycles of trastuzumab deruxtecan plus anastrozole.
According to Bardia, the primary endpoint for the study was a 5% pathologic complete response (pCR) rate, defined as complete tumor regression and no lymph node involvement at the time of surgery.
At the time of first data cutoff, no patients had experienced a pCR in the combination treatment arm, and one out of 19 patients (5.3%) had experienced a pCR in the solo treatment arm. As of the data cutoff, 33 patients had completed neoadjuvant treatment and undergone surgery, seven patients were awaiting surgery, and 13 patients were still undergoing trastuzumab deruxtecan treatment.
Among the response-evaluable population, in the solo treatment arm, the overall response rate was 75%, including 11 partial responses and one complete response. In the combination treatment arm, the overall response rate was 63%, including 10 partial responses and two complete responses.
The most common treatment-related adverse events of grade 3 or higher were hypokalemia, diarrhea, neutropenia, fatigue, headache, vomiting, dehydration, and nausea, each of which occurred in fewer than 6% of patients. One patient developed grade 2 interstitial lung disease, which resolved after treatment discontinuation.
Total patient numbers and efficacy data are immature and will be updated at the time of the meeting.
Hurvitz stressed that the clinical outcome results, including pCR and overall response rate, are not mature, as not all patients had scans or underwent surgery by the time of data cutoff. Overall, the tolerability and overall response data were encouraging and may warrant future studies on trastuzumab deruxtecan in this patient population, Hurvitz said.
“The study demonstrated that trastuzumab deruxtecan was relatively safe in HER2-low, hormone receptor-positive, localized breast cancer. It provides translational framework for future studies, including combination regimens in the neoadjuvant setting to further improve clinical outcomes,” Bardia said.
Bardia, Hurvitz and colleagues aim to follow up on this work by analyzing potential biomarkers from tumor tissue and blood samples taken before, during, and after treatment. Bardia hopes these biomarkers will help researchers more accurately assess HER2 status, predict which tumors will have the best responses to trastuzumab deruxtecan treatment, and illuminate potential mechanisms of trastuzumab deruxtecan resistance.
Limitations of this study include a small sample size characteristic of phase II studies, which did not allow for a formal comparison of the two treatment arms. Additionally, the primary and secondary endpoints of this study assessed response but did not evaluate long-term survival.
The study was conducted as an investigator-initiated study by the Translational Research In Oncology (TRIO)-US network. Funding for this study was provided by Daiichi Sankyo.
Note: a HER2 is expressed at a low level (IHC 1+ or 2+) in approximately 60-70% of HR+ breast cancer.
Trastuzumab Deruxtecan Alone or in Combination With Anastrozole for the Treatment of Early Stage HER2 Low, Hormone Receptor Positive Breast Cancer – NCT04553770
Highlights of prescribing information
Trastuzumab deruxtecan (T-DXd; Enhertu®; Daiichi Sankyo and AstraZeneca [Prescribing Information]
Anastrozole (Arimidex®; AstraZeneca)[Prescribing Information]
 Bardia A. TRIO-US B-12 TALENT: Neoadjuvant trastuzumab deruxtecan with or without anastrozole for HER2-low, HR+ early stage breast cancer. Abstract GS2-03, presented during the 2022 San Antonio Breast cancer Symposium, held December 6 – 10.
Featured image: Aditya Bardia, MD, MPH speaks during the SABCS 2022 San Antonio Breast Cancer Symposium being held at the Henry B. Gonzalez Convention Center in San Antonio, TX. Photo courtesy: © 2022 AACR/SABCS MedMeetingImages/Todd Buchanan Used with permission.