This ongoing trial was presented at the American Society of Clinical Oncology (ASCO) Annual Meeting, which was held virtually 4-10 June, 2021 [1]. Physician’s Weekly spoke with principle investigator medical oncologist Dr. Sarah Hurvitz (UCLA Jonsson Comprehensive Cancer Center).

Sarah Hurvitz, MD, UCLA Jonsson Comprehensive Cancer Center

Sarah Hurvitz, MD, UCLA Jonsson Comprehensive Cancer Center presented Phase 2 TALENT trial (NCT04553770), run by translational research in oncology, TRIO-US and UCLA. The research team assessed a novel treatment regimen in the neoadjuvant setting, evaluating FDA approved antibody drug conjugate (ADC). trastuzumab deruxtecan, either alone or in combination with anastrozole, for patients with HER2 low expressing, but non amplified hormone receptor positive breast cancer.

Trastuzumab deruxtecan is used in the third-line setting and beyond for HER2-positive, meaning HER2 amplified or overexpressing metastatic breast cancer, and has shown remarkable efficacy with an objective response rate of over 60% and a median progression-free survival of over 19 months at the last check. These data from a phase two single arm trial led to the FDA approval of this drug in the metastatic setting with confirmatory phase 3 trials, having recently completed enrollment with data with anticipated release in 2021 or 2022.

The goal of the trial was to assess trastuzumab deruxtecan (TDXD) in the early stage setting in patients who do not have HER2 over expression or amplification, but have low expression as tested by immunohistochemistry, either 1+ or 2+ expression of HER2 protein and if 2+, confirmed to be non-amplified, following a phase 1 study recently published by Shanu Modi and colleagues, in HER2 low-expressing metastatic breast cancer demonstrated efficacy data with an objective response rate and over 35%, close to 40%, of patients [2].

“We know that about two thirds of hormone receptor positive breast cancer has low expression of HER2,” says Dr. Hurvitz, “and so our study is aimed to look at the activity of this drug in patients who have an intact breast tumor, to see if we can improve the responses or pathologic complete response rate in the neoadjuvant setting. We know that fewer than 10% of patients with hormone receptor positive, HER2 non amplified breast cancer achieve a pathological compete response (CR) in fact, it is closer to less than 5% of patients with standard chemo or standard endocrine therapy or CDK4/6 inhibitors, and so this is sort of an area of unmet need. Can we improve on the responsiveness of tumors in the neoadjuvant or pre-surgical setting?” So we designed a phase 2 open-label, randomized 2-arm trial in the neoadjuvant setting. Patients with stage one to three, operable HER2, one plus or two plus, hormone receptor positive breast cancer are eligible. Men and pre or post-menopausal women are eligible, but men and pre-menopausal women would need to use a luteinizing hormone releasing hormone (LHRH) agonist as an adjunctive therapy.

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Patients are randomized to receive the TDXD at 5.4 mg, every 21 days, either alone or in combination with an anastrozole, receiving therapy for six cycles prior to surgery. “We are doing intensive biomarker analysis, taking tumor tissue at baseline prior to therapy, after cycle one, and at the time of surgery. And we are also taking blood samples for correlative biomarker work, including circulating tumor (CT) DNA. The primary endpoint is pathological CR rate at the time of definitive surgery,” says Dr. Hurvitz. “It is a two-stage design, such that, in stage one, there will be 58 participants, randomized one-to-one. So 29 patients per arm.”

“If more than 2 patients achieve pathological CR, that arm will go on and expand in stage two to enroll an additional 15 participants for a total of 44 per arm. The studies will be deemed to be positive if either arm achieves the path CR rate of greater than 10%, meaning five out of the 44 participants.”

According to Dr. Hurvitz, positive trial results would warrant further evaluation in a larger clinical trial. “We are also looking at a bunch of exploratory end points, including changes in Ki67 expression, the residual cancer burden index and serial cell-free DNA analysis as well as health-related quality of life. As of the time of us reporting, we have nine sites open and active with locations in California, Florida, Indiana, Massachusetts, and Kansas,” she says. “We have 13 participants enrolled to date and, we anticipate that we will be completing the stage one evaluation sometime in Q3 2022. So I am very excited to see whether or not this novel therapy, actually benefits women and to test the safety, and biomarkers associated with this trial.”

 

  1. Hurvitz S et al. TRIO-US B-12 TALENT: Phase II neoadjuvant trial evaluating trastuzumab deruxtecan with or without anastrozole for HER2-low, HR+ early stage breast cancer. DOI: 10.1200/JCO.2021.39.15_suppl.TPS603 Journal of Clinical Oncology 39, no. 15_suppl
  2. Modi S et al. Antitumor Activity and Safety of Trastuzumab Deruxtecan in Patients With HER2-Low–Expressing Advanced Breast Cancer: Results From a Phase Ib Study. Journal of Clinical Oncology 2020 38:17, 1887-96.