Fam-trastuzumab deruxtecan-nxki active in early HER2-low breast cancer
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SAN ANTONIO — Fam-trastuzumab deruxtecan-nxki induced encouraging response rates among certain patients with early breast cancer, according to findings presented at San Antonio Breast Cancer Symposium.
Results of the single-arm phase 2 TRIO-US B-12 TALENT trial — which included patients with localized hormone receptor-positive, HER2-low breast cancer — showed a majority of patients responded to neoadjuvant treatment with the agent alone or in combination with anastrozole.
This is the first report of neoadjuvant fam-trastuzumab deruxtecan-nxki (Enhertu; AstraZeneca, Daiichi Sankyo) for patients with hormone receptor-positive, HER2-low localized breast cancer, according to researcher Aditya Bardia, MD, MPH, director of the breast cancer research program at Massachusetts General Hospital and associate professor of medicine at Harvard Medical School.
“The results of this trial are not practice changing,” Bardia told Healio. “The recommendation is not to use trastuzumab deruxtecan as a single agent as standard of care in this setting. Rather, these results provide the groundwork for future studies of antibody-drug conjugates for patients with early breast cancer. Now that we know what single-agent trastuzumab deruxtecan does in this setting, we can look at biomarkers to develop combination therapies and design randomized phase 2 or phase 3 trials, some of which could be practice changing.”
Background
Patients with localized, high-risk hormone receptor-positive breast cancer often receive neoadjuvant chemotherapy. However, the pathologic complete response rate is about 5% or less, Bardia said.
Standard chemotherapy — typically a combination of anthracyclines and taxanes — also can result in considerable toxicity.
“There definitely is a need for better and safer therapies,” Bardia said.
An estimated 60% to 70% of hormone receptor-positive breast cancers express HER2 at low levels, defined as immunohistochemistry scores of 1+ or 2+.
Trastuzumab deruxtecan is a novel antibody-drug conjugate with three components: a humanized anti-HER2 immunoglobulin G1 monoclonal antibody with the same amino acid sequence as trastuzumab (Herceptin, Genentech); a topoisomerase 1 inhibitor payload; and a tetrapeptide-based cleavable linker.
The agent is approved in the United States for treatment of HER2-positive or HER2-low metastatic breast cancer.
“The DESTINY-Breast04 trial showed remarkable improvement in PFS and OS with trastuzumab deruxtecan compared with chemotherapy, so it’s clearly an active agent in hormone receptor-positive, HER2-low breast cancer,” Bardia said. “But DESTINY-Breast04 was in the metastatic setting, and we wanted to evaluate this agent in early breast cancer. We felt the neoadjuvant setting would be the best place to start.”
Methodology
The phase 2 TRIO-US B-12 TALENT trial assessed the clinical activity and safety of neoadjuvant trastuzumab deruxtecan alone or in combination with anastrozole for treatment-naive patients with hormone receptor-positive, HER2-low early breast cancer measuring more than 2 cm.
In the trial’s first stage, researchers randomly assigned patients 1:1 to 5.4 mg/kg trastuzumab deruxtecan via IV every 21 days with or without 1 mg anastrozole daily. Men and premenopausal women assigned to the combination group also received a gonadotropin-releasing hormone agonist.
A 5% pathologic complete response rate — defined as complete tumor regression and no lymph node involvement at surgery — served as the primary endpoint. Other endpoints included objective response rate, safety, Ki67 expression changes and health-related quality of life.
Researchers enrolled 58 patients — 29 in each treatment group — in the trial’s first stage. The two groups appeared balanced with regard to baseline characteristics, including disease stage and baseline HER2 expression.
Five patients went off study prior to completion of their assigned therapy.
At the data cutoff date of Oct. 5, 17 patients had completed the planned eight cycles of trastuzumab deruxtecan monotherapy followed by surgery, and 16 had completed the planned six cycles of trastuzumab deruxtecan plus anastrozole followed by surgery.
Results
Pathologic complete response and overall response rate data had not matured. Seven patients were awaiting surgery and 13 continued to receive trastuzumab deruxtecan.
At first data cutoff, no patients assigned the combination regimen and one patient (5.3%) assigned trastuzumab deruxtecan monotherapy achieved pathologic complete response.
Among evaluable patients, 12 of 16 (75%) in the trastuzumab deruxtecan monotherapy group responded to therapy, including one complete response and 11 partial responses. Twelve of 19 (63.1%) patients in the combination group responded, including two complete responses and 10 partial responses. One patient in the combination group exhibited progressive disease.
“There are three broad points to note,” Bardia said. “First, neoadjuvant trastuzumab deruxtecan demonstrated preliminary evidence of clinical activity with objective responses, as well as pathologic complete response. Second, the study showed there are dynamic changes in HER2 expression after treatment with trastuzumab deruxtecan.
“Third, we need to do a lot more work in terms of HER2-based assays,” Bardia said. “There was only modest concordance between central and local labs related to HER2, so we need better analytical methods — or at least better analytical standardization of tissue collection, processing and type of antibodies used for HER2 assessment. We also need to understand mechanisms for resistance to trastuzumab deruxtecan as a single agent so we can develop combination therapies to further improve outcomes in this setting.”
Trastuzumab deruxtecan exhibited a safety profile consistent with prior reports, Bardia said.
The labeling includes a boxed warning for interstitial lung disease and embryo-fetal toxicity. In the trial’s first stage, one patient (1.7%) developed grade 2 interstitial lung disease that resolved 11 days after therapy cessation.
The most common treatment-related grade 3 or higher adverse events — each of which occurred among fewer than 6% of patients — included hypokalemia, diarrhea, neutropenia, fatigue, headache, vomiting, dehydration and nausea.
Next steps
Researchers acknowledged study limitations, including a small sample size that did not allow for a formal comparison of the two treatment groups. In addition, trial endpoints did not assess long-term survival.
The overall efficacy and safety data appear encouraging and warrant additional studies of trastuzumab deruxtecan for this patient population, researchers concluded.
Investigators intend to perform biomarker analyses on blood and tumor tissue obtained before, during and after treatment.
“There are three broad objectives to these analyses,” Bardia told Healio. “The first is more robust assays related to HER2 expression. The second is identifying biomarkers to predict response to single-agent trastuzumab deruxtecan. The third would be understanding potential mechanisms of resistance so we can develop combination therapies that may further improve outcomes.”
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Hurvitz SA, et al. Abstract GS2-03. Presented at: San Antonio Breast Cancer Symposium; Dec. 6-10, 2022; San Antonio.
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