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Enhertu Shows Activity in Early-Stage HER2-Low Breast Cancer Patients in Study Reported at SABCS

SAN ANTONIO – AstraZeneca and Daiichi Sankyo's Enhertu (trastuzumab deruxtecan) has for the first time shown activity in patients with hormone receptor (HR)-positive HER2-low localized breast cancer as a neoadjuvant treatment.

The data presented at the San Antonio Breast Cancer Symposium on Wednesday follow the US Food and Drug Administration's approval of Enhertu in August as a treatment for previously treated patients with unresectable or metastatic HER2-low breast cancer. The agency approved that indication after seeing a 50 percent lower risk of disease progression or death in Enhertu-treated patients compared to those on physician's choice of chemotherapy in the DESTINY-Breast04 study.

However, the efficacy of Enhertu in patients with localized early-stage HER2-low breast cancer is not known, Aditya Bardia, an oncologist at Massachusetts General Hospital, said at the meeting in presenting the data from the TRIO-US B-12 TALENT trial. There's a need for better neoadjuvant treatments for this subset of patients who typically receive anthracycline-taxane combination chemotherapy but have low pathological complete response rates and experience significant toxicities. In addition to looking at the activity of single-agent Enhertu in HR-positive HER2-low breast cancer patients, Bardia's group recognized that ER expression can increase the rate of HER2-low expression and also assessed whether adding endocrine therapy to Enhertu would improve patient outcomes.

Bardia and colleagues reported that as of the Nov. 25 data cutoff, 68 percent, or 17 out of 25 evaluable patients with HR-positive HER2-low tumors, responded to Enhertu, while 58 percent, or 14 out of 24 patients, responded to Enhertu with the endocrine therapy anastrozole. In this initial analysis, the addition of anastrozole didn't appear to enhance treatment efficacy, but Bardia cautioned that this study was small and more patients need to be evaluated before definitive conclusions are drawn.

The primary endpoint in the study is a 5 percent pathologic complete response rate, meaning that at the time of surgery patients must have complete tumor regression and no lymph node involvement following Enhertu treatment. Researchers used the residual cancer burden index to measure pathologic complete response. If patients had a residual cancer burden index score of 0, they had pathological complete response; a score of 1 meant the patient had a near pathological complete response.

As of the Nov. 24 data cutoff, one patient on single-agent Enhertu achieved full pathological complete response and two patients nearly did. In the combination Enhertu-anastrozole arm, two patients had near pathological complete responses. Bardia noted that surgical outcomes are pending for seven out of 29 patients on just Enhertu and nine out of 29 patients in the combination arm.

In terms of adverse events, around 5 percent of patients needed dose reductions because of drug-related toxicities; there were no cases of grade 3/4 pneumonitis, and no one experienced cardiomyopathy or neuropathy. One patient died from myocardial infarction due to severe gastro-intestinal toxicities that may have been related to Enhertu treatment.

"This is the first report of neoadjuvant [Enhertu] for patients with HR-positive HER2-low breast cancer and provides the groundwork for future studies with antibody-drug conjugates for patients with early-stage breast cancer," Bardia said.

Meanwhile, the approval of Enhertu in the HER2-low metastatic setting earlier this year has challenged oncologists to reconsider whether patients with HER2-low expression have distinct tumor biology, spurred labs to advance new methods of detecting low HER2 expression to more accurately identify responders to antibody-drug conjugates like Enhertu, and placed a spotlight on the need to reduce inter-laboratory and pathologist variability in calculating HER2-low status. 

These debates, as well as calls for new, more quantitative tests, took center stage at SABCS (see related story), and the TRIO-US B12 TALENT investigators also explored these issues. Patients could partake in the study, for example, if they had HER2-low expression defined as an immunohistochemistry 1+ or 2+ result by central or local testing. There was a 57 percent overall concordance between local and central HER2-low assessments. Local and centrally conducted tests agreed 52 percent of the time when reporting IHC 1+ results and 21 percent of the time when reporting IHC 2+ results.

Bardia reflected that the "modest" concordance in HER2 IHC results between central and locally performed tests highlights the need for better analytical tools for gauging HER2-low expression. There is also a need to improve analytical standardization of tissue fixation conditions, processing methods, and antibodies used, he added.

Researchers tested patients' HER2 status at baseline, during treatment, and at the time of surgical resection to track how expression levels changed in response to Enhertu treatment. In 17 out of 35 patients there was a change in HER2 IHC expression after Enhertu treatment, and among these individuals 88 percent had a decrease in HER2 expression. Although researchers observed "dynamic changes" in HER2 expression after Enhertu treatment, Bardia cautioned that the changes in IHC immunostaining is not necessarily reflecting a change in HER2 protein in the carcinoma cells.

Ultimately, Bardia concluded that data from the translational TRIO-US B-12 TALENT trial "provides a rich platform for additional research to evaluate other methods of HER2 detection, develop predictive biomarkers, and understand mechanisms of resistance in the residual disease that could guide future therapeutic strategies, including combination therapy."