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SAN ANTONIO -- A headline-making antibody-drug conjugate (ADC) continued to impress breast cancer specialists by demonstrating activity in tumors with low HER2 expression and in some breast cancers with undetectable HER2.

As expected, trastuzumab deruxtecan (T-DXd, Enhertu) showed robust activity in HER2-overexpressing metastatic breast cancer, producing objective responses in 71% of patients. Additionally, 38% of patients with low HER2 expression responded to the ADC, as well as almost 30% of patients with no detectable HER2 expression.

The activity in HER2-undetectable tumors just missed the prespecified cutoff for clinical success, and breast cancer specialists at the San Antonio Breast Cancer Symposium (SABCS) differed as to whether the investigation of T-DXd should continue in that subgroup.

"In the HER2-not detected group, there was intriguing efficacy," said Priyanka Sharma, MD, of the University of Kansas Cancer Center in Westwood, who reviewed the SABCS poster presentation. "The key question here is, are we seeing activity when HER2 is totally absent or was it simply failure to detect low-level HER2 expression?"

"The challenge with HER2 testing, especially at lower levels, is the testing technique and reproducibility," she noted. "HER2 zero is defined as weak or incomplete staining in less than 10% of tumor cells, which does not necessarily mean complete lack of expression, as these tests were not geared to detect and report low levels of expression."

Responses in the HER2-not detected group included several patients with triple-negative breast cancer. Given the "kind of crummy responses in triple-negative disease with most treatments ... is that really an area that should be abandoned, or does it require further work?" asked Hope Rugo, MD, of the University of California San Francisco.

SABCS poster presenter Veronique Diéras, MD, of the Eugène Marquis Center in Rennes, France, pointed out that the study was part of a larger, ongoing translational research program.

"We do see responses of some duration, but we have to discuss the results considering the landscape of ADCs, and we have a very active ADC for triple-negative tumors," she said. "Do we need to target HER2 according to bystander effect (cells not directly affected by the treatment) in HER2-negative breast cancer or do we have to look to other targets. I think we are awaiting new data."

T-DXd made a huge splash at the 2021 European Society of Medical Oncology virtual meeting, when data from the DESTINY-Breast03 trial showed an "absolutely startling" doubling of 12-month progression-free survival (PFS) in previously treated metastatic HER2-positive breast cancer versus trastuzumab emtansine (Kadcyla). Some breast cancer specialists said the results warranted elevation of T-DXd to the new second-line standard for metastatic HER2 breast cancer.

Diéras and colleagues reported findings from the phase II , which evaluated single-agent T-DXd in 177 patients with previously treated metastatic breast cancer. The patients were separated into three cohorts on the basis of HER2 expression status: overexpression (n=68), low expression (n=72), and undetected expression (n=37). The study population was heavily pretreated as 80% of patients had received more than two prior lines of therapy.

The trial was preceded by a showing a 37% response rate with T-DXd in 48 patients with HER2-low breast cancer. Hormone receptor-negative tumors had a higher response rate (40% vs 28%). Additionally, the RC-48-ADC led to responses in 40% of a small cohort of patients with HER2-low breast cancer.

The DAISY results in tumors exhibiting HER2 overexpression were consistent with the DESTINY-Breast03 trial, as responses were seen in 70.6% of patients. The 38% response rate in patients with HER2-low expression also were in line with previous trials in the same HER2-expression category.

The trial had a prespecified response rate of 32.5% (13 of 40) as the cutoff for treatment success in the HER2-undetected subgroup. Eleven responses occurred in 37 evaluable patients (29.5%). Analysis by receptor status showed a response rate of 42% in patients with triple-negative disease versus 23% in patients with HR-positive tumors.

Some concern had arisen with regard to a risk of interstitial lung disease (ILD) in patients treated with T-DXd. DAISY had an ILD incidence of 2.8%, and all cases were grade 1/2. A total of 13 patients discontinued treatment because of adverse events, including the five with ILD.

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