Trastuzumab ADC active in HER2-low, HER2-undetected breast cancer

SAN ANTONIO – An antibody-drug conjugate (ADC) has continued to impress breast cancer scientists 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 metastatic breast cancer overexpressing HER2, producing objective responses in 71% of patients. Additionally, 38% of patients with low HER2 expression responded to ADC, as did nearly 30% of patients without detectable HER2 expression.

Activity in undetectable HER2 tumors narrowly missed the pre-defined threshold for clinical success, and breast cancer specialists at the San Antonio Breast Cancer Symposium (SABCS) have differed over whether the T-DXd investigation should proceed. continue in this subgroup.

“In the undetected HER2 group, there was an intriguing efficacy,” said Priyanka Sharma, MD, of the University of Kansas Cancer Center in Westwood, who reviewed the poster presentation of SABCS. “The key question here is: are we seeing activity when HER2 is completely absent or is it simply a failure to detect low level expression of HER2? “

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

Responses in the undetected HER2 group included several patients with triple negative breast cancer. Considering the “type of lousy responses in triple negative disease with most treatments … is this really an area that should be given up, or does it require additional work?” asked Hope Rugo, MD, of the University of California at San Francisco.

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

“We are seeing responses of some duration, but we need to discuss the results taking into account the ADC landscape, and we have a very active ADC for triple-negative tumors,” she said. “Do we need to target HER2 based on the bystander effect (cells not directly affected by treatment) in HER2-negative breast cancer or do we need to look to other targets. I think we’re waiting to new data. “

T-DXd caused a stir at the 2021 European Society for Medical Oncology virtual meeting, when data from the DESTINY-Breast03 trial showed an “absolutely surprising” doubling of progression-free survival (PFS) to 12 months in previously treated HER2- metastatic patients. positive breast cancer versus trastuzumab emtansine (Kadcyla). Some breast cancer specialists have said the results support raising T-DXd to the new second-line standard for HER2 metastatic breast cancer.

Dieras and his colleagues reported the results of phase II DAISY Study, which evaluated T-DXd as monotherapy in 177 patients with previously treated metastatic breast cancer. 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 because 80% of patients had received more than two previous lines of treatment.

The trial was preceded by a phase I study 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%). In addition, the Experimental ADC RC-48-ADC led to responses in 40% of a small cohort of patients with HER2-low breast cancer.

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

The trial had a predefined response rate of 32.5% (13 out of 40) as the threshold for treatment success in the undetected HER2 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 concerns had arisen about a risk of interstitial lung disease (ILD) in patients treated with T-DXd. DAISY had an incidence of LTD of 2.8% and all cases were grade 1/2. A total of 13 patients discontinued treatment due to adverse events, including all five with IRS.

  • Charles Bankhead is Editor-in-Chief for Oncology and also covers Urology, Dermatology and Ophthalmology. He joined MedPage Today in 2007. To follow


The study was supported by UNICANCER in collaboration with Daiichi Sankyo Europe.

Dieras disclosed relationships with Roche / Genentech, Novartis, Lilly, Pfizer, AstraZeneca, AbbVie, MSD, Daiichi Sankyo, Seattle, Genetics, Gilead, Eisai and Pierre Fabre Oncology.

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