Trastuzumab ADC Active in HER2-Low, HER2-Undetected Breast Cancer

SAN ANTONIO — A headline-making antibody-drug conjugate (ADC) continued to galvanize breast most cancers consultants by demonstrating exercise in tumors with low HER2 expression and in some breast cancers with undetectable HER2.

As anticipated, trastuzumab deruxtecan (T-DXd, Enhertu) showed sturdy exercise in HER2-overexpressing metastatic breast most cancers, producing goal responses in 71% of patients. Additionally, 38% of patients with low HER2 expression replied to the ADC, as successfully as nearly 30% of patients with out a detectable HER2 expression.

The exercise in HER2-undetectable tumors upright uncared for the prespecified cutoff for scientific success, and breast most cancers consultants on the San Antonio Breast Cancer Symposium (SABCS) differed as as to whether the investigation of T-DXd ought to continue in that subgroup.

“In the HER2-no longer detected community, there used to be bright efficacy,” said Priyanka Sharma, MD, of the University of Kansas Cancer Heart in Westwood, who reviewed the SABCS poster presentation. “The key inquire of here is, are we seeing exercise when HER2 is entirely absent or used to be it merely failure to detect low-level HER2 expression?”

“The grief with HER2 testing, especially at decrease stages, is the testing technique and reproducibility,” she famed. “HER2 zero is printed as dilapidated or incomplete staining in lower than 10% of tumor cells, which does no longer necessarily mean total lack of expression, as these tests weren’t geared to detect and articulate low stages of expression.”

Responses in the HER2-no longer detected community incorporated a complete lot of patients with triple-negative breast most cancers. Given the “roughly crummy responses in triple-negative illness with most treatments … is that genuinely an blueprint that needs to be abandoned, or does it require extra work?” asked Hope Rugo, MD, of the University of California San Francisco.

SABCS poster presenter Veronique Diéras, MD, of the Eugène Marquis Heart in Rennes, France, identified that the peep used to be share of a bigger, ongoing translational analysis program.

“We assemble stumble on responses of some interval, but now we must at all times talk in regards to the outcomes serious in regards to the landscape of ADCs, and now we admire a extraordinarily active ADC for triple-negative tumors,” she said. “Will now we must at all times goal HER2 in accordance with bystander invent (cells circuitously tormented by the treatment) in HER2-negative breast most cancers or assemble now we must at all times peer to assorted targets. I deem we’re attempting forward to contemporary info.”

T-DXd made an mountainous splash on the 2021 European Society of Clinical Oncology virtual meeting, when info from the DESTINY-Breast03 trial showed an “fully startling” doubling of 12-month progression-free survival (PFS) in beforehand treated metastatic HER2-obvious breast most cancers versus trastuzumab emtansine (Kadcyla). Some breast most cancers consultants said the outcomes warranted elevation of T-DXd to the contemporary second-line typical for metastatic HER2 breast most cancers.

Diéras and colleagues reported findings from the half II DAISY peep, which evaluated single-agent T-DXd in 177 patients with beforehand treated metastatic breast most cancers. The patients were separated into three cohorts on the premise of HER2 expression assert: overexpression (n=68), low expression (n=72), and undetected expression (n=37). The peep population used to be closely pretreated as 80% of patients had got more than two prior lines of treatment.

The trial used to be preceded by a half I peep exhibiting a 37% response rate with T-DXd in 48 patients with HER2-low breast most cancers. Hormone receptor-negative tumors had a larger response rate (40% vs 28%). Additionally, the investigational ADC RC-48-ADC resulted in responses in 40% of a puny cohort of patients with HER2-low breast most cancers.

The DAISY ends in tumors exhibiting HER2 overexpression were consistent with the DESTINY-Breast03 trial, as responses were considered in 70.6% of patients. The 38% response rate in patients with HER2-low expression additionally were in accordance with earlier trials in the same HER2-expression class.

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%). Evaluation by receptor assert showed a response rate of 42% in patients with triple-negative illness versus 23% in patients with HR-obvious tumors.

Some grief had arisen with regards to a threat of interstitial lung illness (ILD) in patients treated with T-DXd. DAISY had an ILD incidence of two.8%, and all cases were grade 1/2. A total of 13 patients discontinued treatment attributable to of damaging events, including the 5 with ILD.